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cancercontroljournal.org Vol. 23, No. 4, October 2016 H. LEE MOFFITT CANCER CENTER & RESEARCH INSTITUTE, AN NCI COMPREHENSIVE CANCER CENTER Barriers to Clinical Trial Enrollment in Racial and Ethnic Minority Patients With Cancer Racial and Ethnic Differences in the Epidemiology and Genomics of Lung Cancer Black Heterogeneity in Cancer Mortality: US-Blacks, Haitians, and Jamaicans Genomic Disparities in Breast Cancer Among Latinas Clinical Considerations of Risk, Incidence, and Outcomes of Breast Cancer in Sexual Minorities Construction and Validation of a Multi-Institutional Tissue Microarray of Invasive Ductal Carcinoma From Racially and Ethnically Diverse Populations Determinants of Treatment Delays Among Underserved Hispanics With Lung and Head and Neck Cancers Geographical Factors Associated With Health Disparities in Prostate Cancer Disparities in Penile Cancer Chemoprevention in African American Men With Prostate Cancer Disparities in Adolescents and Young Adults With Cancer Tobacco-Related Health Disparities Across the Cancer Care Continuum Cancer Control is included in Index Medicus/MEDLINE Editorial Board Members Editor: Lodovico Balducci, MD Senior Member Program Leader, Senior Adult Oncology Program Moffitt Cancer Center Deputy Editor: Julio M. Pow-Sang, MD Senior Member Chair, Department of Genitourinary Oncology Director of Moffitt Robotics Program Moffitt Cancer Center Editor Emeritus: Conor C. Lynch, PhD Assistant Member Tumor Biology Production Team: Kristen J. Otto, MD Associate Member Head and Neck and Endocrine Oncology Sherri Damlo Medical Copy Editor Michael A. Poch, MD Assistant Member Genitourinary Oncology Jeffery S. Russell, MD, PhD Assistant Member Endocrine Tumor Oncology John Horton, MB, ChB Professor Emeritus of Medicine & Oncology Elizabeth M. Sagatys, MD Assistant Member Pathology - Clinical Moffitt Cancer Center Journal Advisory Committee: Saïd M. Sebti, PhD Senior Member Drug Discovery Daniel A. Anaya, MD Associate Member Gastrointestinal Oncology Bijal D. Shah, MD Assistant Member Malignant Hematology Aliyah Baluch, MD Assistant Member Infectious Diseases Lubomir Sokol, MD, PhD Senior Member Hematology/Oncology Dung-Tsa Chen, PhD Associate Member Biostatistics Hey Sook Chon, MD Assistant Member Gynecological Oncology Jasreman Dhillon, MD Assistant Member Pathology - Anatomic Jennifer S. Drukteinis, MD Associate Member Diagnostic Radiology Clement K. Gwede, PhD, RN Associate Member Health Outcomes and Behavior Sarah E. Hoffe, MD Associate Member Radiation Oncology John V. Kiluk, MD Associate Member Breast Oncology Richard D. Kim, MD Associate Member Gastrointestinal Oncology Bela Kis, MD, PhD Assistant Member Diagnostic Radiology Rami Komrokji, MD Associate Member Malignant Hematology Hatem H. Soliman, MD Assistant Member Breast Oncology Jonathan R. Strosberg, MD Assistant Member Gastrointestinal Oncology Veronica Nemeth Editorial Coordinator Diane McEnaney Graphic Design Consultant Associate Editor of Educational Projects John M. York, PharmD Akita Biomedical Consulting 1111 Bailey Drive Paso Robles, CA 93446 Phone: 805-238-2485 Fax: 949-203-6115 E-mail: [email protected] For Consumer and General Advertising Information: Veronica Nemeth Editorial Coordinator Cancer Control: Journal of the Moffitt Cancer Center 12902 Magnolia Drive – MBC-JRNL Tampa, FL 33612 Phone: 813-745-1348 Fax: 813-449-8680 E-mail: [email protected] Jennifer Swank, PharmD Clinical Pharmacist Medical Oncology/Internal Medicine Sarah W. Thirlwell, MSc, MSc(A), RN Nurse Director Supportive Care Medicine Program Eric M. Toloza, MD, PhD Assistant Member Thoracic Oncology Nam D. Tran, MD Assistant Member Neuro-Oncology Jonathan S. Zager, MD Senior Member Cutaneous Oncology Cancer Control is a member of the Medscape Publishers’ Circle®, an alliance of leading medical publishers whose content is featured on Medscape (www.medscape.com). Most issues and supplements of Cancer Control are available at cancercontroljournal.org Cancer Control: Journal of the Moffitt Cancer Center (ISSN 1073-2748) is published by H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL 33612. Telephone: 813-745-1348. Fax: 813-449-8680. E-mail: [email protected]. Internet address: cancercontroljournal.org. Cancer Control is included in Index Medicus ®/MEDLINE® and EMBASE®/ Excerpta Medica, Thomson Reuters Science Citation Index Expanded (SciSearch®) and Journal Citation Reports/Science Edition. Copyright 2016 by H. Lee Moffitt Cancer Center & Research Institute. All rights reserved. Cancer Control: Journal of the Moffitt Cancer Center is a peer-reviewed journal that is published to enhance the knowledge needed by professionals in oncology to help them minimize the impact of human malignancy. Each issue emphasizes a specific theme relating to the detection or management of cancer. The objectives of Cancer Control are to define the current state of cancer care, to integrate recently generated information with historical practice patterns, and to enlighten readers through critical reviews, commentaries, and analyses of recent research studies. Disclaimer: All articles published in this journal, including editorials and letters, represent the opinions of the author(s) and do not necessarily reflect the opinions of the editorial board, the H. Lee Moffitt Cancer Center & Research Institute, Inc, or the institutions with which the authors are affiliated unless clearly specified. The reader is advised to independently verify the effectiveness of all methods of treatment and the accuracy of all drug names, dosages, and schedules. Dosages and methods of administration of pharmaceutical products may not be those listed in the package insert and solely reflect the experience of the author(s) and/or clinical investigator(s). Table of Contents Letter From the Editor Better Cancer Treatment for All 322 Lodovico Balducci, MD Editorial Highlighting Health Disparities in Racial and Ethnic Minorities and Other Underserved Populations 323 Clement K. Gwede, PhD, RN, Gwendolyn P. Quinn, PhD, and B. Lee Green, PhD Articles Barriers to Clinical Trial Enrollment in Racial and Ethnic Minority Patients With Cancer 327 Lauren M. Hamel, PhD, Louis A. Penner, PhD, Terrance L. Albrecht, PhD, Elisabeth Heath, MD, Clement K. Gwede, PhD, RN, and Susan Eggly, PhD Racial and Ethnic Differences in the Epidemiology and Genomics of Lung Cancer 338 Matthew B. Schabath, PhD, W. Douglas Cress, PhD, and Teresita Muñoz-Antonia, PhD Black Heterogeneity in Cancer Mortality: US-Blacks, Haitians, and Jamaicans 347 Paulo S. Pinheiro, MD, PhD, Karen E. Callahan, MPH, Camille Ragin, PhD, MPH, Robert W. Hage, MD, PhD, DLO, MBA, Tara Hylton, MPH, and Erin N. Kobetz, PhD, MPH Genomic Disparities in Breast Cancer Among Latinas 359 Clinical Considerations of Risk, Incidence, and Outcomes of Breast Cancer in Sexual Minorities 373 Filipa Lynce, MD, Kristi D. Graves, PhD, Lina Jandorf, MA, Charité Ricker, MS, Eida Castro, PsyD, Laura Moreno, Bianca Augusto, Laura Fejerman, PhD, and Susan T. Vadaparampil, PhD Anne E. Mattingly, MD, John V. Kiluk, MD, and M. Catherine Lee, MD Construction and Validation of a Multi-Institutional Tissue Microarray of Invasive Ductal Carcinoma From Racially and Ethnically Diverse Populations 383 Edward Seijo, MS, Diana Lima, MPH, Egiebade Iriabho, MS, Jonas Almeida, PhD, Jesus Monico, MPH, MS, Margarita Echeverri, PhD, Sylvia Gutierrez, MD, Idhaliz Flores, PhD, Ji-Hyun Lee, PhD, Kate Fisher, MA, William E. Grizzle, MD, PhD, Gabriel L. Sica, MD, PhD, Charles Butler, Chindo Hicks, PhD, Cathy D. Meade, PhD, RN, Stephen Olufemi Sodeke, PhD, Krzysztof Moroz, MD, Domenico Coppola, MD, and Teresita Muñoz-Antonia, PhD October 2016, Vol. 23, No. 4 Cancer Control 319 Table of Contents Articles, continued Determinants of Treatment Delays Among Underserved Hispanics With Lung and Head and Neck Cancers 390 Evelinn A. Borrayo, PhD, Katie L. Scott, PhD, Ava R. Drennen, PhD, Tiare MacDonald, PhD, and Jennifer Nguyen, MS Geographical Factors Associated With Health Disparities in Prostate Cancer 401 Scott M. Gilbert, MD, Julio M. Pow-Sang, MD, and Hong Xiao, PhD Disparities in Penile Cancer 409 Pranav Sharma, MD, Kamran Zargar-Shoshtari, MD, Curtis A. Pettaway, MD, Matthew B. Schabath, PhD, Anna R. Giuliano, PhD, and Philippe E. Spiess, MD Chemoprevention in African American Men With Prostate Cancer 415 Nagi B. Kumar, PhD, RD, Julio M. Pow-Sang, MD, Philippe E. Spiess, MD, Jong Y. Park, PhD, Ganna Chornokur, PhD, Andrew R. Leone, MD, and Catherine M. Phelan, PhD, MD Disparities in Adolescents and Young Adults With Cancer 424 Leidy L. Isenalumhe, MD, Olivia Fridgen, MPH, Lynda K. Beaupin, MD, Gwendolyn P. Quinn, PhD, and Damon R. Reed, MD Tobacco-Related Health Disparities Across the Cancer Care Continuum 434 Vani Nath Simmons, PhD, Bárbara Piñeiro, PhD, Monica Webb Hooper, PhD, Jhanelle E. Gray, MD, and Thomas H. Brandon, PhD Departments Case Series: Human Metapneumovirus Infection in Immunocompromised Patients 442 Sharmeen Samuel, MD, Sowmya Nanjappa, MBBS, MD, Christopher D. Cooper, MD, and John N. Greene, MD Special Report: Systematic Review and Case Series Report of Acinar Cell Carcinoma of the Pancreas 446 Special Report: A Single-Institution Study of Demographics and Outcomes of Adult Patients With Multiple Cancers 455 Evan S. Glazer, MD, PhD, Kevin G. Neill, MD, Jessica M. Frakes, MD, Domenico Coppola, MD, Pamela J. Hodul, MD, Sara E. Hoffe, MD, Jose M. Pimiento, MD, Gregory M. Springett, MD, PhD, and Mokenge P. Malafa, MD, PhD Thanh P. Ho, MD, Nathan R. Foster, MS, and Aminah Jatoi, MD 320 Cancer Control October 2016, Vol. 23, No. 4 Table of Contents Departments, continued Ten Best Readings Related to Health Disparities in Oncology 461 Peer Reviewers, 2016 463 Index for 2016, Volume 23 465 About the art in this issue: Bryan Whitney is a photographer based in New York City. His experimental, architectural, and fine art work have been featured in many magazines, books, and has been exhibited in the United States and Europe. He has been the recipient of a Fulbright lecture grant and currently teaches at the International Center for Photography. To view more of Bryan’s work or to contact him, please visit www.x-rayphotography.com or www.bryanwhitney.com. Cover: Calla Lillies Articles: Cherry Blossoms Fiddle Head Cactus Chrysanthemum Stag Horn Proteus Lily Orchid Birds Nest Rose Yellow Tulips Iris October 2016, Vol. 23, No. 4 Cancer Control 321 Letter From the Editor Better Cancer Treatment for All The best scientific and technological advances may reduce cancer-related mortality only when they are fully available to the people at risk. Availability is a multifaceted construct that includes economical and social resources, education, and cultural adherence. This issue of Cancer Control could not be timelier because it addresses the obstacles that prevents access by different minority groups to cancer diagnoses and treatments. The articles in this issue propose practical solutions to this mounting problem. Minority groups include African Americans, Hispanics, Asian Americans, new immigrants, and gay, lesbians, and transgender persons, among others. When taken together, these select minority groups represent a sizable portion of the US population as well as many Americans living with cancer. Given our globalization and the reduced birth rate among white Americans, these minority groups may embody a majority of patients with cancer in the future. These minority groups deserve to become a main focus of cancer control in our country, because the rate of cancer-related mortality is highest among them.1 In the accompanying editorial, our guest editors describe the burden of cancer affecting selected minorities and found that it is largely due to remediable causes, including poor access to screening and early detection, lifestyle choices, cultural beliefs, and limited socioeconomic resources. In addition, they outline some biological issues that have been largely ignored until recently and instead deserve immediate attention, such as the development of deadly types of breast cancer in young African American women. Cancer control in minorities is an ethical and social imperative. In addition to improving the welfare of the general population, it will likely reduce the cost of medical care and provide a trait d’union among the different ethnic/racial, religious, and gender-identity groups that represent the demographical richness of our country. It is not far fetched to assume that the common fight against the suffering related to cancer may cement the alliance of these different groups and provide a sense of common national identity. Older patients with cancer represent another group with increased rates of morbidity and mortality due in part to the inadequate care they receive.2 This group has been the subject of multiple studies and the focus of medical societies,3 but they have not been included in the present review — appropriately in my opinion. My personal experience with the Middle Eastern Cancer Control group, which was led by a visionary Israeli surgeon and included representatives of 32 countries in the Middle East, taught me that the common goal to relieve pain and discomfort caused by cancer may bring peace and cooperation, even in the most war-torn regions of the world.4,5 The cooperation of different cultures, even those from the poorest countries, is a 2-way street. I learned how important spirituality can be in the delivery of palliative care, even when the technology is primitive and the resources are scarce. I wish we could look to our minority patients as an opportunity to learn to provide better cancer treatment to all patients. Lodovico Balducci, MD Senior Member, Senior Adult Oncology Program Editor, Cancer Control H. Lee Moffitt Cancer Center & Research Institute Tampa, Florida [email protected] References 1. Tehranifar P, Goyal A, Phelan JC, et al. Age at cancer diagnosis, amenability to medical interventions, and racial/ethnic disparities in cancer mortality. Cancer Causes Control. 2016;27(4):553-560. 2. Balducci L. Studying cancer treatment in the elderly patient population. Cancer Control. 2014;21(3):215-20. 3. Wildiers H, Heeren P, Puts M, et al. International Society of Geriatric Oncology consensus on geriatric assessment in older patients with cancer. J Clin Oncol. 2014;32(24):2595-2603. 4. Silbermann M, Dweib Khleif A, Balducci L. Healing by cancer. J Clin Oncol. 2010;28(8):1436-1467. 5. Silbermann M, Epner DE, Charalambous, A et al. Promoting new approaches for cancer care in the Middle East. Ann Oncol. 2013;24(suppl 7):vii5-vii10. 322 Cancer Control October 2016, Vol. 23, No. 4 Editorial Highlighting Health Disparities in Racial and Ethnic Minorities and Other Underserved Populations More than 50 years ago, Martin Luther King Jr said, “Of all the forms of inequality, injustice in health care is the most shocking and inhumane.”1 Yet more than 30 years after the report from Heckler2 in 1985 on the national state of minority health in the United States, inequities in cancer care have persisted, widened, and, in some cases, emerged in new areas.3-7 Disparities in health status refer to the variation in rates of disease occurrence and disabilities between populations defined by demographical, socioeconomical, or geographical factors, most of which exist in populations referred to as minorities and underserved groups.3-5 These groups may be classified by race (eg, black, Asian), ethnicity (eg, Hispanic, Ashkenazi Jewish), sexual orientation (eg, gay, lesbian), gender (eg, transgender, gender queer), socioeconomic status (eg, low income, poor, underserved), or age (eg, seniors, adolescents and young adults [AYAs]).3-7 Evidence suggests that health disparities in the United States result from a combination of poverty, limited access to quality care, perceived racism/discrimination, genetics, biology, and environmental exposure.8,9 A common thread in health disparities specific to cancer is their multidimensionality and complex nature: covering the lifespan, across the continuum of cancer care from prevention to survivorship, and transcending socioecological and transcultural contexts.5,8,9 A growing body of literature suggests that cancer-related disparities are fueled by a multifaceted and concurrent interplay of factors that range from biology and genetics to lifestyle and behavior.5,8-10 As such, intersectionality, a theoretical focus on the interlocking factors of cultural influence and the multiple identities perceived by patients (eg, a racial/ethnic minority who also identifies as a sexual minority), helps explain how these complex realities exacerbate disparities.11 It is important to consider reducing health disparities in terms of modifiable factors. That is, race and ethnicity do not change, but certain contextual and behavioral aspects, including cancer risk, screening behavior, and cancer care needs, can be identified and addressed. The core of critical interventions requires appropriate attention to the cultural and health literacy levels of individuals and groups.12-14 Furthermore, as a community of clinicians, researchers, and educators, we can change the way cancer control and prevention services are delivered by reducing the perOctober 2016, Vol. 23, No. 4 ceived racism/discrimination and associated stress in minority and underserved populations. Psychological stress caused by perceived discrimination and stereotyping, poverty, and differential access to care can produce higher rates of depression and other morbidities that in turn impact quality of life and health outcomes.13,14 Articles in this issue of Cancer Control examine multiple aspects of health disparities in a variety of racial/ethnic minorities and other underserved patient populations. This issue is a collection of articles that broadly address health disparities in cancer care from 2 perspectives: going beyond race and ethnicity (addressing subethnicity and emerging disparate populations, eg, AYAs, gender and sexual minorities) and addressing multiple points across the continuum of cancer control and contextual factors (eg, geography). These articles explore pathways and mechanisms propelling cancer-related disparities, and they offer summary evidence to address such disparities. A narrative review of the literature by Dr Hamel and colleagues examines participation in clinical trials and takes a close look at the barriers to enrollment in clinical trials, with an emphasis on the under-representation of racial and ethnic minorities in research studies. The authors identify barriers across 3 levels — system, individual, and interpersonal — and conclude that many of the interventions utilized to address minority accrual to clinical trials have focused on a single level. They suggest that successful interventions must be multilevel. Dr Schabath and fellow researchers review the literature to summarize the rates of incidence, mortality, and survival among racial and ethnic minorities with lung cancer. Identifying racial and ethnic differences in lung cancer will aid in the creation of effective prevention and treatment strategies that in turn may reduce the overall burden of lung cancer. Dr Pinheiro and others examine a unique aspect of disparities research by focusing on the subethnic groups within blacks. The authors examined the mortality rates among blacks in the United States (eg, blacks, Haitians, Jamaicans) and compared them with their country of origin. Their research suggests that US-born blacks have the highest risk of cancer-related mortality when compared with blacks from other countries. Dr Lynce and colleagues summarize what is Cancer Control 323 known about Latinas and breast cancer, noting the exyond racial disparities to include younger age, lower istence of genetic mutations of high and moderate peneducational and income levels, marital status, lack of etrance within this ethnic population. They conclude circumcision, and a number of sexual behaviors as that reduced awareness and uptake of genetic counselfactors that compound disparities in this disease. This ing were observed within this group and that tailored article reminds readers to broaden their view of disinterventions are needed. parities beyond race and ethnicity. Dr Mattingly and fellow researchers summarize Dr Kumar and colleagues tackle a topic fraught the literature on sexual minority women with breast with clinical and scientific uncertainties: screencancer, concluding that limited research exists on this ing, early detection, and prevention of prostate canpopulation primarily due to lack of collection of sexual cer among high-risk African American men. Their orientation information in databases. work examines biological etiology, biomarkers, and Mr Seijo and coauthors address the lack of banked pathways, specifically underscoring the need for chetissue among racial and ethnic minorities. Their team moprevention agents and strategies. This synthesis reports on an established infrastructure for a biobankidentifies unique potential pathways that drive excess ing hub in the southeastern United States and Puerto risk and burden of disease and the potential of green Rico to create a web-based database and tissue microtea catechins as a chemoprevention agent in African arrays for breast cancer. American men diagnosed with high-grade prostatic inDr Borrayo and colleagues examine the determitraepithelial neoplasia. nants of treatment delays among underserved HisDr Isenalumhe and fellow researchers examine panics with lung and head and neck cancers. They the literature on AYAs with cancer for whom survival report that women experience longer delays than rates have not improved as they have in younger and men. Other observed factors associated with longer older patients. Disparities in this population range delays include fewer comorbidities, receiving treatfrom the unique biology of the cancer itself to delays ment at a public facility, and being underserved (eg, in diagnoses further exacerbated by the psychosouninsured). This article identifies actionable factors cial needs of this population (eg, reproductive presamenable to intervention to improve outcomes in diservation). Their article focuses on identifying these advantaged Hispanic patients. unique needs and the research advancements made Dr Gilbert and others take an innovative apto improve outcomes and quality of life in AYAs. proach to addressing racial and ethnic disparities in Dr Simmons and coauthors attend to racial/ethnic prostate cancer treatment and outcomes by going and socioeconomic disparities in tobacco use, one of beyond the traditional factors of race and socioecothe leading preventable causes of lung cancer–related nomic factors. Their focus is on the geographic disdeath. Their contribution focuses attention on importribution of disparities (ie, how a place of residence tant disparities that can occur across the cancer coninteracts with race and socioeconomic factors). Using tinuum — from prevention to survivorship. They synthe Geographic Information System, they illustrate thesize the research that has reduced tobacco-related an example showing locations in the state of Florida where disparities in prostate cancer Race and ethnicity are terms often interchangeably used, although are the most problematic. The they describe 2 different but complex concepts. They are often comauthors identify geographical ingled in describing populations in health care and health disparities differences in treatment across research. In addition, the criticism is growing about the shortcomings racial and socioeconomic straof using these classifications in health research. ta, thus availing a better tool for Race is a social classification (not a biological category) that depublic health officials, health scribes a person’s observable physical characteristics and identity systems, health care profesbased on phenotypic genetic characteristics such as anatomical or sionals, and policymakers to bone structure and skin, hair, or eye color. use when addressing health Ethnicity describes the shared identity of a population based on disparities. sociocultural factors, linguistic or religious traits, or national heriDr Sharma and coauthors tage, regardless of race that often shape that group’s world-view, lifeaddress a less-common cancer style, and behaviors. and rare disparity in developed Individuals can be of “mixed race or more than 1 race” and can nations, penile cancer, in which have more than 1 ethnicity. Advances in genomic and precision racial differences exist in both medicine are helping to elucidate the genetic and biological basis of rates of disease incidence and health disparities. associated survival outcomes. Their chief findings extend be324 Cancer Control October 2016, Vol. 23, No. 4 disparities, pointing to the limited successes of both pharmacotherapy and behavioral counseling for racial and ethnic minorities, concluding with a critical call for innovative efforts directed at each point along that continuum. These authors remind us of the critical role of culture and socioeconomic status in addition to racial and ethnic status. The Centers for Disease Control and Prevention suggests the key to reducing cancer-related inequities is to increase screening and early detection, promote healthy behaviors, and expand access to health care for underserved populations and groups at greatest risk.3 The articles in this issue of Cancer Control help us identify the ever-expanding definition of what it means to be “at risk” as well as how minority and underserved populations are disproportionately affected by an excess burden of cancer. These articles also point us in the direction of key areas for expanding cancer care and new research to help us identify and reduce cancer-related inequities. This issue highlights promising strategies for reducing the cancer-related burden and improving the quality of life of all patients. A heightened understanding of both differences and similarities across age, sex, gender, race, ethnicity, socioeconomic class, and sexual orientation is essential to the delivery of equitable cancer care. It is incumbent upon us to focus on ways to reduce the cancer burden and disparities in rates of cancer incidence, morbidity, and mortality so that no one is left behind. 4. National Institutes of Health; National Cancer Institute. About cancer health disparities. https://www.cancer.gov/about-nci/organization/crchd/ about-health-disparities. Accessed October 3, 2016. 5. Alcaraz K, Sly J, Ashing K, et al. The ConNECT Framework: a model for advancing behavioral medicine science and practice to foster health equity. J Behav Med. 2016. Epub ahead of print. 6. Quinn GP, Sanchez JA, Sutton SK et al. Cancer and lesbian, gay, bisexual, transgender/transsexual, and queer/questioning (LGBTQ) populations. CA Cancer J Clin. 2015;65(5):384-400. 7. Committee on Lesbian, Gay, Bisexual, and Transgender Health Issues and Research Gaps and Opportunities; Board on the Health of Select Populations; Institute of Medicine. The Health of Lesbian, Gay, Bisexual, and Transgender People: Building a Foundation for Better Understanding. Washington, DC: National Academies Press; 2011. 8. Freeman HP. Poverty, culture, and social injustice: determinants of cancer disparities. CA Cancer J Clin. 2004;54(2):72-77. 9. Freeman HP, Chu KC. Determinants of cancer disparities: barriers to cancer screening, diagnosis, and treatment. Surg Oncol Clin N Am. 2005;14(4):655-669. 10. Dressler WW, Oths KS, Gravlee CC. Race and ethnicity in public health research: models to explain health disparities. Ann Rev Anthropol. 2005;34:231-252. 11. Hsieh N, Ruther M. Sexual minority health and health risk factors: Intersection effects of gender, race, and sexual identity. Am J Prev Med. 2016;50(6):746-755. 12. Kagawa-Singer M, Dressler WW, George SM, et al. The Cultural Framework for Health: An Integrative Approach for Research and Program Design and Evaluation. Bethesda, MD; National Institutes of Health; 2016. 13. Smedley BD, Stith AY, Nelson AR, eds; Committee on Understanding and Eliminating Racial and Ethnic Disparities in Health Care. Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care. Washington, DC: National Academies Press; 2003. 14. LaVeist TA, Isaac LA, eds. Race, Ethnicity, and Health: A Public Health Reader. 2nd ed. San Francisco, CA: Josey-Bass; 2012. Clement K. Gwede, PhD, RN Associate Member, Health Outcomes and Behavior Program H. Lee Moffitt Cancer Center & Research Institute Tampa, Florida [email protected] Gwendolyn P. Quinn, PhD Senior Member, Health Outcomes and Behavior Program H. Lee Moffitt Cancer Center & Research Institute Tampa, Florida [email protected] B. Lee Green, PhD Vice President, Diversity, Public Relations and Strategic Communications Senior Member, Health Outcomes and Behavior Program H. Lee Moffitt Cancer Center & Research Institute [email protected] References 1. King ML Jr. Presentation at: Second National Convention of the Medical Committee for Human Rights; Chicago, IL; March 25, 1966. 2. Heckler MM. Report of the Secretary’s Task Force on Black and Minority Health. Washington, DC: US Department of Health and Human Services; US Government Printing Office; 1985. 3. Centers for Disease Control and Prevention. Health disparities in cancer. http://www.cdc.gov/cancer/dcpc/resources/features/cancerhealthdisparities. Accessed September 26, 2016. October 2016, Vol. 23, No. 4 Cancer Control 325 Health Outcomes and Behavior Program H. Lee Moffitt Cancer Center & Research Institute The Health Outcomes and Behavior Program contributes to the prevention, detection, and control of cancer through the study of health-related behaviors, health care practices, and health-related quality of life. Work toward this goal involves research across the disease spectrum, from prevention and detection through survivorship or advanced disease. The program’s 4 specific aims are to: (1) understand the determinants of health behaviors that can lead to the prevention and early detection of cancer and develop effective methods of promoting those behaviors, (2) understand and improve the quality of life of patients and family members throughout the disease course, (3) contribute to the evidence base and synthesis of evidence regarding the delivery of cancer care and clinical outcomes, and (4) understand and intervene upon the social, cultural, and behavioral determinants of cancer-related health disparities. Awareness is growing of the disparities that occur across the cancer continuum, including prevention, incidence, diagnosis, treatment, and outcomes. These disparities occur with respect to sex, gender identity, race, ethnicity, socioeconomic status, and other patient characteristics. To understand and address these disparities, program members conduct community-based participatory research throughout the catchment area. Program members have translated their earlier observational research into numerous ongoing, randomized controlled trials of interventions designed to reduce a range of cancer-related health disparities. DEPARTMENT CHAIR/ PROGRAM LEADER Thomas H. Brandon, PhD VICE DEPARTMENT CHAIR Susan Thomas Vadaparampil, PhD Faculty Daniel A. Anaya, MD Lodovico Balducci, MD Alicia Best, PhD Margaret Booth-Jones, PhD Ellen M. Daley, PhD Benjamin Djulbegovic, MD, PhD Kristine A. Donovan, PhD David J. Drobes, PhD David Evans, PhD Martine Extermann, MD, PhD Michael Fradley, MD Scott M. Gilbert, MD B. Lee Green, PhD Clement K. Gwede, PhD, RN Ming Ji, PhD Heather S. Jim, PhD Julio C. Jiminez Chavez, MD Peter A.S. Johnstone, MD Cecile A. Lengacher, RN, PhD Dinorah Martinez Tyson, PhD Susan C. McMillan, PhD, RN Cathy D. Meade, PhD, RN Teresita Muñoz-Antonia, PhD Michael A. Poch, MD Gwendolyn P. Quinn, PhD Maija Reblin, PhD Carmen S. Rodriguez, PhD, ARNP-BC Richard G. Roetzheim, MD Lori A. Roscoe, PhD Julian Sanchez, MD Vani Nath Simmons, PhD Brent J. Small, PhD Marilyn Stern, PhD Steve K. Sutton, PhD Tawee Tanvetyanon, MD Lora M.A. Thompson, PhD Christine Vinci, PhD Hsiao-Lan Wang, PhD For more detailed information about the Health Outcomes and Behavior Program, please visit www.moffitt.org/research-science/research-programs/health-outcomes-and-behavior www.moffitt.org 326 Cancer Control October 2016, Vol. 23, No. 4 Barriers to racial and ethnic minorities enrolling in clinical trials exist at system, individual, and interpersonal levels. Cherry Blossoms. X-Ray image courtesy of Bryan Whitney. www.x-rayphotography.com. Barriers to Clinical Trial Enrollment in Racial and Ethnic Minority Patients With Cancer Lauren M. Hamel, PhD, Louis A. Penner, PhD, Terrance L. Albrecht, PhD, Elisabeth Heath, MD, Clement K. Gwede, PhD, RN, and Susan Eggly, PhD Background: Clinical trials that study cancer are essential for testing the safety and effectiveness of promising treatments, but most people with cancer never enroll in a clinical trial — a challenge exemplified in racial and ethnic minorities. Underenrollment of racial and ethnic minorities reduces the generalizability of research findings and represents a disparity in access to high-quality health care. Methods: Using a multilevel model as a framework, potential barriers to trial enrollment of racial and ethnic minorities were identified at system, individual, and interpersonal levels. Exactly how each level directly or indirectly contributes to doctor–patient communication was also reviewed. Selected examples of implemented interventions are included to help address these barriers. We then propose our own evidence-based intervention addressing barriers at the individual and interpersonal levels. Results: Barriers to enrolling a diverse population of patients in clinical trials are complex and multilevel. Interventions focused at each level have been relatively successful, but multilevel interventions have the greatest potential for success. Conclusion: To increase the enrollment of racial and ethnic minorities in clinical trials, future interventions should address barriers at multiple levels. Introduction Clinical trials focused on cancer research are essential for testing the safety and effectiveness of potential From the Department of Oncology (LMH, LAP, TLA, EH, SE) and Population Studies Disparities Research Program (LMH, LAP, TLA, SE), Wayne State University, Karmanos Cancer Institute, Detroit, Michigan, and the Department of Oncologic Sciences/Population Sciences (CKG), H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida. Submitted January 26, 2016; accepted May 3, 2016. Address correspondence to Lauren M. Hamel, PhD, Wayne State University, Karmanos Cancer Institute, Department of Oncology, Population Studies Disparities Research Program, 4100 John R Street, MM03CB, Detroit, MI 48201. E-mail: [email protected] This work was funded in part by National Institutes of Health/ National Cancer Institute grant no. R01CA200718-01. No significant relationships exist between the authors and the companies/organizations whose products or services may be referenced in this article. October 2016, Vol. 23, No. 4 treatments and translating new knowledge into tangible benefits for patients; they also represent options for novel therapy for cancer.1,2 However, approximately 2% to 3% of all patients with cancer ever enroll in a trial.3,4 Estimates of the number of trials that fail to meet scientific objectives because of insufficient accrual rates range from 22% to 50%.5,6 Low accrual rates jeopardize the ability of researchers to assess the safety and effectiveness of new approaches to cancer care, wastes resources, precludes follow-up studies, and reduces the ability of our clinical research system to translate research into evidence-based practice.6-8 Underenrollment is an even greater challenge among racial and ethnic minorities — particularly African Americans — despite a requirement by the National Institutes of Health that members of minority Cancer Control 327 populations be represented in clinical research.1,3,4,9-11 A systematic review compared the proportion of underrepresented minority participants in phase 3 cancer treatment and prevention clinical trials conducted between the periods 1990 to 2000 and 2001 to 2010.12 In the treatment studies conducted between 2001 and 2010 that reported race/ethnicity, the reviewers found that 82.9% of participants were white, 6.2% were African American, 3.3% were Asian, 2.2% were Hispanic, and 0.1% were Native American.12 This is in contrast to studies conducted between 1990 and 2000, in which 89% of participants were white, 10.5% were African American, 0.4% were Hispanic, and 0.04% were Asian.12 In other words, even though the proportion of white participants decreased, whites continued to comprise a large majority of participants in cancer treatment trials, and the proportion of African American participants decreased between the periods 1990 to 2000 and 2001 to 2010. However, during those same periods, the proportion of African American participants in clinical prevention trials increased (5.5% from 1990–2000, 11.6% from 2001–2010).12 Although several patient populations are underrepresented in clinical trials, including elderly patients (≥ 65 years), residents of rural areas, and those with low socioeconomic status, the current review focuses on racial and ethnic minority underenrollment for several reasons.4,10,13-16 Racial and ethnic minorities — particu- larly African Americans — bear the greatest cancer burden in the United States, so they should be adequately represented in cancer research.17-19 Under-representation of racial and ethnic minorities also limits the generalizability of research findings.20-22 The Institute of Medicine has recommended that every individual with cancer have access to high-quality clinical trials, so we believe that under-representation of racial and ethnic minorities represents a disparity in health care.2 Underenrollment of racial and ethnic minorities in clinical trials may therefore contribute to preventable disparities in treatment outcomes and survival.1,17,23,24 Purpose The purpose of this paper is to identify and describe potential barriers to the enrollment of racial and ethnic minorities in clinical trials at the system, individual (health care professional, patient, and family), and interpersonal levels (eg, doctor–patient relationship). The paper also describes selected examples of evidence-based interventions already implemented to address some of these barriers at the patient-, physician-, and doctor–patient interpersonal communication levels. We take this approach because multilevel interventions, as compared with single-level interventions, may have the greatest potential to achieve substantial and sustained change and to produce additive — and possibly multiplicative — effects.25,26 System Level Availability of clinical trials Supporting infrastructure Cost/payer Strict eligibility criteria Lack of community engagement Individual Level Health Care Professional • Awareness of clinical trials • Perception of the hospital/infrastructure • Attitude/bias/experience • Perception of patient’s race/ethnicity Patient/Family • Awareness of clinical trials • Eligibility • Personal identity: ethnicity, race, religion • Attitude/bias/experience (eg, suspicion of medical care) • Access (eg, transportation) Interpersonal Level Perception of the institutional infrastructure Attitude/perception of each other and care received Doctor–patient relationship Disparities Fig 1. — A multilevel model of factors contributing to disparities in clinical trials. 328 Cancer Control October 2016, Vol. 23, No. 4 We propose a multilevel model derived from general systems theory, which posits that organizations are comprised of discrete but related levels (Fig 1).27 Our multilevel model demonstrates how system- and individual-level barriers contribute to interpersonal-level barriers to the enrollment of racial and ethnic minorities in clinical trials. System-Level Barriers Barriers at the level of health care systems and hospitals include the limited number of trials nationally and regionally available; hospital infrastructures that lack the resources to support trials; financial costs to hospitals and patients; restrictive study designs and eligibility criteria; and lack of community engagement. Many of these barriers have a disproportionate effect on minority enrollment because members of minority populations are more likely to receive care at underresourced hospital systems where few clinical trials are available, to be underinsured, and to present with comorbidities that make them ineligible for trials that may be available.28-30 Available clinical trials supported by a well-resourced and functional infrastructure are critical to the enrollment of minority patients.31 For example, this infrastructure includes staff dedicated to enrolling, managing, and tracking participants; data collection and management capabilities; and an efficient Institutional Review Board. Without a functional infrastructure, efforts at increasing the enrollment of minorities in other levels are less likely to be successful.31-33 The financial costs of enrollment to institutions and individual patients affect all patient populations, but they have a disproportionate impact on minorities compared with nonminorities. Minorities are more likely to be underinsured, to seek care at under-resourced hospitals, and to have concerns about the cost of participating in a clinical trial.29,34 In addition, lack of or inadequate health insurance acts as a barrier to enrollment in clinical trials for several under-represented populations, including racial and ethnic minorities.29,35 As a way to enhance community engagement, the infrastructure of clinical trials should exist within a medical institution that has an established, trusted relationship with the members of the community it serves.36 Building trust within a community requires that an institution conduct its research in an open and honest manner that involves a complete and accurate description of the known and potential differences in the risks and benefits for different racial and ethnic populations. Ways and means to facilitate and encourage open discussions into research ethics, including the past abuse of minority patients in research, are needed, as are efforts to create and sustain partnerships with the community to share ownership of the research.37-40 In response to system-level barriers, several nationOctober 2016, Vol. 23, No. 4 al, regional, and consortia efforts have implemented programs to increase enrollment among racial and ethnic minority populations.8,41,42 For example, the Minority-Based Community Clinical Oncology Program of the National Cancer Institute was designed to increase minority participation in cancer clinical trials by developing outreach efforts at health care institutions that serve large numbers of minority patients with cancer.32 McCaskill-Stevens et al32 reported that the success of this program was largely due to system- and hospital-level factors, such as opening trials that matched the clinical characteristics of patient populations and developing relationships with local physicians and cancer advocacy groups that increased their willingness to enroll or refer minority patients to clinical trials. However, their success was limited by lack of funding for minority outreach activities, lack of system support to provide staff and mentoring for minority investigators, and lack of funding to provide protocol-related drugs and related services for uninsured patients.32 The Community Oncology Research Program of the National Cancer Institute is a national network of health care professionals, investigators, and organizations that conducts cancer-related research across the United States.43 The program focuses on determining the reasons for the existence of racial and ethnic disparities in clinical trial participation, as well as ways to increase the participation of racial and ethnic minorities in clinical trials through numerous interventions.43 Because its inauguration was in 2014, evaluation data have not yet been published. In recent years NRG Oncology convened a workshop on the challenges and opportunities of clinical trial enrollment in an attempt to address the issue of minority underenrollment in clinical trials.44 Experts in oncology, including members of the Minority-Based Community Clinical Oncology Program of the National Cancer Institute, and a large patient advocacy group were in attendance.44 Ten themes emerged regarding future plans and interventions to increase minority enrollment in clinical trials; of these, 8 themes focused on the system level44: 1. Target recruitment and emphasize the personalized nature of trials as a way to improve minority enrollment to specialized studies 2. Define study populations at the molecular level rather than by traditional and less-precise eligibility criteria 3. Make the delivery of cancer care research available at the community and academic levels so studies are designed to better improve health outcomes 4. Improve local infrastructure by providing translation and navigation services and research-friendly electronic medical records 5. Expand and standardize the collection of demoCancer Control 329 graphics and real-time information about accruals for all patient populations 6. Strengthen the infrastructure of information technology 7. Improve recruitment, training, and mentorship of young investigators, particularly those of racial and ethnic minority backgrounds and those with an interest in cancer disparities 8. Continue and improve budgetary support from the US Congress for all clinical cancer research within the National Cancer Institute Individual-Level Barriers Our multilevel model emphasizes individual factors that may present a barrier to the enrollment of racial and ethnic minorities in clinical trials. The term individuals is meant to refer to persons directly involved in the clinical trial enrollment process, including health care professionals, patients, and their family members. Barriers on a system level can influence how individuals perceive the enrollment of minority patients in clinical trials and how they communicate about trials. For example, an investigation of physician perceptions of clinical trials and trial support available at their institution revealed that most physicians held a favorable attitude about clinical trials, both as a source of high-quality patient care and as a professional benefit to themselves.33 However, approximately two-thirds of practicing oncologists perceived a lack of needed infrastructure to conduct trials.33 This included a low number of trials open and lack of nonphysician staff to support patient participation in clinical trials.33 Similarly, the health care system can also influence patient concerns about the cost of participating in trials and, in turn, their decisions to enroll or not enroll in a clinical trial.34 Thus, these 2 levels are linked in terms of whether and how health care professionals and minority patients discuss clinical trials and whether minority patients agree to enroll. Health Care Professionals Health care professionals play a critical role in facilitating or inhibiting the enrollment of a diverse population of patients into clinical trials.33,45,46 Several factors are related to the reluctance of health care professionals to enroll their patients in trials, regardless of whether or not they are members of minority groups themselves. A major barrier is the lack of awareness of available trials: Health care professionals must be made aware of national, regional, and local trials currently taking patients and the eligibility criteria for each of those trials to discuss such enrollment with their patients.45,46 In addition, the attitudes of health care professionals about trials and discussing such trials with patients and their families present a major barrier to trial enrollment, and they likely affect the quality of communication during discussions of clinical trials.33,45 330 Cancer Control For example, health care professionals may not fully agree with or understand the scientific value of trials in general or the details of specific trials; they may feel they do not have adequate system support; or they may have concerns about practical issues such as strict protocol designs, patient inconvenience, and added work for the health care staff.33,45 Some clinicians find it difficult to reconcile the roles of physician and researcher, or are concerned about unduly influencing patient decisions about enrolling in a clinical trial.47 Some attitudinal factors are specific to the enrollment of minority patients, such as the concern about harming the therapeutic relationship. For example, a focus-group study involving community physicians found that some physicians were hesitant to discuss clinical trials with their African American patients because of their perceptions that African Americans are often mistrustful of physicians and medical institutions.48 An additional attitudinal factor that may deter health care professionals from discussing trials with minority patients is implicit bias against members of minority groups. Prior research has shown that implicit bias (comprised of conscious and unconscious biases) among physicians toward members of minority groups has an impact on clinical interactions with minority patients.49-52 We are unaware of studies that specifically investigate whether the implicit bias of health care professionals is a barrier to the enrollment of minorities in clinical trials, but research in other contexts suggests that some physicians may have implicit negative attitudes about African Americans that may lead them to believe they will be poor candidates for clinical trials.53-56 For example, research has shown that primary care physicians tend to trust minority patients less than they trust white patients.54 Research has also shown that physicians high in implicit bias may view their minority patients as less likely to comply with recommended treatment,57 and that physicians’ diagnoses and treatment of African Americans can be influenced by racial stereotypes.55 This body of research suggests that physicians may limit offers for trial enrollment to those patients they perceive as good study candidates so that the studies will be conducted in a timely and efficient manner.58 This may mean physicians are less likely to offer a clinical trial to patients who are racial and ethnic minorities than to white patients, and research has shown this to be the case.46,59 Recommendations have been made for evidencebased approaches to reduce the impact of health care professional bias in clinical interactions.60 One approach is to train health care professionals in the use of high-quality patient-centered communication, which requires the development of a positive interpersonal relationship.61 Patient-centered communication focuses on patient needs and perspectives, and it does not ignore the racial and ethnic background of the patient, October 2016, Vol. 23, No. 4 because doing so denies an important part of an individual.61 Results of the NRG Oncology workshop identified the commitment of physicians and study investigators to the enrollment of minorities into clinical trials as critical to the future of clinical cancer research.44 They also emphasized that physicians must be culturally sensitive and aware of the impact appropriate communication and patient trust have on minority enrollment in clinical trials.44 Several communication curricula are available, but they include little training on discussing clinical trials with patients or with specific patient populations.62 One exception is an Australian study, which reported on a 1-day intensive course for physicians to improve aspects of their communication related to discussing clinical trials with patients.45 Results showed that physicians improved in some shared decision-making behaviors and were more likely to describe some of the key clinical or ethical aspects of the trial.63 However, we are unaware of any specific training curriculum that emphasizes ways to communicate about clinical trials with minority patients. Patients and Families Some major barriers to enrolling racial and ethnic minority patients in clinical trials are that patients are often not aware they are eligible for an existing trial; they are often underinsured and cannot afford the extra expenses related to trial participation; and they may not meet the clinical criteria due to comorbid conditions or age restrictions.29,30,64 Similar to health care professionals, patients hold attitudes and beliefs that may also affect their willingness to participate and the way they communicate during clinic visits in which trials are discussed.65,66 Despite this, research shows that, overall, minorities are as likely as whites to consent if they are offered a trial.30,59,67,68 For example, an assessment of more than 4,000 racially diverse patients with cancer found no significant association between race and ethnicity and refusal to participate in a clinical trial or lack of desire to participate in research.30 Similarly, Katz et al69 implemented the Tuskegee Legacy Project to address and understand if and how the Tuskegee syphilis experiment impacted the trial recruitment and retention of African Americans into biomedical studies. The researchers found no difference in self-reported willingness among African Americans to participate in biomedical research.69 A systematic review of the available research on the factors that influence participation in clinical trials among African Americans concluded that the strongest inhibitors of participation were low levels of knowledge and lack of awareness of clinical trials.66 The most important facilitators of participation were social support and recommendations from physicians, family members, and friends.66 Several patient-focused interventions designed to October 2016, Vol. 23, No. 4 improve knowledge of, attitudes about, and participation in clinical trials among racial and ethnic minority patients has been developed and tested.70,71 A multicenter, randomized trial of a web-based, interactive, educational tool was designed to increase knowledge, decrease attitudinal barriers, and improve preparation for making decisions about clinical trial enrollment among minority patients with cancer.70 At baseline, the level of knowledge about clinical trials, attitudinal barriers to participation, and preparation for decision-making among the participants were assessed.70 Prior to their initial visit with an oncologist, patients in the intervention arm watched a set of brief, individually tailored videos addressing knowledge and attitudinal barriers to clinical trial participation, whereas those assigned to the control arm received text-based general information about clinical trials from the National Cancer Institute. The study results showed that, compared with baseline levels, participants in the intervention and control arms both showed improved knowledge (control arm: mean [standard deviation {SD}] = 2.5 [3.1]; intervention arm: mean [SD] = 3.2 [3.1]; P < .001) and decreased attitudinal barriers (control arm: mean [SD] = –0.2 [0.4]; intervention arm: mean [SD] = –0.3 [0.5]; P < .001).70 However, patients in the intervention arm had a significantly greater increase in knowledge and decrease in attitudinal barriers compared with patients in the control arm (P < .001).71 All patients had a significant increase in their preparedness to consider participation in clinical trials (control arm: mean [SD] = 3.4 [13.5]; intervention arm: mean [SD] = 4.7 [12.8]; P < .001).70 Another intervention specifically addressed the negative perceptions and attitudes of patients about clinical trials by assessing the effectiveness of a multimedia, psychoeducational intervention compared with printed educational materials.71 The intervention was designed to improve patient attitudes and knowledge of clinical trials, their ability to effectively make decisions, their receptivity to receiving more information, and their willingness to participate in clinical trials.71 The researchers observed that study participants who received the intervention had more positive attitudes toward clinical trials (mean [SD] = 0.21 [0.01]; P = .02), and, although the 2 interventions were not developed and tested with minority patients, the study results showed no significant difference between intervention by patient demographics.71 Thus, the intervention could potentially be adapted to specifically benefit racial and ethnic minority patient populations. Although racial and ethnic minority patients are overall as likely as white patients to agree to enroll in a clinical trial, reasons for declining may differ by racial and ethnic background.30,59,66-68 Minority patients — particularly African Americans — may hold negative race-related attitudes and beliefs that could diCancer Control 331 rectly and indirectly influence interactions with their health care professional regarding trials and decisions about enrollment.38,40,66,72 These attitudes, which have been derived in large part from issues of racism, uninformed consent, and poor health care for minorities in the United States, include greater mistrust in medical institutions and health care professionals and a greater sense of having been the target of discrimination.20,23,29,38,69,72-78 A systematic review of the research assessing the multiple barriers to minority enrollment in clinical trials found that mistrust in research and the medical system was the most common barrier to patients’ willingness to participate in a clinical trial.29 The attitudes of African American patients toward medical research were assessed using focus groups of African American adult patients from a single urban public hospital.72 Results showed that most were in favor of medical research as long as they were not treated as “guinea pigs.”72 The authors also reported that many of the participants had a limited understanding of the informed consent process, and many patients assumed the consent form was protecting hospitals and doctors from any legal responsibility, not to protect patients.72 Another study that assessed and compared the racial differences in factors that influence patient willingness to enroll in clinical research studies found that African Americans were less willing to participate in medical research if they attributed a high importance to the race of the physician when seeking routine medical care and believed that minorities bear most of the risks of medical research.40 Interventions designed to increase the recruitment of minorities in clinical trials are generally focused on communities, rather than on individuals.32,79 One such intervention targeted minority recruitment using strategic planning, which included meetings and conferences with key stakeholders and minority organizations as a means to increase minority enrollment.79 The authors examined institutions that employed these strategies and those that did not, and they found a significant increase in the rate of minority accrual in institutions that implemented strategic planning compared with those that did not.79 This effort suggests that the mistrust of the medical system seen among minority patients might be addressed with culturally sensitive and open community engagement. Other identified patient-level barriers to the enrollment of racial and ethnic minorities in clinical trials include lack of transportation, inadequate insurance, lack of childcare, and poor access to health care.42,66 The NRG Oncology workshop also identified direct-topatient communication and advertising as critical for the future of minority enrollment in clinical trials, emphasizing that this should be done with collaboration with key stakeholders such as community groups, survivor advocacy groups, and religious institutios.44 The 332 Cancer Control intersection between the impact of patient attitudes and access to trial participation illustrates the complex and multilevel nature of this issue and the need for more comprehensive interventional strategies. Interpersonal-Level Barriers Our model suggests that system- and individual-level barriers to minority enrollment in clinical trials affect whether and how trials are discussed during doctor–patient clinical interactions. This suggestion is based on our work and that of others showing that patient and physician attitudes affect the quality of communication during clinical interactions with African Americans.80-88 Our model also partly explains why communication during these interactions is often of a lower quality and may affect racial and ethnic minorities’ decisions about enrollment. For example, implicit bias among health care professionals (eg, oncologists) negatively affects communication with minority patients.89 An investigation of the impact of the implicit racial bias of oncologists on their clinical interactions with African Americans with cancer revealed that oncologists with higher rates of implicit bias against African Americans had shorter interactions with African Americans than oncologists with lower levels of implicit bias.90 In addition, oncologists with higher rates of implicit bias used less patient-centered communication.90 Although this study was not specifically focused on clinical trials, the findings suggest that implicit bias among health care professionals may affect clinical interactions with African Americans who are eligible or express interest in participating in a clinical trial.90 Racial and ethnic differences in the quality of communication are due to both patient-related communication behaviors (eg, African Americans often ask fewer questions),82,86 general communication behaviors among physicians, including amount of patient centeredness, information giving, and shared decisionmaking,61,81,86,91 and communication specific to discussing trials.45,63,92-95 Although few researchers have specifically focused on discussions with minority patients about enrolling in cancer trials, a single study of video-recorded interactions was undertaken in which oncologists discussed clinical trials with whites and African Americans.96 Using linguistic analyses, the interactions with African Americans compared with whites were found to be shorter, the topic of clinical trials was less frequently mentioned, and, when clinical trials were mentioned, less time was spent discussing them.96 Compared with whites, differences were observed in the discussion of some of the key aspects of clinical trials: Oncologists and African American patients spent less time discussing the purpose of the trial, its risks and benefits, and alternatives to participating in the trial; however, they spent more time discussing the volOctober 2016, Vol. 23, No. 4 untary nature of trials.96 These findings are particularly problematic because very few oncologists are African American, and so racially discordant interactions may be considered the norm for African American patients with cancer.96,97 Few patient-focused interventions designed to improve doctor–patient discussions of clinical trials exist, and none of them focus on minority patient populations.98 One study assessed an intervention designed to improve patient understanding of early-phase clinical trials for which they were eligible and which would be discussed during a subsequent oncology visit.99 Prior to the visit with the oncologist to discuss the trial, study participants in the intervention group viewed an interactive, computer-based presentation about clinical trials that included information about several aspects of clinical trials and urged them to discuss the risks and benefits of the trial with their oncologist; those assigned to the control group were provided a pamphlet that covered similar topics.99 Following the clinic visit, participants assigned to the intervention were more likely than the controls to understand that the purpose of an early-phase trial was related to the safety and dosing of the drug; however, the majority of participants in both groups reported that the main purpose of an early-phase trial was “to see if the drug works.”99 In addition, those in the intervention group were also more likely than the control group to believe that the physician talked to them about joining an early-phase trial because they might benefit from the drug compared with controls. Brown et al100 developed and pilot tested another patient-focused intervention that provided eligible patients with a booklet with trial-related questions they could ask their oncologist during the clinic visit. Findings suggested that the study patients had high informational needs prior to the visit, selected most of the questions to ask their oncologist, and asked many of the questions during the visit.100 Although these interventions were not tested in populations with minority patients, they could potentially be Individual Level Health Care Professional Training to address negative attitudes and biases to improve communication about clinical trials Patient/Family Question prompts to encourage active patient participation in clinical interaction Interpersonal Level Team building adapted for specific populations. The clinical interaction is based on a relationship, so focus on the social interaction between patients and physicians from differing social backgrounds may be valuable. Research from the field of social psychology suggests that patients and physicians in racially discordant clinical interactions should create a sense of common purpose, support, and understanding as ways to reduce bias and increase cooperation and trust.101,102 This approach formed the basis of a “team” intervention in a primary care clinic that succeeded in increasing patient trust and adherence following such clinic visits.103 Thus, this type of approach may reduce the impact of racial bias in interactions when clinical trials could be discussed. Proposed Multilevel Interventional Model Our multilevel model and supporting research identify and describe factors that may inhibit the enrollment of minorities in clinical trials. Authors have challenged researchers to move beyond reductionist, single-level interventions.25,26,104 We have met this challenge by proposing a multilevel intervention comprised of evidence-based strategies focused at the patient, oncologist, and patient–oncologist interpersonal levels. Although the proposed intervention does not directly address the system level, addressing these other 2 levels may, in combination, have a greater and longer-lasting impact on increasing enrollment among minority patients (Fig 2). Ideally, an intervention should address all levels; however, in reality, it may be difficult for all interventions to address all of them. Our proposed intervention builds on previously published descriptive and interventional research on individual attitudes and clinical communication by addressing these 3 levels of barriers. The intervention places emphasis on the communication about clinical trials that occurs between patients and physicians in clinical settings. We place the focus on clinical communication for 3 reasons: High-quality communication about clinical trials Greater rates of informed racial and ethnic minority participation in clinical trials Reduced disparities, improved cancer treatments Fig 2. — Our proposed model for a system-level intervention. October 2016, Vol. 23, No. 4 Cancer Control 333 • The quality of doctor–patient communication during clinic visits is considered the most central and proximal influence on a patient’s decision to participate in a clinical trial. • Health care is transacted through these interpersonal processes among health care organizations, health care professionals, and patients and their families.105-107 • The quality of communication during clinical interactions with minority patients is less than that seen among similar interactions with whites.80-88 However, even multilevel interventions will have limited success if they occur in a vacuum; in other words, they must be implemented within institutions with the appropriate infrastructure to support trials that match the clinical characteristics of an engaged, diverse patient population. Our proposed multilevel intervention illustrates some potential ways to influence the attitudes and communication skills of minorities related to engaging in discussion about clinical trials with oncologists; the attitudes and communication skills of oncologists when discussing trials with minority patients; and doctor–patient interactions in which trials may be discussed. The first aspect of the intervention is a patient-focused communication intervention called a questionprompt list. A question-prompt list is a list of questions related to the physical and psychosocial aspects of a medical condition that patients may wish to ask their physician during a medical visit. Question-prompt lists are designed as a simple, inexpensive way to support patients in gaining information about their diagnosis and treatment and improve doctor–patient communication by encouraging patients to actively participate in their health care (eg, ask questions, state concerns).108-111 Active participation has been shown to influence the amount of information physicians provide, treatments they recommend, topics discussed, and patient psychosocial and physical health outcomes.112-116 Questionprompt lists have been developed and tested in several medical settings, and, given the research showing that racially discordant interactions are often characterized by poor-quality communication, it is surprising that this type of intervention has not been tested in this context.98,100,117,118 We have collaborated with community members, African American patients and their families, and oncologists to develop a question-prompt list for use in the context of racially discordant oncology treatment interactions.119 Preliminary findings from a randomized trial of the question-prompt list show that its use was feasible and acceptable in this patient population, and it was successful in improving their level of active participation.120 For the purpose of a multilevel intervention relevant to minority enrollment in clinical trials, we suggest adapting a question-prompt list developed for use 334 Cancer Control in the context of clinical trials, although it has never been tested among minority patients.100 This questionprompt list includes 33 questions divided into 11 categories (eg, finding out more about the trial, understanding the trial’s purpose and background, understanding possible risks). Adapting the question-prompt list for use in a diverse population of patients will require engaging community members and patients to ensure that it reflects findings from focus groups and other research with individuals representative of the patients likely to be the recipients of the intervention.121 The second aspect of the intervention is intended to enhance the patient-focused intervention by improving physician attitudes and communication skills related to discussing trials with minority patients. The physician-focused intervention would include 2 components, one focused on communication skills and the other focused on trial-related attitudes. The communication component would build on prior work on training physicians to improve physician communication skills related to discussing trials but would also involve increasing physician knowledge about the fact that most patients, including racial and ethnic minority groups, are willing to participate in trials if their physician offers a trial and does so using high-quality, patient-centered communication.45,63,67,92,122 In clinical communication, participants exchange both informational and relational messages, and the training intervention would involve skill-building in both.92 Skill-building in informational communication would include guidelines for discussing information patients need to make an informed decision about participating in a trial based on international guidelines.123,124 Skill-building in relational communication would include explanations and illustrations of communication strategies such as using organizing statements, eliciting questions and concerns by utilizing strategies such as the ask–tell–ask method, using plain language rather than technical jargon, assessing understanding by using the teach-back method, directly acknowledging and empathically responding to questions and concerns, and using shared–decision-making principles.125-127 The attitudinal component of the physician-focused intervention would occur following the communication component. This aspect of the intervention would be designed to increase the likelihood that physicians will discuss and offer trials to their minority patients. Asking people to think about their attitudes affects both their attitudes and relevant behavior, and asking people to form a situation-specific plan for a type of behavior, such as discussing a trial with a patient, increases the likelihood they will engage in the behavior.128-130 Our proposed intervention translates that research into an intervention in which physicians are provided with a brief e-mail message prior to a visit with a patient potentially eligible for a trial. In the mesOctober 2016, Vol. 23, No. 4 sage, physicians would be asked to rate the scientific and clinical benefits of offering a trial to minority patients and to consider exactly how they will discuss the trial with the patient. The interpersonal aspect, which is the third aspect of the intervention, involves both patients and physicians. It is based on research that suggests the encouragement of patients and physicians to create a sense of common purpose, support, and understanding may assist in reducing bias and increasing cooperation and trust.101,102 Based on this research, members of our research group tested a team intervention in a primary care clinic that successfully increased patient trust and adherence following racially discordant clinic visits.103 A similar team intervention could be provided to physicians who have the ability to offer trials to a diverse population of patients as well as their patients who are potentially eligible for an ongoing trial. Patients and oncologists would receive simple instructions about working together as a team to achieve a common goal — providing high-quality care to treat cancer — and they would be provided with team items, such as pens and buttons, with a team logo. This type of intervention may overcome — or reduce — some of the effects of patient mistrust of physicians and researchers, physician implicit bias toward minorities, and concerns about harming the therapeutic relationship with these patients. Conclusions Although racial and ethnic disparities in cancer and other conditions have been documented for decades, researchers, health care professionals, and policymakers have been unable to eliminate these persistent and preventable contributors to poor health.17,23 Underenrollment of racial and ethnic minority populations in clinical trials is a health care disparity that results from preventable and interlinked policies, practices, and barriers at the system, individual, and interpersonal levels.23 Although many interventions designed to increase the clinical trial enrollment of racial and ethnic minorities and other under-represented groups have experienced varying levels of success, multilevel interventions are likely to be the most effective method for increasing enrollment among a well-informed, diverse population of patients.25 When members of these groups decide to enroll in a clinical trial based on a supportive and efficient system-level environment and high-quality communication with their health care professionals, medical researchers will be able to move toward their goal of translating new knowledge into tangible benefits and providing high-quality cancer care for all patients. 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Racial and Ethnic Differences in the Epidemiology and Genomics of Lung Cancer Matthew B. Schabath, PhD, W. Douglas Cress, PhD, and Teresita Muñoz-Antonia, PhD Background: Lung cancer is the most common cancer in the world. In addition to the geographical and sex-specific differences in the incidence, mortality, and survival rates of lung cancer, growing evidence suggests that racial and ethnic differences exist. Methods: We reviewed published data related to racial and ethnic differences in lung cancer. Results: Current knowledge and substantive findings related to racial and ethnic differences in lung cancer were summarized, focusing on incidence, mortality, survival, cigarette smoking, prevention and early detection, and genomics. Systems-level and health care professional–related issues likely to contribute to specific racial and ethnic health disparities were also reviewed to provide possible suggestions for future strategies to reduce the disproportionate burden of lung cancer. Conclusions: Although lung carcinogenesis is a multifactorial process driven by exogenous exposures, genetic variations, and an accumulation of somatic genetic events, it appears to have racial and ethnic differences that in turn impact the observed epidemiological differences in rates of incidence, mortality, and survival. Introduction Lung cancer is the most common cancer worldwide.1,2 In 2012, new diagnoses of lung cancer reached approximately 1.8 million worldwide, accounting for 13% of the global cancer burden. 2 Among men, lung cancer remains the most common cancer diagnoFrom the Departments of Cancer Epidemiology (MBS), Molecular Oncology (WDC), and Tumor Biology Program (TM-A), H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida. Submitted February 19, 2016; accepted May 11, 2016. Address correspondence to Matthew B. Schabath, PhD, Department of Cancer Epidemiology, Moffitt Cancer Center, 12902 Magnolia Drive, MRC-CANCONT, Tampa, FL 33612. E-mail: [email protected] No significant relationships exist between the authors and the companies/ organizations whose products or services may be referenced in this article. This work is supported in part by the James & Esther King Biomedical Research Program (5JK06), National Institutes of Health Grant from the National Cancer Institute (U54-CA 163068), and by a cancer center support grant at the H. Lee Moffitt Cancer Center & Research Institute (P30-CA76292). 338 Cancer Control sis. Approximately 1.2 million cases among men alone were diagnosed in 2012.2 In the United States, lung cancer is the second most common cancer in men after prostate cancer and the second most common cancer in women after breast cancer.3 In 2016, an estimated 224,390 new cases of lung cancer will be diagnosed.3 Lung cancer is also the leading cause of cancerrelated death in the United States and accounts for more deaths than prostate, breast, colorectal, and pancreatic cancers combined.3 In 2016, an estimated 158,080 deaths related to lung cancer will occur.3 From 2008 to 2012, the mortality rate among men was 59.8 per 100,000 and 37.8 per 100,000 persons for women.3 Although lung carcinogenesis is a multifactorial process driven by exogenous exposures (eg, cigarette smoking), inherited genetic variations, and an accumulation of somatic genetic events, it also appears to have racial and ethnic differences. However, many of these observed differences attributed to underlying raOctober 2016, Vol. 23, No. 4 cial and ethnic disparities in lung cancer are not fully understood. Health disparities can also occur as a result of systems-level issues, such as access to care, insurance, and hospital-level factors.4-6 Other potential sources of racial and ethnic disparities are derived from health care professional–related factors, such as limited cultural sensitivity, stereotyping, and poor doctor–patient relationships.7 Studies have shown that, even after controlling for these factors, treatment disparities persist, suggesting that patient-specific factors may also contribute to lung cancer differences.8,9 In addition to the established geographical and sex-specific differences in the incidence, mortality, and survival rates of lung cancer, certain racial and ethnic differences exist.10,11 Although the terms race and ethnicity are often inconsistently applied, a commonly used definition describes race as a social construct that incorporates beliefs about language, history, and culture, forming the basis on which social identity, traditions, and politics are built.12,13 In the United States, the race classification scheme used in the 2000 census, which is often used in biomedical research, includes 5 major groups: white, black/African American, Asian, Native Hawaiian/Pacific Islander, and American Indian/Alaska Native.14 Broadly, this classification scheme emphasizes the geographical region of origin of an individual’s ancestry. Ethnicity is a broader construct that takes into consideration cultural tradition, common history, religion, and, oftentimes, a shared genetic heritage.13 Thus, to avoid confusion, we will use the terms (race or ethnicity) as reported in the originally cited work to describe the population studied. Epidemiology Incidence The incidence rates of lung cancer are generally lower among women (583,000 new lung cancer diagnoses in 2012).2 The highest incidence rates occur in eastern and Central Europe as well as eastern Asia; by contrast, the lowest rates occur in western and Central Africa.2 The geographical variations for incidence and mortality differ between men and women, largely attributed to geographical differences in cigarette smoking between the 2 sexes.2,15 The highest incidence rates in women are observed in North America and northern Europe, whereas the lowest rates are found in western and Central Africa.2 In the United States, the incidence rates have been declining in men in the past 20 years and in women since the mid-2000s: From 2008 to 2012, they annually decreased by 3.0% among men and 1.9% among women.3 During this time period, the incidence rate among men was 76.7 per 100,000 and 54.1 per 100,000 persons for women.3 Race and ethnicity are complex social and cultural constructs, but they are also often associated with October 2016, Vol. 23, No. 4 socioeconomic status. Racial and ethnic differences in disease burden can reveal specific issues of a particular population or subpopulation. Racial and ethnic differences in rates of incidence, mortality, and survival of lung cancer are well documented.10,11 The most comprehensive report in the United States is based on data from the Surveillance, Epidemiology, and End Results (SEER) program, which revealed that blacks have higher rates of incidence and mortality than any other racial or ethnic group.10 A report from the Centers for Disease Control and Prevention assessed potential racial/ethnic disparities and geographical differences in incidence rates of lung cancer from 1998 to 2006 using data from SEER and the National Program of Cancer Registries.11 In this report, the annual incidence rate of lung cancer was highest among blacks, followed by whites, American Indians/Alaska Natives, and Asian/Pacific Islanders.11 Hispanics had lower rates of lung cancer incidence than non-Hispanic whites.11 In the United States, the highest rate of lung cancer incidence was found in the South and the lowest rate of incidence was in the West.11 Among whites, the highest rate of lung cancer incidence was in the South; the highest incidence rates among blacks, American Indians/Alaska Natives, and Hispanics were in the Midwest; and the highest incidence among Asian/Pacific Islanders was in the West.11 The identification of geographical differences in incidence rates among racial and ethnic populations presents novel opportunities for targeted efforts in primary prevention and early detection. Survival Despite considerable improvements in patient survival during the past several decades for breast and prostate cancers, few improvements have been seen in survival rates of lung cancer. Improvements in survival are lacking because the majority of lung cancers are at an advanced stage by the time a diagnosis is made and treatment options are limited. Because of its high mortality rate, variability in survival is lacking in different world regions.2 In the United States, the 5-year relative survival rate for all lung cancers is 17%.3 Among all stages of non–small-cell lung cancer (NSCLC) and small-cell lung cancer, the combined 5-year relative survival rates are 21% and 6%, respectively.3,16 The overall prognosis for NSCLC remains poor, and prognostic factors associated with poor survival include late-stage diagnosis, current smoking status, advanced age, male sex, poor pulmonary function, presence of cardiovascular disease, nonsquamous cell histology, and pneumonectomy.17-21 Among individuals with small-cell lung cancer, poor prognosis is associated with age older than 70 years, male sex, relapsed disease, extensive disease, weight loss of more than 10% of total body weight at diagnosis, and poor perCancer Control 339 formance status.22-26 Despite the poor outcomes associated with a diagnosis of lung cancer, the emergence of immunotherapy and immune checkpoint inhibitors has demonstrated durable rates of long-term survival in select patients.27,28 As such, these therapies may lead to improved survival rates and, in the early stage, possibly curable disease.29 Published data have demonstrated that the survival rates of those with lung cancer also differ based on race and ethnicity.4,30-33 Blacks are less likely to receive surgical resection than whites, a finding that likely contributes to data that show blacks have lower rates of survival for early-stage NSCLC.4,30-32 Using SEER data linked to Medicare claims data during 1995 and 1999, Shugarman et al31 reported that blacks were 66% less likely to receive timely and appropriate treatment than whites, and black men were least likely to receive resection (22.0% for black men vs 43.7% for white men). The authors also reported that blacks were 34.0% less likely to receive timely surgery, chemotherapy, or radiotherapy for stage III disease and were 51.0% less likely to receive chemotherapy in a timely fashion for stage IV disease relative to whites.31 Howington et al33 reported that American Indians and Alaskan Natives have worse survival rates than non-Hispanic whites. With regard to potential ethnic differences, a study by Lin et al34 compared rates of stage-appropriate treatment among blacks, Hispanics, and nonminority patients and did not observe treatment-related disparities among Hispanics. However, the authors did find that blacks were less likely than nonminorities to receive stage-appropriate treatment, similar to data reported in previous studies.5,34-36 (18.8%) than females (14.8%), and nearly 17% of adults still continue to smoke cigarettes.41,43 By racial and ethnic groups, smoking prevalence rates were highest among American Indians/Alaska Natives (29.2%) and multiracial adults (27.9%) and lowest among Asians (9.5%).41,43 For other racial and ethnic groups, smoking prevalence rates were 18.2% for whites, 17.5% for blacks, and 11.2% for Hispanics.41,43 Although the annual incidence is highest among blacks compared with any other race, the prevalence of smoking among blacks is lower than American Indians/Alaska Natives, multiracial adults, and whites.41,43 Moreover, significant differences have been reported in the association between cigarette smoking and the risk of lung cancer among 5 ethnic/racial groups.44 Among those who smoked no more than 30 cigarettes per day, African Americans and Native Hawaiians had significantly greater risks of lung cancer than the other groups studied.44 As such, these data provide further support for ethnic/racial differences, which could be attributed to innate genetic differences in the smokingassociated risk of lung cancer. Other established and putative risk factors for lung cancer include exposure to secondhand smoke (ie, passive smoke), history of chronic obstructive pulmonary disease, family history of lung cancer, radon exposure, and occupational exposure (eg, asbestos, arsenic, diesel exhaust, chromium).19,45,46 Evidence is conflicting regarding the impact of exogenous hormones on women, diet, and body mass index in association with risk of lung cancer.46-53 Moreover, few studies have assessed the potential racial and ethnic differences for such risk factors.50 Risk Factors Tobacco smoking is the most important and prevalent risk for lung cancer.37-39 Lung cancer is one of the first chronic diseases to be causally linked to tobacco smoking, and approximately 90% of lung cancer diagnoses in the United States are attributed to tobacco smoking.19,20 Cigarette smoke contains more than 7,000 chemicals, including more than 60 established carcinogens and other toxicants associated with chronic diseases.40 Although approximately 1 in 9 individuals who smoke develops lung cancer, the relative risk of lung cancer in those who are long-term smokers is estimated to be between 10- and 30-fold higher than that of a lifetime never-smoker.19 The percentage of cigarette smoking among adults in the United States and most Western nations has been steadily declining during the past several decades — from 20.9% in 2005 to 16.8% in 2014 — and it continues to decline today due to successful tobacco-control efforts.2,41 In the United States, smoking rates have steadily declined since the 1960s.42 In 2014, the prevalence of smoking was higher among males Prevention and Early Detection 340 Cancer Control Until recently, no screening method was shown to decrease the mortality rates for NSCLC. The National Lung Screening Trial (NLST) randomized 53,452 individuals who were former or current cigarette smokers, between the ages of 55 and 74 years, and had a pack-year smoking history of at least 30 years into either low-dose helical computed tomography (LDCT) or standard chest radiography — both arms were administered 3 annual screenings (baseline screening and 2 follow-up screening sessions approximately 12 months apart).54 After a median follow-up period of 6.4 years, a 20% relative reduction in rate of lung cancer mortality was observed for the LDCT group compared with those assigned to standard chest radiography.54 The rate of lung cancer detected via screening (ie, diagnosed on follow-up screening intervals) accounted for 58% of all LDCT-detected cases of lung cancer, were 2.7-fold higher in the LDCT arm vs the chest radiography arm, were associated with a stage shift from late-stage to more early-stage lung cancer, and demonstrated improved rates of 5-year survival October 2016, Vol. 23, No. 4 compared with cancers diagnosed at the baseline prevalence screening.54 An important benefit of early detection is the ability to detect more cases of early-stage lung cancer. A meta-analysis revealed that the rate of detection of stage I lung cancer was 70% with LDCT screening compared with 16% when detected during routine care.55 Thus, the incidence of lung cancer detected in screening and then diagnosed as a result of LDCT have better surgical outcomes and improved 5-year survival rates than prevalence and routine care–detected lung cancer diagnosed when patients develop symptoms of late-stage disease.19 Based on the findings from the NLST, the US Preventive Services Task Force issued a recommendation in December 2013 for annual screening for lung cancer using LDCT in adults aged 55 to 80 years who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years.54,56 Of the 53,452 participants in the NLST, 90.8% were white (n = 48,549), 4.4% were black (n = 2,376), 1.7% were Asian (n = 895), 2.0% were of other racial groups or reported more than 1 race or ethnic group (n = 1,062), and 1.7% were Hispanic or Latino (n = 935).54 Although the NLST did not provide ethnic-/racial-specific results,54 a posthoc analysis by Tanner et al57 assessed racial differences in outcomes between blacks and whites who participated in the NLST. Although demographics associated with improved survival in lung cancer, such as higher education, former smoking status, and fewer comorbidities, were less commonly found among blacks in the NLST, their analysis revealed that screening with LDCT reduced mortality in all racial groups, but more so in blacks (hazard ratio [HR] 0.61 for blacks vs HR 0.86 for whites).57 Among all racial groups, Tanner et al57 also noted that study participants who currently smoked had worse rates of lung cancer–specific mortality; however, the risk was 2-fold higher in blacks who were current smokers compared with white current smokers. In addition, the rate of all-cause mortality was 1.35 times higher in blacks vs whites, but blacks screened with LDCT had a statistically significant reduction in all-cause mortality when compared with whites.57 As such, screening for lung cancer appears to be beneficial in blacks, but different strategies are needed to achieve a significant reduction in lung cancer–related mortality in this population.57 Ongoing disparities in access to screening and follow-up visits (in the case of abnormal results) underscore the importance of health care institutions to offer screening and then quickly resolve any abnormal findings. In a separate posthoc analysis of the NLST, Kumar et al58 examined racial differences in smoking behaviors among white and black study participants in the NLST who were current smokers at screening. They analyzed data from a follow-up survey on 24-hour and October 2016, Vol. 23, No. 4 7-day cessation attempts, 6-month continuous abstinence from smoking, and the use of smoking cessation programs and cessation aids 12 months after screening. The authors reported that blacks were more likely than whites to have 24-hour and 7-day cessation attempts; however, these attempts did not translate to increased rates of 6-month continuous abstinence among blacks.58 Specifically, 1 year after screening, blacks were more likely to report a 24-hour (52.7% for blacks vs 41.2% for whites; P < .01) or 7-day (33.6% for blacks vs 27.2% for whites; P < .01) cessation attempt.58 Although no statistically significant racial differences were found in 6-month continuous abstinence (5.6% for blacks vs 7.2% for whites), black race was a statistically significant predictor in multivariable analyses of a higher likelihood of a 24-hour and 7-day cessation attempt.58 Race was not associated with 6-month, continuous abstinence; by contrast, a positive result on screening for lung cancer was the only significantly predictor of successful 6-month, continuous abstinence.58 At present, knowledge is lacking about the effectiveness of screening for lung cancer with LDCT in other racial and ethnic groups. The data from the NLST demonstrated that screening with LDCT can mitigate lung cancer mortality via early detection.55 Screening with LDCT appears to be second only to primary prevention (ie, smoking prevention/cessation) for mitigating lung cancer–related mortality — and the single remaining option for those who have already quit smoking. The risk of lung cancer caused by smoking is reduced following smoking cessation, but this risk always remains elevated compared with those who are lifetime never-smokers.59 Genomics The most frequently mutated genes in lung cancer are TP53 (53.6%), KRAS (16.1%), STK11 (9.8%), EGFR (7.2%), KEAP1 (6.6%), and NFE2L2 (4.5%).60 The frequency of mutations in oncogenes and tumor-suppressor genes differ across racial and ethnic populations and are selectively shown in the Table. Advances in tumor genomic profiling have resulted in a paradigm shift, whereby types of lung cancer are characterized and classified by genetic alternations in oncogenes and tumor-suppressor genes critical to tumor growth and survival and can be exploited with specific targeted agents.61 The focus of this paper is on specific oncogenes and tumor-suppressor genes where published studies have assessed potential racial and ethnic differences. Although other genes have also been studied, including MET, PI3KCA, PTEN, and ROS1, current data are limited and suggest that no differences exist in these genes.62 Because most types of lung cancer harbor somatic mutations, alterations, or both, the use of targeted therapy is important to improve outcomes.63 Research Cancer Control 341 Table. — Estimated Frequencies of Select Mutated Genes in Lung Cancer Gene Frequency, % EGFR By region Asian populations 30.0–40.0 Western populations 10.0–20.0 By country Argentina 19.3 Colombia 24.8 Costa Rica 26.0–35.3 Mexico 31.2 Panama 24.8 Peru 67.0 KRAS By region Asian populations Western populations 3.8–8.0 18.0–26.0 STK11 By region Asian populations 3.0–7.0 Western populations 9.0–17.0 BRAF a Overall 1.0–3.5 PIK3CAa Overall 1.0–3.0 ALK Fusion 3.0–7.0 By region Asian populations 2.3–6.7 Western populations 1.0–3.0 a No published reports have assessed racial and ethnic differences. has been limited on the impact of race and ethnicity in targeted therapies. The impact and frequency of tumor mutations are not as well characterized in blacks and Hispanics/Latinos to the same extent as they are in Asians and whites.62,64 Although evidence suggests that racial and ethnicity differences exist in markers of susceptibility, we have chosen to focus on somatic mutations because of their clinical implications and observed racial and ethnic differences, as well as because germline variations in lung cancer have yet to be deemed clinically actionable.62,65 EGFR Epidermal growth factor receptor (EGFR) is a transmembrane protein with cytoplasmic kinase activity that facilitates critical growth-factor signaling from the extracellular milieu to the cell.66 EGFR is expressed on the cell surface. Tyrosine kinase inhibitors can be ef342 Cancer Control fective therapy for patients whose tumors harbor activating mutations in the tyrosine kinase domain of EGFR.66 Therefore, mutation testing is routinely performed to identify patients harboring targetable EGFR mutations, given that selection based on clinical and pathological characteristics alone is inadequate. Overall, approximately 10% of patients with NSCLC in Western countries and 35% of patients in East Asia have a tumor that exhibits an EGFR mutation.67,68 The most frequent EGFR mutations occur in exons 18 to 21, encoding a portion of the EGFR kinase domain; in addition, EGFR mutations are often heterozygous, with the mutant allele also showing gene amplification.69 Approximately 90% of these mutations are exon 19 deletions or exon 21 L858R point mutations.70 Irrespective of ethnicity, EGFR mutations are more often found in females who are never-smokers and have adenocarcinoma histology.67,68 However, EGFR mutations can also be found in other histological subtypes of NSCLC, and they can be found in former and current smokers.71-73 In-frame deletions and insertions in exon 19 and the point mutation L858R in exon 21 are the most common activating EGFR mutations, and their prevalence is significantly higher in individuals of Japanese, Korean, and Chinese descent than American or European whites.74 Based on data from the Iressa Pan-Asia Study, the frequency of activating EGFR mutations in Asian never-smokers or light smokers with advanced-stage adenocarcinoma was nearly 60%.75 By contrast, the rate of frequency was 15% in non-Asian patients based on data from phase 3 trials of retrospective EGFR mutation testing of archival samples.76,77 One study compared EGFR mutations in individuals of Asian and Russian descent with advanced NSCLC and reported that the frequency of EGFR mutations in adenocarcinoma was 49% in East Asians and 18% in Russians, and the frequencies of EGFR mutations in nonadenocarcinoma lung cancers were 14% and 4%, respectively.78 Several studies have explored whether the frequencies of EGFR mutations differ by race and ethnicity, and others have compared the frequencies of EGFR mutations between blacks and whites with NSCLC; however, the results are conflicting.79-82 Specifically, Yang et al79 and Leidner et al80 found a lower frequency of EGFR mutations among blacks, whereas Riely et al,81 Cote et al,82 and Reinersman et al83 did not find a statistically significant difference between the 2 groups. Few studies have addressed the frequency of mutations in lung cancer among Hispanics/Latinos. Arrieta et al84 analyzed 1,150 biopsy specimens from patients with NSCLC who were from Argentina, Colombia, Peru, and Mexico and found that the combined frequency of EGFR mutations among all 4 countries was 32.5%. The frequencies of mutations by country were 19.3% in Argentina, 24.8% in Colombia, 31.2% in Mexico, and 67.0% in Peru.84 The high frequency of October 2016, Vol. 23, No. 4 EGFR mutations in Peru could be attributed to Asian migration.62 The frequency of EGFR mutations ranges from 26.0% to 35.3% in Costa Ricans and is 24.8% in Panamanians.85-87 By contrast, a lower frequency of EGFR mutations has also been reported among Hispanics/Latinos, and other conflicting reports have found no statistically significant difference between Hispanics/Latinos and whites.62 KRAS The RAS family, which includes HRAS, NRAS, and KRAS, encodes for membrane-bound guanosine triphosphate–binding proteins that regulate cell growth, differentiation, and apoptosis by interacting with mitogen-activated protein kinase, phosphoinositide 3-kinase, and signal transducer and activator of transcription cascades.88,89 When aberrantly activated, KRAS is a potent oncogenic driver when a point mutation occurs at codon 12 or 13 in exon 2 or codon 61 in exon 3.90 These mutations result in impaired guanosine-triphosphatase activity and a constitutive activation of RAS signaling.91 Mutations in KRAS occur frequently in NSCLC — particularly adenocarcinoma (20%–30%) — and less commonly in squamous cell carcinoma (~ 7%).92,93 Although mutationally activated KRAS tumors were originally identified in 1982,78 no successful treatment strategies target these tumors,93 and their impact on survival and prognosis in lung cancer is unclear and controversial.94,95 To date, more than 50 studies have evaluated KRAS mutations on clinical outcomes in lung cancer, the results of which are varied and inconsistent.94,95 A metaanalysis of 41 studies concluded that KRAS mutations are associated with a poor prognosis in patients with NSCLC, and this was particularly true for those with adenocarcinoma and early-stage NSCLC.95 Data have also suggested that the rates of frequency of KRAS mutations differ by race and ethnicity. Specifically, KRAS mutations in the setting of lung cancer are less common in Asians compared with whites.96,97 The frequency of KRAS mutations ranged from 3.8% to 8.0% in studies of Chinese study participants with NSCLC — a rate lower than that seen in whites (range, 18%–26%).65,80,98 Few studies have assessed KRAS mutational status among blacks, and the published data are inconsistent: 3 studies reported no statistically significant difference in frequency of KRAS mutations between whites and blacks,80,83,99 and some noted that the frequency in Hispanics may actually be lower.84,100 STK11 STK11 encodes a tumor suppressor located on chromosome 19p13.3 that encodes the serine/threonine kinase 11 (STK11) protein. The gene is made up of coding exons 1 to 9 and a final, noncoding exon 10. STK11 regulates cellular energy metabolism and cell polarity by initiating adenosine monophosOctober 2016, Vol. 23, No. 4 phate–activated protein kinase (AMPK) and other members of the AMPK family.101,102 As a multifunctional kinase, STK11 is involved in a broad spectrum of cellular activity that includes metabolism, polarity, and epithelial-mesenchymal transition, as well as cell-cycle regulation, apoptosis, and autophagy.103 Germline mutations in STK11 were first identified in patients with Peutz-Jeghers syndrome,104 a rare autosomal dominant disorder associated with an increased risk of gastrointestinal and other malignancies.105 Studies have also reported that STK11 somatic mutations are common in NSCLC: The prevalence of inactivating mutations can occur in more than 50% of cases (range, 0.6%–44.4%), thus revealing an important role of STK11 in lung tumorigenesis.103,106-112 Previously published data have reported that STK11 inactivating mutations occur in other histology subtypes of lung cancer and include 19% of squamous cell carcinomas, 14% of large cell carcinomas, and 25% of adenosquamous carcinomas.103,109,110,113-115 Similar to KRAS and EGFR, ethnic and racial differences appear in STK11 mutations. Studies in Asian populations (those of Japanese, Korean, and Chinese descent) have reported lower rates of STK11 mutations than whites (range, 3%–7%).115-118 This observation is similar to that seen in KRAS mutations in the setting of lung cancer, because they frequently co-occur with STK11. Lung tumors in Western populations harbor a higher frequency of KRAS mutations compared with Asian populations.98,119 Asian populations have also been found to express an STK11 germline F354L polymorphism at a frequence of approximately 10%.117 This allele has been called a nonfunctional polymorphism in lung cancer, but it also affects cell polarity maintenance in an AMPK-dependent manner.120 At present, no data have been published on the frequency of STK11 mutations among blacks and Hispanics/Latinos. BRAF BRAF is a proto-oncogene that belongs to a family of serine-threonine protein kinases that also includes ARAF and RAF1. Mutant BRAF has been implicated in the pathogenesis of several cancers.98 The most commonly identified BRAF mutation is V600E, which accounts for 90% of BRAF mutations in melanoma.121 By contrast, the frequency of BRAF mutations in NSCLC ranges from 1.0% to 3.5%.122-125 No reports have assessed racial and ethnic differences of BRAF mutations in patients with lung cancer, likely because this mutation is rare in this population. PIK3CA PIK3CA belongs to a gene family of lipid kinases involved in many cellular processes, including cell growth, proliferation, differentiation, motility, and survival. PIK3CA is mutated in more than 30% of Cancer Control 343 colorectal cancer cases.126 By contrast, mutations in PIK3CA have been found in 1% to 3% of all types of NSCLC.126,127 Similar to BRAF, no reports have been published that have assessed racial and ethnic differences of PIK3CA mutations in the setting of lung cancer, likely because this mutation is rare in this patient population. ALK Anaplastic lymphoma kinase is a tyrosine kinase receptor abnormally expressed by forming a fusion gene with one of several other genes, by gaining additional gene copies, or by somatic mutations. The EML4-ALK fusion was first documented in 2007 in NSCLC as a potentially novel oncogenic-driver mutant kinase.128 Approximately 3% to 7% of all lung tumors harbor ALK fusions, and EML4-ALK fusions are usually found in light- or never-smokers and are typically diagnosed at a young age.128-132 EML4-ALK rearrangements may differ across different racial groups. The frequency of translocation ranges from between 2.3% and 6.7% among Asians.133-135 By contrast, EML4-ALK rearrangement is lower in whites and ranges from 1.0% to 3.0%.128,131,136 One study analyzed a cohort of NSCLC samples collected from Italy and Spain and found that 7.5% of the samples expressed EML4-ALK transcripts — a finding more similar to the data seen in Asians than whites.137 Conclusions Lung cancer is the most common cancer in the world and the second most common cancer in both men and women in the United States.1-3 Although lung carcinogenesis is a multifactorial process driven by exogenous exposure (eg, cigarette smoking), inherited genetic variations, and an accumulation of somatic genetic events, it also appears to have racial and ethnic differences. However, many observed racial and ethnic disparities in lung cancer are not fully understood. The genomic diversity of oncogenes and tumor-suppressor genes across racial and ethnic groups poses unique but important challenges for therapeutic opportunities to provide personalized medicine. Molecular genomic profiling for specific alterations is necessary to identify patients likely to benefit from targeted therapy. As such, identifying novel but actionable targetable mutations exclusive to specific racial and ethnic groups is critical to ensure these populations benefit from such therapies. Even after smoking cessation is successfully accomplished, former smokers remain at significant risk of developing lung cancer.19 Although effective smoking cessation programs and early cancer detection will reduce the overall lung cancer burden, improvements to the access of these modalities and the affordability of health care are important topics to address.55 Screen344 Cancer Control ing with low-dose helical computed tomography can mitigate the risk because it can detect early-stage lung cancer.54,55 Identifying and addressing cultural factors may also help improve the implementation of racially and ethnicity sensitive, population-based interventions. Identifying and eliminating regional and racial and ethnic differences in lung cancer could contribute to more effective, preventive treatment strategies to help reduce the disproportionate burden of lung cancer in the United States.43 References 1. American Cancer Society. 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Distinct clinical features and outcomes in never-smokers with nonsmall cell lung cancer who harbor EGFR or KRAS mutations or ALK rearrangement. Cancer. 2012;118(3):729-739. 136. Shinmura K, Kageyama S, Tao H, et al. EML4-ALK fusion transcripts, but no NPM-, TPM3-, CLTC-, ATIC-, or TFG-ALK fusion transcripts, in non-small cell lung carcinomas. Lung Cancer. 2008;61(2):163-169. 137. Martelli MP, Sozzi G, Hernandez L, et al. EML4-ALK rearrangement in non-small cell lung cancer and non-tumor lung tissues. Am J Pathol. 2009;174(2):661-670. October 2016, Vol. 23, No. 4 We must continue to focus attention and effort to reduce the disproportionate burden of cancer among blacks living in the United States. Cactus. X-Ray image courtesy of Bryan Whitney. www.x-rayphotography.com. Black Heterogeneity in Cancer Mortality: US-Blacks, Haitians, and Jamaicans Paulo S. Pinheiro, MD, PhD, Karen E. Callahan, MPH, Camille Ragin, PhD, MPH, Robert W. Hage, MD, PhD, DLO, MBA, Tara Hylton, MPH, and Erin N. Kobetz, PhD, MPH Introduction: The quantitative intraracial burden of cancer incidence, survival and mortality within black populations in the United States is virtually unknown. Methods: We computed cancer mortality rates of US- and Caribbean-born residents of Florida, specifically focusing on black populations (United States, Haiti, Jamaica) and compared them using age-adjusted mortality ratios obtained from Poisson regression models. We compared the mortality of Haitians and Jamaicans residing in Florida to populations in their countries of origin using Globocan. Results: We analyzed 185,113 cancer deaths from 2008 to 2012, of which 20,312 occurred in black populations. The overall risk of death from cancer was 2.1 (95% CI: 1.97–2.17) and 1.6 (95% CI: 1.55–1.71) times higher for US-born blacks than black Caribbean men and women, respectively (P < .001). Conclusions: Race alone is not a determinant of cancer mortality. Among all analyzed races and ethnicities, including Whites and Hispanics, US-born blacks had the highest mortality rates while black Caribbeans had the lowest. The biggest intraracial difference was observed for lung cancer, for which US-blacks had nearly 4 times greater mortality risk than black Caribbeans. Migration from the islands of Haiti and Jamaica to Florida resulted in lower cancer mortality for most cancers including cervical, stomach, and prostate, but increased or stable mortality for 2 obesity-related cancers, colorectal and endometrial cancers. Mortality results in Florida suggest that US-born blacks have the highest incidence rate of “aggressive” prostate cancer in the world, rather than Caribbean men. Introduction Cancer is the second leading cause of death among blacks in the United States. In relative terms, black men and women suffer the largest cancer burden, with higher mortality and lower survival compared to all major racial-ethnic groups: whites, Asians, Hispan- From the School of Community Health Sciences University of Nevada Las Vegas, Las Vegas, Nevada (PSP, KEC), the African-Caribbean Cancer Consortium (PSP, CR, RWH), College of Public Health, Temple University and Fox Chase Cancer Center, Philadelphia, Pennsylvania (CR), Department of Anatomy, St. George's University, St. George’s, Grenada, West Indies (RWH), Florida Department of Health, Tallahassee, Florida (TH), and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida (ENK). Submitted November 23, 2015; accepted March 4, 2016. This document is the unedited authors’ version of a submitted work that was accepted for publication. Address correspondence to Paulo S. Pinheiro, MD, PhD, University of Nevada Las Vegas, School of Community Health Sciences, AfricanCaribbean Cancer Consortium, 4505 South Maryland Parkway, Las Vegas, NV 89154. E-mail: [email protected] No significant relationships exist between the authors and the companies/organizations whose products or services may be referenced in this article. Data provided by the Florida Department of Health, Bureau of Vital Statistics. Any conclusions are the authors’ own and do not necessarily reflect the opinion of the Florida Department of Health. Dr Pinheiro is sponsored by 8 P20 GM103440-11 from the National Institute of General Medical Sciences as a NV/INBRE recipient. October 2016, Vol. 23, No. 4 Cancer Control 347 ics, and American Indians.1,2 Black males also have the greatest cancer incidence.2 These cancer disparities by race are the result of a complex and entangled web of differences in risk factors that directly impact not only cancer incidence, but also access to and availability of early detection and timely treatment. In turn, these affect the capacity to successfully combat cancer, thus impacting cancer survival. Cancer mortality is a result of the interplay between both incidence and survival. Assessing each of these 3 components — incidence, survival, and mortality — is critical to understanding how disparities between populations arise and how they can be reduced or eliminated. Black men and women in the United States are often categorized under a single ostensibly homogenous umbrella: blacks, United States blacks, African Americans, or people of African descent. For researchers, the use of different denominations for describing populations can lead to confusion. “United States blacks”, commonly used for data collection, may or may not characterize blacks born outside of the United States, and “African descent” may include North African populations. For well-documented historical reasons, the vast majority of black people living in the Western hemisphere are genetic admixtures of African, European, and/or Native American populations, warranting caution when attributing risk to race, a social construct.3 Most importantly, however, the use of one aggregate term obscures considerable heterogeneity in health outcomes among the black population in the United States, irrespective of whether these differences are attributable to biological, cultural, or socioeconomic factors.4 Blacks born outside the United States number 3.8 million in the United States, nearly 9% of the black population.5 According to Census projections, this percentage will reach 17% by 2060.6 Substantial black immigration into the United States is a recent dynamic following the Immigration America Act of 1963.7 The majority of black immigrants come from English and French speaking nations of the Caribbean, led by Jamaica and Haiti, the birthplace of 18% and 15% of United States-black immigrants in 2013.6 To the extent that health is partially determined by social and cultural factors, including beliefs on disease etiology, types of family structure and social support, expectations regarding medical care, as well as cumulative lifetime exposure to cancer risk factors, aggregating these distinct Caribbean populations together with blacks who have been in the United States for generations may limit the ability to detect and address culturally driven determinants of health outcomes among all black heterogeneous sub-populations.4,8,9 Two studies have shown lower overall cancer mortality for blacks born outside of the United States than for US-born.10,11 Yet a more detailed analysis of the intraracial cancer heterogeneity in black populations 348 Cancer Control living in the United States is non-existent. Problems studying this topic derive from limitations in the available incidence and survival data. First, cancer registries do not collect demographic data on black ancestries. Secondly, the collection of birthplace is substantially incomplete in the United States cancer surveillance programs.12,13 These limitations have impeded unbiased cancer incidence and survival studies of these populations.14-16 Birthplace reporting on death certificates, however, is nearly complete. Thus, mortality data can be a valuable source of information for assessing the intraracial cancer heterogeneity among blacks in the United States. Here we use cancer mortality data for Florida, a state with a 19% immigrant and 17% black population,17 to analyze cancer outcome heterogeneity. First, we compare US-born populations of all races with Hispanic Caribbean populations and majority-black Caribbean populations born outside the United States. Then, we compare US-born blacks with majority-black Caribbean populations. Within the latter, we look specifically at Haitians, Jamaicans, and other West Indian populations. Through this analysis we aim to characterize race-specific patterns of cancer mortality, explore the intraracial heterogeneity in blacks, and make a contribution that will assist health policy makers in shaping targeted cancer prevention and control efforts to reduce health inequities in cancer outcomes in the United States. Materials and Methods Cancer Data Cancer mortality data for 5 years, January 1, 2008 through December 31, 2012, were obtained from the Florida Department of Health Vital Statistics.18 We considered only resident cases in the state. We analyzed the most common causes of cancer death: lung and bronchus, breast, prostate, colorectal, pancreas, corpus uteri (endometrial); and cancers of special interest in populations born outside the United States: cervix uteri, liver, stomach; and all-sites-combined, which included all cases of malignant cancers. Cancer site was coded according to the International Statistical Classification of Diseases 10th revision. We examined the cancer mortality burden at 2 levels of comparison. First, all Florida populations regardless of race and based on birthplace alone: USborn populations and the following 2 immigrant Caribbean populations: Hispanic Caribbean, including Cuba, the Dominican Republic and Puerto Rico, and majority-black Caribbean including Haiti, Jamaica and Other West Indies (OWI). Haiti and Jamaica are considered separately as they are the 2 largest non-Hispanic Caribbean immigrant groups in Florida as well as the United States.7 The OWI category included the following territories and island nations: Anguilla, Antigua October 2016, Vol. 23, No. 4 and Barbuda, Aruba, Bahamas, Barbados, Cayman Islands, Dominica, Grenada, Guadeloupe, Martinique, Montserrat, Saint Kitts and Nevis, Saint Barthelemy, Saint Lucia, Saint Martin, Saint Vincent and the Grenadines, the Netherlands Antilles, the British Virgin Islands, Trinidad and Tobago, Turks and Caicos, and West Indies not otherwise specified. The vast majority of immigrants from these nations are black, including 99% of all Haitians immigrants and 96% of all Jamaicans.7 Thus, while recognizing that a small number of immigrants born in these countries may not be black, we will for the purposes of this paper refer to these populations as black Caribbean. To strictly adhere to the Caribbean definition as a geographical region distinct from the continental Americas, Belize and Guyana, (although also majority black populations), were excluded from the OWI category. Second, we examined a subset of the Florida population, based on race for US-born populations and birthplace for those born in the Caribbean. We compare US-born blacks with the black population born outside the United States. Caribbean populations combined (Haiti, Jamaica, and OWI), as well as the 2 largest populations, Haitians and Jamaicans. For simplicity purposes in the current study, the Haitian-born, Jamaicanborn, and those born in other West Indies (OWI), and Hispanic Caribbean-born populations are referred to as Haitian, Jamaican, OWI and Hispanic Caribbean. The designation US-blacks will exclusively refer to USborn blacks. Non-Hispanic black populations from Africa or elsewhere outside the United States or the Caribbean were excluded from this study. These excluded populations are relatively young with a more recent immigration history,6,7 and accounted only for 1% — approximately 40 deaths annually — of all cancer deaths in Florida among blacks in 2008–2012. Population Data The American Community Survey estimates for 2010 indicated that 30% (795,500) of the total 2.6 million people of non-Hispanic West Indian ancestry in the United States, lived in Florida.19 Of the 2.4 million blacks in Florida, 33% were of Caribbean ancestry, representing the highest proportion of a Caribbean black-majority population in any American state.19 Since specific ancestry information is unavailable for cancer mortality data, we are using birthplace. While ancestry and birthplace are not exactly overlapping, the overwhelming majority of the Caribbean population in the United States aged 30 and above was born outside the United States.6,7 These older age groups are also the ones where cancer will be an important cause of death; therefore, birthplace and ancestry are not likely to result in substantially different mortality numbers. Looking at birthplace alone in Florida in 2010, October 2016, Vol. 23, No. 4 there were 14.6 million US-born (10.2 million whites, 2.4 million blacks, 2 million other races); 1.3 million Hispanic Caribbean-born; and 570,000 black Caribbean-born (277,000 Haitians, 196,000 Jamaicans and 97,000 OWIs).19 Population denominators for the State of Florida were obtained from the 5-year 2008–2012 American Community Survey using the University of Minnesota interface,20 thus serving the same years as our mortality data. Population numbers were grouped by birthplace and by gender for all groups, and also by race for the US-born. Data Analysis A very small number of cases of non-Hispanic blacks with unknown birthplace (n = 145, 0.7% of the total) were proportionally reassigned by imputation models stratified by age, sex, and cancer site into the United States, Haiti, Jamaica, OWI, and all other non-US birthplaces as described elsewhere.21 Cancer mortality rates for 2008–2012 were calculated per 100,000 persons, annualized and age-standardized to the 2000 US Standard Population and the 2000 World Standard Population using eighteen age group bands, all 5-year except the last, which was 85 and older. We used mortality and population data for a period of 5 years (2008–2012), accumulating cancer mortality data for a total of 2.85 million person-years for black Caribbean populations. Corresponding 95% confidence intervals (CIs) were calculated with gamma intervals modification.22 Site-specific mortality ratios with 95% CIs were computed by using Poisson regression adjusted for 5-year age groups starting at age 35, except for prostate cancer where the groups started at age 50. Because breast cancer risk factors differ between preand post-menopausal women and these rates differ by race,23 we used approximate pre- and post-menopausal ages, using 50 as our dividing age, to calculate preand post- menopausal ratios. SAS 9.3 (SAS Institute Inc., Cary, NC, USA) was used for data analysis. The OWI cancer burden in Florida was distributed between more than 20 different countries and territories of origin, the largest of which were Trinidad and Tobago at 34%, Bahamas at 22% and Barbados at 9%. This diverse origin as well as relatively small numbers makes interpretation of the results difficult. Moreover, unlike Haiti and Jamaica, some of these countries have a more diverse racial composition, including Trinidad and Tobago, with a 38% East Indian population.7 Nonetheless, we present OWI data to demonstrate Caribbean completeness. Finally, we calculated age-adjusted mortality rates, adjusted to the 2000 World Standard, for Haitian and Jamaican immigrant populations and well as US-born blacks living in Florida. For comparison purposes, we used the best availCancer Control 349 able data from each of these countries, the 2009-2011 avliver cancers. Both Hispanic and black Caribbean poperage cancer mortality rates from the World Health Orgaulations had lower rates for lung, pancreas and breast nization Mortality Database24 for Jamaica, and the 2012 cancers when compared to the US-born population. Globocan25 estimates for Haiti. This study was approved by the University of Nevada, Table 1. — Average Annual Age-Adjusted* Mortality Rates for Selected Cancers Las Vegas Institutional Review (per 100,000) by Birthplace: Florida, 2008–2012 Board. A data use agreement US-Born Born Outside the United States was obtained from the Florida United States Hispanic Caribbean** Majority Black Vital Statistics Department. All Races All Races Caribbean All Races Results A total of 841,054 deaths were recorded among Florida residents during 2008–2012; 185,113 were deaths attributed to cancers in US-born and Caribbean-born populations (Table 1). There were 16,119 cancer deaths in US-blacks, and 4,113 among black Caribbeans. People born in Jamaica accounted for 43% of these deaths, those from Haiti, 38%, and from OWI countries, 19%. For 2008–2012 in Florida, cancer was the leading cause of death for US-born women as well as for the black Caribbean populations. It accounted for 27.2% of all deaths among Jamaicans and 23.7% among Haitians. Cancer ranked second only to heart disease as the leading cause of death among the US-born male population as well as males and females born in Hispanic Caribbean countries. In comparison to the total US-born Florida population, both black Caribbeans and Hispanic Caribbeans have lower all-sites-combined cancer mortality rates. However, there is considerable heterogeneity in the rates between them and by cancer site (Tables 1-2). For black Caribbeans, there were significantly higher mortality rates for stomach, prostate and endometrial cancers than the US-born; among Hispanic Caribbeans, mortality rates were higher for stomach and 350 Cancer Control Deaths Rate (95% CI) Deaths Rate (95% CI) Deaths Rate (95% CI) Stomach 1,386 3.2 (3.0–3.4) 235 4.7 (4.2–5.5) 97 6.7| (5.4–8.4) Colorectal 7,455 16.9 (16.6–17.3) 917 18.2 (17.1–19.5) 206 13.8 (11.9–16.1) Liver and Intrahepatic Bile Duct 3,766 8.4 (8.1–8.7) 476 9.3 (8.5–10.3) 109 6.9 (5.6–8.5) Pancreas 5,392 12.1 (11.7–12.4) 540 10.6 (9.7–11.6) 128 9.1 (7.5–11.1) Lung and Bronchus 28,023 62.3 (61.6–63.1) 2,287 44.7 (42.8–46.6) 317 21.0 (18.6–23.6) Prostate 7,936 17.9 (17.5–18.3) 943 19.1 (17.9–20.4) 437 35.5 (32.1–39.3) All combined 89,387 201.7 (200.4–203.1) 8,487 169.4 (165.7–173.2) 2,020 141.4 (134.9–148.2) Stomach 911 1.7 (1.6–1.8) 173 2.6 (2.2–3.2) 92 4.6 (3.7–5.8) Colorectal 6,335 11.7 (11.4–12.0) 855 12.4 (11.6–13.4) 243 11.9 (10.4–13.6) Liver and Intrahepatic Bile Duct 1,518 2.8 (2.7–3.0) 260 3.8 (3.3–4.4) 76 3.9 (3.0–5.0) Pancreas 4,874 8.9 (8.7–9.2) 537 7.6 (7.0–8.4) 129 6.4 (5.4–7.8) Lung and Bronchus 22,217 41.9 (41.4–42.5) 1090 16.1 (15.2–17.2) 194 9.8 (8.4–11.4) Breast 10,819 21.6 (21.2–22.1) 1,100 17.5 (16.4–18.6) 413 19.1 (17.3–21.2) Premenopausal, less than 50 1,141 3.9 (3.7–4.1) 100 2.6 (2.1–3.2) 97 4.8 (3.9–6.0) Postmenopausal, 50 or more 9,678 17.8 (17.5–18.2) 1,000 14.9 (14.0–15.9) 316 14.3 (12.7–16.1) Cervix Uteri 1,140 2.8 (2.6–3.0) 138 2.6 (2.2–3.2) 68 3.3 (2.5–4.3) Corpus and Uterus (endometrial) 1,975 3.8 (3.6–4.0) 278 4.2 (3.7–4.8) 152 7.3 (6.2–8.7) All combined 74,241 141.4 (140.4–142.5) 6,890 104.6 (102.1–107.3) 2,093 103.6 (98.7–108.8) Male Female *2000 US Standard Population **Cuba, Dominican Republic and Puerto Rico October 2016, Vol. 23, No. 4 Table 2. — Average Annual Age-Adjusted* Mortality Rates for Selected Cancers per 100,000 for US-Born and Blacks Born Outside the United States: Florida, 2008–2012 US-Born Blacks Born Outside the United States Black Caribbean** All Races Haitian All Races Jamaican All Races Other West Indian (OWI) All Races Deaths Rate (95% CI) Deaths Rate (95% CI) Deaths Rate (95% CI) Deaths Rate (95% CI) Deaths Rate (95% CI) Stomach 292 9.4 (8.3–10.6) 97 6.7 (5.4–8.4) 45 7.4 (5.2–10.3) 39 6.8 (4.8–11.9) <15 5.0 (2.4–14.5) Colorectal 895 28.3 (26.3–30.4) 206 13.8 (11.9–16.1) 83 12.4 (9.7–15.8) 86 14.7 (11.6–20.3) 37 15.4 (10.4–25.7) Liver and Intrahepatic Bile Duct 436 11.0 (9.9–12.2) 109 6.9 (5.6–8.5) 69 9.4 (7.2–12.2) 28 4.6 (3.0–9.6) <15 4.5 (2.0–14.0) Pancreas 474 14.7 (13.3–16.2) 128 9.1 (7.5–11.1) 34 5.0 (3.4–7.4) 63 11.5 (8.8–17.0) 31 11.6 (7.5–21.4) Lung and Bronchus 2,536 78.9 (75.6–82.3) 317 21.0 (18.6–23.6) 105 17.5 (14.1–21.6) 153 25.1 (21.1–31.2) 59 21.2 (15.6–31.7) Prostate 1,218 50.6 (47.6–53.7) 437 35.5 (32.1–39.3) 142 29.2 (24.3–34.7) 194 37.8 (32.4–45.2) 101 44.0 (35.0–57.3) All combined 8,575 273.9 (267.6–280.3) 2,020 141.4 (134.9–148.2) 753 124.5 (115.1–134.6) 883 154.4 (143.9–166.4) 384 148.3 (132.2–167.6) Stomach 179 4.0 (3.4–4.6) 92 4.6 (3.7–5.8) 42 4.9 (3.5–6.9) 31 3.7 (2.5–6.8) 19 6.4 (3.8–11.8) Colorectal 809 17.7 (16.5–19.0) 243 11.9 (10.4–13.6) 75 8.6 (6.7–11.1) 122 14.2 (11.8–18.1) 46 13.4 (9.7–19.5) Liver and Intrahepatic Bile Duct 169 3.6 (3.0–4.1) 76 3.9 (3.0–5.0) 37 4.6 (3.2–6.6) 28 3.3 (2.2–6.5) <15 3.4 (1.6–8.2) Pancreas 532 11.8 (10.8–12.8) 129 6.4 (5.4–7.8) 53 6.7 (5.0–9.0) 47 5.3 (3.9–8.6) 29 9.3 (6.1–15.0) Lung and Bronchus 1,473 32/3 (30.6–34.0) 194 9.8 (8.4–11.4) 66 8.6 (6.6–11.2) 95 11.1 (8.9–14.7) 33 10.3 (7.0–16.1) Breast 1,514 32.1 (30.4–33.7) 413 19.1 (17.3–21.2) 158 17.0 (14.4–20.2) 187 21.1 (18.2–25.4) 68 19.0 (14.6–25.6) Premenopausal, less than 50 298 6.2 (5.5–6.9) 97 4.8 (3.9–6.0) 50 5.2 (3.9–7.1) 38 5.2 (3.7–8.6) <15 2.6 (1.2–7.3) Postmenopausal, 50 or more 1,216 25.9 (24.4–27.4) 316 14.3 (12.7–16.1) 108 11.8 (9.6–14.6) 149 15.9 (13.5–19.2) <68 16.4 (12.4–22.7) Cervix Uteri 267 5.5 (4.8–6.2) 68 3.3 (2.5–4.3) 36 3.9 (2.7–5.7) 20 2.6 (1.6–5.8) <15 3.6 (1.8–8.5) Corpus and Uterus (endometrial) 373 8.1 (7.3–9.0) 152 7.3 (6.2–8.7) 49 5.7 (4.2–7.8) 75 8.6 (6.7–12.1) 28 7.6 (5.0–12.8) All combined 7,544 163.2 (159.5–167.0) 2,093 103.6 (98.7–108.8) 798 95.6 (88.5–103.3) 902 105.4 (98.4–113.4) 393 121.3 (106.8–137.8) Male Female *2000 US Standard Population **Haiti, Jamaica and OWI combined October 2016, Vol. 23, No. 4 Cancer Control 351 When narrowing the comparisons to Haitian, Jamaican, and US-black populations in Florida, the cancer mortality rate differences are surprisingly even greater (Table 2). Haitians have the lowest mortality rates for all cancers combined, 125 per 100,000 among males and 96 per 100,000 in females, followed closely by Jamaicans with 154 and 105 per 100,000 among males and females, respectively. Contrasting with these relatively low rates, US-blacks had high mortality rates, 274 per 100,000 for males and 163 per 100,000 for females. The risk of cancer death in US-black males is 2.1 times higher than among black Caribbean males and 1.6 times higher for black Caribbean females (P < .05). Of all cancers examined, lung cancer has the greatest risk differential. US-blacks compared to black Caribbeans have an astonishing 4 times greater risk of lung cancer death among males and a 3.5 times greater risk among females (Table 3). The leading cause of cancer mortality among USblack males was lung cancer, at 78.9 per 100,000, followed distantly by prostate cancer at 50.6 per 100.000. For black Caribbean males the opposite was true: pros- Table 3. — Mortality Rate Ratios for Selected Cancers: Florida, 2008–2012 US-Born Blacks in Relation to Black Caribbean (Reference Population) Rate Ratio 95% CI 1.4 (1.13–1.80) Male Stomach Colorectal 2.1 (1.81–2.46) Liver and Intrahepatic Bile Duct 1.9 (1.55–2.39) tate cancer mortality was highest, at 35.5 per 100,000, followed by lung cancer at 21.0 per 100,000 (Table 2). Across the male populations of US-blacks, Jamaicans, Haitians, and OWIs, colorectal was the third leading cause of cancer death, while pancreatic cancer was fourth, except among Haitians for whom liver cancer was fourth. Among US-black women in Florida, the 2 most common causes of cancer mortality were lung and breast, almost equal at 32.3 and 32.1 per 100,000 respectively, followed by colorectal and pancreatic cancers. For black Caribbean women, breast cancer was by far the leading cause of cancer mortality at 19.1 per 100,000, with colorectal cancer second and lung cancer only third (Table 2). Still, US-black women had a 1.7 times greater overall mortality risk for breast cancer than black Caribbean women, although pre-menopausal breast cancer risk was only 1.3 times higher (Table 3). Endometrial cancer was the fourth leading cause of cancer death for black Caribbean women. Notably, cervical cancer rates were relatively low across black Caribbean female populations. Lastly, the cancer mortality rates of Haitian and Jamaican populations residing in Florida when compared to the rates in their respective countries of origin are lower for both males and females for all cancer sites combined (Table 4). This advantage is most marked for cervix, stomach, and prostate cancers for both countries, liver cancer for Haitians and female breast for Jamaicans. On the other hand, for colorectal (male and female), endometrial, and pancreatic cancers, mortality rates are higher for Haitians and relatively similar for Jamaicans in Florida in comparison to rates found in the countries of origin. Also higher in Florida than in countries of origin are rates for lung cancer among Haitian males and Jamaican females as well as breast cancer among Haitian females (Table 4). Pancreas 1.8 (1.45–2.15) Lung and Bronchus 4.0 (3.51–4.45) Prostate 1.4 (1.29–1.61) Discussion All combined 2.1 (1.97–2.17) Stomach 0.9 (0.66–1.09) Colorectal 1.5 (1.30–1.73) This is the first study to address intraracial differences in cancer mortality among persons often categorized under the US-blacks designation. Using birthplace, we differentiate and directly compare black populations born in and outside the United States, presenting the first quantification of the cancer burden for black Caribbeans. In Florida, cancer mortality rates for US-blacks are higher than all analyzed groups. However, black Caribbean populations have the lowest rates, suggesting that racial health disparities in the United States are attributable to more than socioeconomic status (SES) and health care access, for which Caribbeans are likely to be at least equally as disadvantaged as US-blacks. The major contributor for the relatively low overall cancer mortality in blacks born outside the United States is the difference in lung cancer rates. This is most likely a reflection of differences in smoking hab- Female Liver and Intrahepatic Bile Duct 1.0 (0.77–1.34) Pancreas 1.9 (1.55–2.27) Lung and Bronchus 3.5 (2.99–4.03) Breast 1.7 (1.48–1.84) Pre-menopausal, less than 50 1.3 (0.99–1.60) Post-menopausal, 50 or more 1.8 (1.55–1.99) Cervix Uteri 1.7 (1.30–2.24) Corpus and Uterus (endometrial) 1.1 (0.93–1.35) All combined 1.6 (1.55–1.71) *Poisson regression rate ratios adjusted for age group 352 Cancer Control October 2016, Vol. 23, No. 4 represent a healthier sample of the population than those who remain in the country Haitians US-Blacks Jamaicans US-Blacks of origin.32 Having said that, immigrants also likely carry In country In Florida In Florida In Country In Florida In Florida of origin, of Origin, with them baseline protective Haiti Jamaica factors inherent to their counMale tries of origin that are persisStomach 8.7 5.1 6.3 9.6 4.9 6.3 tent in reducing risk, and resistant to the negative effects Colorectal 4.6 9.2 19.3 9.8 10.7 19.3 of acculturation, as has been Liver and 7.5 7.4 8.8 3.1 4.0 8.8 shown for Hispanics, particuIntrahepatic Bile Duct larly for Mexican Hispanics.21 Pancreas 2.6 3.6 10.3 3.1 7.2 10.3 Caribbean immigrants in the United States tend to maintain Lung and 6.6 11.9 55.1 24.1 18.7 55.1 Bronchus traditional dietary patterns Prostate 32.3 17.3 28.8 40.1 22.2 28.8 that include less red meat consumption and higher intake of All-site 88.4 85.6 186.3 131.8 107.4 186.3 combined whole grains, fruits and vegFemale etables, which are protective against colorectal and cancers Stomach 6.0 3.6 2.6 4.1 2.7 2.6 of the upper gastrointestinal Colorectal 5.8 6.4 12.3 9.7 9.5 12.3 tract.33-36 Also, fertility rates Liver and 5.1 3.2 2.6 2.4 2.2 2.6 and breastfeeding patterns Intrahepatic Bile Duct may help explain breast cancer differences.23 Several studPancreas 2.3 4.6 8.2 3.1 3.5 8.2 ies demonstrated significantly Lung and 6.2 5.6 23.1 6.0 7.5 23.1 Bronchus higher odds of breastfeeding initiation among immigrant Breast 11.5 13.4 24.0 21.5 16.0 24.0 black women than US-born Cervix uteri 14.6 3.1 4.4 12.8 2.0 4.4 blacks.37-39 Overall, the lower Corpus and 1.4 4.2 6.0 6.6 5.9 6.0 rates we found for breast and Uterus (endometrial) colorectal cancers among black Caribbeans are all the All-site 80.3 69.2 117.7 99.7 75.0 117.7 combined more surprising in light of previous studies document*Average annual age-adjusted to 2000 World Standard. Country of origin data: Haiti, GLOBOCAN 2012; Jamaica, WHO Mortality Database 200–2011 average. ing lower rates of mammography and colonoscopy among blacks born outside the United its 2 to 4 decades ago. In 1980, the prevalence of smokStates, especially Haitians, in comparison to US-born ing in Haiti (18% males, 6% females) and Jamaica blacks.40-43 Additionally, if they are of low SES, non– (27% males, 7% females) was much lower than in USUS-citizen immigrants are less likely than citizens to blacks (45% males, 31% female).26 Moreover, studies have had consistent health insurance.44 In the case of have documented that blacks born outside the United the undocumented or recently documented, access is States are less likely to smoke than their US-born counblocked to any federal assistance programs in Florida terparts.27,28 The risk factor of smoking may also acexcept limited emergency Medicaid.45 count for some of the differences seen in stomach and While most intraracial cancer mortality differences pancreatic cancers, as well as other tobacco-related in our study seem to be determined by environmental cancer sites like bladder, larynx, and oral cavity which factors, some of which are inherently related to place are included in the all sites combined category.29 of birth, it is important to note that some patterns are Our lower cancer mortality findings among Caribseemingly more related to race and possibly genetics, bean blacks may be partially explained by the Healthy regardless of geography. Endometrial, premenopausImmigrant Effect (HIE), whereby immigrants have betal breast (defined here as below age 50) and prostate ter overall health outcomes not solely related to observcancer rates reveal specific vulnerabilities. Compared able socioeconomic factors such as education and into other groups, all black populations (US-blacks, come.10,30,31 In other words, those who immigrate may Haitians, and Jamaicans) have higher mortality for Table 4. — Mortality Rates* (per 100,000) for Selected Cancers for Haitians and Jamaicans in Country of Origin and in Florida and for US-Blacks: Florida, 2008–2012 October 2016, Vol. 23, No. 4 Cancer Control 353 these 3 cancers. Endometrial cancer is a cancer of the Western world,46 highly related to obesity,36 whose prevalence commonly increases among first generation immigrants to the United States.21 Studies have shown that endometrial cancer survival and mortality outcomes for black women, even after adjustment for their higher proportion of hysterectomies, are worse than all other racial groups.47,48 Black women also have an elevated risk of more aggressive tumor subtypes with poorer prognosis.48,49 For premenopausal breast cancer, the finding of high mortality among all analyzed black populations relative to the all US races category as well as Hispanic Caribbeans is intriguing and requires further study. Given the lack of detailed incidence data for each of these populations, it is impossible to assess whether this finding can be attributed to the well-documented survival disparity between blacks and Whites in the United States,50 or if it reflects a true increased risk for premenopausal breast cancer among black women. For prostate cancer, black African descent has been well established as a risk factor.1,51,52 Our results confirm high rates among both US-born and Caribbean-born blacks. However, the significantly higher rates we find for US-blacks compared to Caribbeanborn blacks is notable, given the lower prostate cancer screening rates for the latter compared to the former.40,53,54 While prostate cancer incidence rates are challenging to compare globally due to increased use of prostate-specific antigen (PSA) screening in some countries,55,56 mortality rates in Florida likely reflect the incidence of aggressive prostate cancer. Thus, our study is highly indicative of US-blacks having the highest aggressive prostate cancer incidence in the world, not Caribbeans as previously suggested.57 Three infection-related cancers — cervical, liver and stomach cancer — are more commonly found in developing countries.46 Strangely, the mortality rates are similar or even higher for US-blacks compared to the black populations born outside the United States. For cervical cancer, despite the fact that the pap test screening rates are higher among US-black women than Caribbean-born black women23,53,58 which would predict earlier stages at diagnosis with better prognosis, the mortality rates for cervical cancer are higher in US-blacks than Caribbean-born black women. For liver cancer, it is possible that the epidemiology and patterns of transmission are different between these populations, resulting in different gender-specific incidence and thus mortality. Hepatitis C, a more common liver cancer risk factor than hepatitis B in the United States, is largely transmitted by sharing contaminated intravenous drug needles.59 The greater differential in liver cancer between males and females in US-blacks than in Caribbean blacks may be the result of greater IV drug use among US-black men than US-black wom354 Cancer Control en.60 For Caribbeans, Hepatitis B likely accounts for the high rates, especially among Haitians,61 and would not result in a marked gender difference. As a result, liver cancer mortality rates are higher for US black males but similar between US-black females and black Caribbean females in our study. Haitians and Jamaicans were clearly distinct in their cancer mortality patterns, although the precision of the statistical comparisons may be impacted by the relatively small size of the populations in Florida. Haitians had lower all-sites-combined mortality rates than Jamaicans as well as all other analyzed populations. However, for all 3 infection-related cancers, liver, cervical and stomach, Haitian mortality rates exceeded those of Jamaicans. Haitian rates were lower than Jamaicans’ for prostate, breast, endometrial and colorectal cancers: all cancers commonly associated with a “Western” lifestyle.62 Jamaicans have a longer immigration history in Florida than Haitians;20 therefore it is possible that these differences reflect acculturation patterns, predicted by length of time in the United States, and the extent of assimilation into US culture, which may be greater for English-speaking Jamaicans. Additionally, since the country of Jamaica has been more developed than Haiti for at least the past 25 years,63 the prevalence of baseline immigrant risk factors such as obesity may already be more “Westernized”.64 Additional important findings arise from the examination of differences in mortality rates between Haitians and Jamaicans in their countries of origin compared to those same populations in Florida. Since mortality is a function of cancer incidence and survival, changes in mortality rates may reflect a difference in either or both of these. If the healthcare infrastructure in Florida is better than in Jamaica and Haiti, we would expect cancer survival to be higher, and thus mortality rates to be lower among Jamaicans and Haitians in Florida than in their countries of origin. Despite the fact that survival data accuracy for blacks born outside the United States can be problematic,16 some studies have documented this pattern.65-68 On the other hand, if Caribbeans living in Florida have higher or even stable cancer mortality rates compared to their counterparts in their countries of origin, then these changes likely reflect true increases in incidence rather than decreases in survival. In our study, mortality rates for Haitians and Jamaicans in Florida compared to their countries of origin were predictably lower for all 3 infection-related cancers, except for liver cancer in male Jamaicans. Stomach cancer gains are likely attributable to a higher standard of living in the United States coinciding with a lower prevalence of infection with Helicobacter pylori.69,70 Likewise, lower liver cancer mortality rates in Florida populations compared to their countries of origin suggest lower incidence, at least in part due to October 2016, Vol. 23, No. 4 a lower prevalence among US blacks (0.9%) of chronic hepatitis B compared to prevalence in Jamaica (3.7%) or Haiti (13.6%).61,71 Gains for cervical cancer were substantial in both Haitian and Jamaican populations in Florida, with mortality rates reduced to less than 25% of the rates in their countries of origin. This likely reflects improved access to health care, including screening and radiotherapy treatment, which would impact incidence and survival, respectively. The same likely applies to the substantial improvement for female breast cancer among Jamaicans. We also found an advantage for prostate cancer for immigrants living in Florida. Mortality rates among Haitians and Jamaicans are substantially lower in Florida than in the country of origin. This is not remarkable given the complexity of prostate cancer control: including screening, computed tomography and bone scans for staging, surgery, hormone therapy and radiotherapy. The mortality rates for colorectal cancer in both sexes and endometrial cancer in women suggest an increased risk in Florida compared to the country of origin. For Haitians, the rates are significantly higher than in their countries of origin, while for Jamaicans there is minimal change. Yet, in the United States, access to colorectal screening if utilized would result in either averted cancer by removal of precancerous lesions or earlier cancer diagnosis.72 Moreover, since there is no knowledge of latent forms of either colorectal or endometrial cancers, which eventually progress to death if left untreated, access to better health care facilities should result in improved treatment, prolonged survival, and lower mortality in Florida. Therefore, the lack of decreases seen in mortality for these cancers must be rooted in an increase in incidence, which is a worrisome finding. Unfortunately, a common risk factor for both cancers is obesity.1 Data at the population level shows a trend of increasing prevalence of obesity and transition to a high caloric fatty diet when immigrants settle in the United States.64,73,74 Some of the results did not follow known or expected patterns. Breast cancer has protective risk factors associated with fertility patterns23 that have been shown to change with migration to the United States, including delayed childbearing and a reduction in total number of pregnancies.75,76 In our study, for Haitian females, breast cancer mortality rates were somewhat higher in Florida than Haiti. Offsetting a possible gain in survival due to screening and more access to quality treatment, the increased mortality among Haitians in Florida may well derive from an increased incidence of breast cancer which may be higher due to diminished fertility and delayed childbearing among other factors. On the other hand, for Jamaican women, breast cancer mortality rates were much lower in Florida than in Jamaica. It is possible that Jamaican women in Florida, who tend to have higher levels of education,7 may reap October 2016, Vol. 23, No. 4 the benefit of better health care access. The greater total baseline fertility rate in Haiti than Jamaica (3.1 compared to 2.3 children77) as well as higher obesity rates in Jamaica64 may also play a role in explaining why breast cancer rates in Florida are higher among Jamaican than Haitian women. For lung cancer, for Haitian males and Jamaican females, rates were significantly higher in Florida than Haiti. Lung cancer has a poor survival prognosis regardless of gender, SES, or race, and even location.78 Therefore, this difference would suggest an increase in incidence rather than a change in survival. Yet among Jamaican men, lung cancer rates were much lower in Florida than in Jamaica, suggesting an intriguing decreased incidence. It is possible that these results reflect changes in smoking prevalence when immigrants settle in the United States.79 Given the importance of smoking as a risk factor for many cancers, these changes need to be carefully monitored. Our study has the usual limitations of descriptive epidemiology. There is a lack of both individual level risk factor data for all subjects as well as group level risk factor data specific to Caribbean-born populations in Florida. We also had some relatively small population sizes, which sometimes resulted in a lack of precision in our mortality rates, particularly for the small OWI group. We attempted to mitigate this by accumulating 5 years of mortality experience and annualizing the rates. Another limitation is that Globocan mortality estimates for 2012 for Haitians are modelled, relying on the last date for which real data were available, which may be several years old. Our study examines black populations in Florida, which may not be representative of all black populations in the United States. Additionally, in theory, our mortality numbers could reflect a “salmon bias”, whereby small numbers of immigrants who are very ill return to their home countries of origin to die, which would artificially lower mortality rates for those born outside the United States in our study. However, the magnitude of this out-migration for Hispanics has been found to be very small,80 and the literature for this phenomenon among black immigrants in the United States is non-existent. Relying on birthplace rather than ancestry may result in a small degree of misclassification. Haitian, Jamaican and other West Indian ancestry populations, which may include second generation Caribbeans, are larger than the birthplace populations we used for this study. Some of the people in the US-born blacks category in our study are quite possibly of Haitian, Jamaican or OWI ancestry. However, given the trend of relatively recent immigration for these populations, this would likely only affect cancer sites with mortality in relatively younger age groups, such as cervical cancer. Our Florida mortality data provided information Cancer Control 355 on Haitian ancestry, but not any other Caribbean ancestry. To test for differences between using birthplace and ancestry, we calculated mortality rates using the Haitian ancestry information and found that the differences in rates were negligible, thus reducing the likelihood of a threat to validity based on misclassification. Strengths of our study include the very high completeness (99%) of birthplace information among all deaths in the state of Florida, allowing for reliable classification of the different populations, which is unfortunately never achieved in cancer incidence data. We also used detailed denominators based on birthplace available from the American Community Survey. Overall, cancer mortality rates among black Caribbeans are remarkably low. While there has been much research demonstrating health advantages for Hispanics, our results point to an even greater health advantage for black Caribbeans than Hispanic Caribbeans in Florida. More striking is the markedly worse cancer mortality rates for US-blacks when compared to Caribbean blacks. The low mortality among Caribbean blacks has the effect of improving the overall US cancer rates for blacks. Not surprisingly, of the 17 states with black populations over 1 million, Florida and New York, states with the highest proportions of black Caribbean populations, have the lowest cancer mortality rates for blacks in the United States.1 To our knowledge these are the only results available looking at cancer outcomes on a population basis that analyze US-born blacks separately, directly comparing them to Caribbean-born people residing in the United States. The mortality rates presented here will also constitute a baseline for monitoring the cancer burden among Caribbean populations and help the fight against cancer across all majority-black Caribbean nations. Cancer literature is somewhat scarce for the Caribbean region due to a lack of reliable data. Phillips et al. used estimates from Globocan 2002 data to characterize cancer incidence and mortality in the Caribbean nations.81 However, in a quickly evolving world, these data are possibly now outdated. Fortunately, cancer registration in Jamaica and other Caribbean nations is showing signs of improvement.46 The current study highlights once again the need to thoroughly address known racial disparities in cancer risk and outcomes in the United States. To analyze intraracial differences, it is fundamental to have specific and accurate cancer data, including data on immigrant groups. In states with large Caribbean populations, such as Florida and New York, it would be beneficial to have health data on this population collected methodically as has been done for other racial/ ethnic subgroups in California and New York City. An active role of the North American Central Cancer Registries Association and the central cancer registries in Florida and New York would greatly improve the 356 Cancer Control knowledge of cancer epidemiology among black populations, especially regarding incidence data. Better understanding of intraracial cancer patterns including the extent to which acculturation impacts cancer incidence, survival, and mortality among black US immigrants will help in targeted US cancer prevention and control efforts. Conclusions The US-born black population has the highest cancer mortality risk in the nation — even higher than previously documented when rates for blacks born outside the United States are calculated separately. Continued attention and effort is required to reduce the disproportional burden of cancer in US blacks. On the other hand, a record 3.8 million black immigrants, accounting for 9% of the current black population in the United States,5 are currently low risk populations for most cancers. It is important to monitor these trends, looking for ways to help all populations acquire protective factors and resist risk factors for cancer. More studies into the mechanisms that would avoid an unfavorable trend towards worse cancer outcomes in Caribbean blacks are necessary. Our study suggests that obesity, a known risk factor for many US blacks, may be an important focus for intervention in Caribbean blacks, especially among females, as immigrants have higher colorectal and endometrial cancer mortality rates in relation to their countries of origin. Targeted screening programs and expanding access to care would also help these immigrant populations. Concurrently, the public health community must clarify and address the reasons for such poor cancer outcomes among USborn blacks so that the interracial gaps can be significantly narrowed. References 1. American Cancer Society. Cancer Facts & Figures for African Americans 2013-2014. Atlanta, GA: American Cancer Society; 2013. 2. Kohler BA, Sherman RL, Howlader N, et al. Annual report to the nation on the status of cancer, 1975-2011, featuring incidence of breast cancer subtypes by race/ethnicity, poverty, and state. J Natl Cancer Inst. 2015;107(6):djv048. 3. Benn-Torres J, Bonilla C, Robbins CM, et al. Admixture and population stratification in African Caribbean populations. Ann Hum Genet. 2008;72(pt 1):90-98. 4. Arthur CM, Katkin ES. Making a case for the examination of ethnicity of Blacks in United States Health Research. J Health Care Poor Underserved. 2006;17(1):25-36. 5. Colby SL, Ortman JM. 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Cancer Invest. 2007;25(6):476-483. 358 Cancer Control October 2016, Vol. 23, No. 4 There is an urgent need to ensure that existing genomic research considers the unique needs of US Latinas with breast cancer. Chrysanthemum. X-Ray image courtesy of Bryan Whitney. www.x-rayphotography.com. Genomic Disparities in Breast Cancer Among Latinas Filipa Lynce, MD, Kristi D. Graves, PhD, Lina Jandorf, MA, Charité Ricker, MS, Eida Castro, PsyD, Laura Moreno, Bianca Augusto, Laura Fejerman, PhD, and Susan T. Vadaparampil, PhD Background: Breast cancer is the most common cancer diagnosed among Latinas in the United States and the leading cause of cancer-related death among this population. Latinas tend to be diagnosed at a later stage and have worse prognostic features than their non-Hispanic white counterparts. Genetic and genomic factors may contribute to observed breast cancer health disparities in Latinas. Methods: We provide a landscape of our current understanding and the existing gaps that need to be filled across the cancer prevention and control continuum. Results: We summarize available data on mutations in high and moderate penetrance genes for inherited risk of breast cancer and the associated literature on disparities in awareness of and uptake of genetic counseling and testing in Latina populations. We also discuss common genetic polymorphisms and risk of breast cancer in Latinas. In the treatment setting, we examine tumor genomics and pharmacogenomics in Latina patients with breast cancer. Conclusions: As the US population continues to diversify, extending genetic and genomic research into this underserved and understudied population is critical. By understanding the risk of breast cancer among ethnically diverse populations, we will be better positioned to make treatment advancements for earlier stages of cancer, identify more effective and ideally less toxic treatment regimens, and increase rates of survival. Introduction An estimated 55 million individuals living in the United States identify as being Hispanic or Latino.1 Latinos are a culturally and genetically diverse group with origins in Mexico, the Caribbean, Central America, and South America. In the United States, 64.0% of Latinos are of Mexican background, 9.6% of Puerto Rican background, 3.8% of Salvadoran background, 3.7% of Cuban background, 3.2% of Dominican background, 2.4% of Guatemalan background, and the remainder From Georgetown Lombardi Comprehensive Cancer Center (FL, KDG), Washington, District of Columbia, Department of Hematology and Oncology (FL), MedStar Georgetown University Hospital, Washington, District of Columbia, Department of Oncology (KDG), Georgetown University, Washington, District of Columbia, Department of Oncological Science (LJ), Icahn School of Medicine at Mount Sinai, New York, New York, Department of Medicine (CR), University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California, Department of Psychiatry (EC), Ponce Health Sciences University, Ponce, Puerto Rico, Health Outcomes and Behavior Program, H. Lee Moffitt Cancer Center & Research Institute (LM, BA, STV), Tampa, Florida, and the Department of Medicine (LF), University of California, San Francisco, California. Submitted April 4, 2016; accepted September 8, 2016. Address correspondence to Susan T. Vadaparampil, PhD, Health Outcomes and Behavior Program, Moffitt Cancer Center, 12902 Magnolia Drive, MRC-CANCONT, Tampa, FL 33612. E-mail: [email protected] No significant relationships exist between the authors and the companies/organizations whose products or services may be referenced in this article. Funding for this work was supported in part by U54 CA163071 (Ponce Health Sciences University) and U54 CA163068 (Moffitt Cancer Center). October 2016, Vol. 23, No. 4 Cancer Control 359 are of other origins.2 Although the terms Hispanic and Latino/Latina are often interchangeably used, we selected the term Latina for the current manuscript as we feel it extends beyond spoken language to reflect both origin and cultural traditions of women from Latin America. Breast cancer is the most common cancer diagnosed among Latinas in the United States and is the leading cause of cancer-related death in this population.3 Although the overall prevalence of breast cancer in Latinas is lower than in non-Latina whites, Latinas tend to be diagnosed at a later stage and have worse prognostic features (eg, triple-negative disease, ERBB2 [formerly HER2 or HER2/neu]–positive disease).4 A myriad of socioeconomic and cultural factors contribute to health disparities in breast cancer among Latinas,5-7 but biological factors — particularly genomics — remain an important but understudied consideration. High and Moderate Penetrance Genes Approximately 10% to 15% of breast cancer cases are attributed to inherited gene mutations. 8 Although multiple genes confer an inherited risk for cancer,9 BRCA mutations are the most prevalent and penetrant mutations, accounting for the majority of hereditary types of breast cancer.10 BRCA mutations result in an increased lifetime risk of breast cancer of up to approximately 60% to 70% and a lifetime ovarian cancer risk of up to 40%.11-13 Among Latinas, breast cancer is often diagnosed at younger ages and with worse prognostic features, including increased rates of triple-negative disease, than their non-Hispanic white counterparts.3,14-16 Triple-negative disease and premenopausal breast cancer are both clinical characteristics associated with a higher probability of having a BRCA1 or BRCA2 mutation.17,18 Prevalence of BRCA The prevalence of BRCA mutations in the general US population is estimated to be 1 in 400, excluding women of Ashkenazi Jewish descent in whom the prevalence is 1 in 40.19-21 However, less is known about the prevalence among racial and ethnic minority groups, including Latinas as a whole or by subethnicity based on country of origin. A review examined the spectrum of BRCA1 and BRCA2 mutations in Latin America and the Caribbean using studies published between the years 1994 and 2015.22 Six of the 33 studies were conducted among Latinas living in the United States, with the vast majority of participants drawn from clinic-based samples of patients of Mexican origin with breast cancer residing in California, Arizona, and Texas.22 Prevalence estimates of carrying a BRCA mutation for this US Latina group ranged from 0.7% to 42.0% and varied based on whether cases were select360 Cancer Control ed or unselected for family history or clinical characteristics (eg, affected vs unaffected, age at diagnosis), cancer site (eg, breast, ovarian), and type of testing (eg, inclusion of large rearrangement testing).22 In the cohorts of unselected patients with breast cancer, the BRCA mutation prevalence was 1.2% to 4.9%, which was consistent with expected rates.22 BRCA mutations have also been documented in all residents of Latin American countries where these genes have been studied, including Argentina, Brazil, Chile, Colombia, Costa Rica, Cuba, Mexico, Peru, Puerto Rico, Uruguay, and Venezuela.23-54 Most studies have focused on the spectrum of BRCA mutations.22,55 In a review of BRCA1 and BRCA2 mutations in persons living in Latin America and the Caribbean, 36% of the 33 studies primarily focused on Mexican or Mexican American patients.22 Of the Mexican study population, the mutation prevalence was between 4.3% and 23.0%.22 For other Latina subethnic groups, the mutation prevalence estimates of each country studied were: Colombia (1.2%–15.6%; 2 studies), Costa Rica (4.5%; 1 study), Cuba (2.6%; 1 study), Peru (4.9%; 1 study), Uruguay (17%; 1 study), and Venezuela (17.2%; 1 study).22 These studies provide insight into areas of future research of BRCA mutation distribution and frequency based on country of origin, the role of specific founder mutations, the contribution of large genomic rearrangements to the spectrum of mutations across various Latina subethnic groups, and the consideration of other non-BRCA genes that increase the risk of breast cancer. Although recurrent mutations were identified within most studies, the specific mutation varied by study and country.22 BRCA1 185delAG has also been documented in Latinas across Latin America and the United States.40,42-44,47,56-58 One of the 3 Jewish founder mutations, BRCA1 185delAG is estimated to have arisen about 800 years ago or earlier and is believed to have been introduced into Latin America about 650 years ago.59 When this mutation is identified in Latinos, haplotype analysis supports that this mutation is of the same origin as the Jewish founder mutation, rather than a separate genetic event.60,61 Pooled mutation estimates performed by Porchia et al55 found that BRCA1 185delAG is the second most prevalent BRCA1 mutation and its frequency is not significantly different between Mexico and other Latin American countries (P = .70). However, it is worth noting that not all Central and South American countries were represented in their analysis.55 The most common BRCA1 mutation in the same meta-analysis was deletion of exons 9 to 12.55 This mutation is estimated to have originated nearly 1,500 years ago near Puebla Mexico.48,58 However, to date, it has been reported in Mexicans and Mexican Americans alone.22,32,55,61,62 The contribution of large genomic reOctober 2016, Vol. 23, No. 4 arrangements to BRCA1 in Latin American patients was evaluated in a study of US Latinas and described the prevalence of rearrangements by racial and ethnic groups.63 Large rearrangements were significantly more common in individuals who reported Latin American ancestry, and the prevalence of rearrangements was two-fold higher than in the overall population tested.63 This laboratory-based cohort extracted ethnicity data from genetic testing request forms; therefore, no data about subethnicity was available.63 However, the 2 most frequent BRCA1 rearrangements identified in this study were deletion of exons 9 to 12 and deletion of exons 1 and 2, likely reflecting the underlying US Latino population in whom the majority is of Mexican ancestry.63 In a Puerto Rican study, BRCA1 deletion of exons 1 to 2 was seen in nearly 20% of study patients positive for BRCA1.49 Because Puerto Ricans represent the second largest US Latino group after those of Mexican ancestry, these findings support utilizing an assay that includes large rearrangements when testing Latinos.49 The study results also highlight the importance of understanding more granular aspects of ethnicity, such as country of origin, to ensure that all mutations that contribute significantly are captured. Dutil et al22 noted that most Latin American studies they reviewed identified a higher proportion of BRCA1 than BRCA2 mutations, a finding similar to reports in other populations. However, studies from 4 different countries (Costa Rica,37 Cuba,35 Puerto Rico,49 Uruguay64) reported more BRCA2 mutations than those in BRCA1. While these studies may have been limited by sample size and the mutation-detection strategies and technologies,35,37,49,64 this finding has been also reported in a single US-based clinical site and may warrant further exploration.65 The meta-analysis performed by Porchia et al55 identified recurrent BRCA2 mutations across all studies with the following pooled prevalence: H372N (0.88%; 95% confidence interval [CI]: 0.24–1.92), E49X (0.38%; 95% CI: 0.13–0.75), and 3492insT (0.32%; 95% CI: 0.24–0.53). BRCA2 3492insT has been identified in different regions of Spain with a frequency as high as 2.08%.65-71 Although it is possible that this mutation was introduced in Latin America by the Spaniards, no haplotype studies of this specific mutation were identified to confirm a shared ancestry rather than a separate mutational event.49 BRCA1 and BRCA2 account for the majority of hereditary breast cancer, but other high- and moderate-risk genes also predispose individuals to breast cancer, including TP53, PTEN, CDH1, STK11, CHEK2, PALB2, and ATM, among others.26,27,54,72-80 Limited studies have been performed of non-BRCA genes in Latina breast-cancer cohorts, leaving much to be learned about the prevalence and spectrum of October 2016, Vol. 23, No. 4 mutations in these genes among Latinas with breast cancer (Table 1).26,27,54,72-80 One exception is the Brazilian founder mutation in TP53, R337H. Mutations in TP53 cause Li-Fraumeni syndrome, which is associated with an elevated risk for a wide spectrum of cancers, including adrenal cortical carcinoma, soft-tissue and bone sarcomas, brain tumors, and breast cancer.81-83 The overall contribution of TP53 mutations to breast cancer is estimated to be less than 1%, unless selecting for early-onset breast cancer.84,85 In studies of women diagnosed with breast cancer at or before the age of 30 or 35 years, 5% to 8% had TP53 mutations.81,86-88 TP53 R337H was first identified in individuals with childhood adrenal cortical carcinomas living in southern Brazil.89 This mutation occurs in 2.4% to 8.6% of Brazilian women with breast cancer.78,79,89,90 In a large study, which included 403 patients with breast cancer diagnosed at 45 years or younger, 12.1% carried the TP53 R337H mutation. Although the mutation was significantly more frequent in younger patients compared with those diagnosed at 55 years or older (P < .001), 5.1% of the older group carried the mutation.79 To date, no other populations have been identified in whom TP53 makes such a significant contribution to breast cancer. The prevalence of this mutation in southern Brazil has been estimated to be approximately 0.3%.91,92 Additional haplotype analyses support the hypothesis that this recurrent mutation is a founder mutation from a shared ancestor.79,93 Historically, the genetic assessment for hereditary breast cancer involved the formation of a differential diagnosis followed by a syndrome-by-syndrome evaluation through the sequential testing of genes. However, the rapid integration of next-generation sequencing has enabled simultaneous testing of multiple inherited cancer genes, thereby expanding the use of multigene panels in clinical testing at a reduced cost.94 This expansion is reflected in the emerging body of literature on breast cancer focused on multigene panel findings from the research, clinical, and laboratory settings.95-103 These literature cohorts are predominantly non-Hispanic whites, with Latinas representing less than 1.0% to 7.4% of study participants, thus highlighting another area where future research is needed.95-97,99-102 One study of 475 patients undergoing multigene panel testing included 228 Latino patients (47.6% of the study population), and it reported that the likelihood of detecting a deleterious mutation was no different among the ethnic and racial groups represented.96 Of the patients with breast cancer (n = 197), 14.8% (n = 28) carried mutations, and, as expected, BRCA1 and BRCA2 were the most commonly mutated genes; however, 16 mutations were identified in other genes (CDH1 = 4, CHEK2 = 3, MUTYH = 3, PALB2 = 2, Cancer Control 361 TP53 = 1, RAD50 = 1, RAD51D = 1, BARD1 = 1).96 Of note, the likelihood of identifying more than 1 variant of uncertain significance in Latinos was significantly higher than that of non-Hispanics whites.104 Thus, a need exists for further research to better classify rare variants, especially given the under-representation of Latinos in laboratory and research databases. Genetic Counseling and Testing Patient- and Health Care–Related Factors An important step toward understanding the role of BRCA and other high- and moderate-risk breast cancer genes in Latinas is to increase the number of individu- als who receive genetic counseling and subsequently elect to undergo testing. However, growing evidence identifies disparities in awareness of and access to genetic counseling among Latinas compared with non-Hispanic white women. Data from health interview surveys from 2000, 2005, and 2010 show that Latinas had the lowest level of awareness about genetic testing for inherited cancer risk than all of the other US racial ethnic groups.105-107 Using telephone surveys, Gammon et al108 studied 63 Latinas and 84 non-Hispanic whites at increased risk for carrying a BRCA1 or BRCA2 mutation, examining their awareness, cognition level, and psychosocial needs related to genetic Table 1. — Select Non-BRCA Genes Observed in Latina Populations Study Country Cohort No. of Patients Assumpção78 Brazil Gene Analysis Findings Inclusion Criteria 123 Family history of breast cancer Family history of ovarian cancer Sporadic breast cancer Carraro54 54 Early-onset breast cancer diagnosis < 30 y Felix 26 106 HBOC testing Giacomazzi79 874 Family history of cancer (group 1) Consecutive breast cancer (group 2) Silva 27 120 HBOC testing TP53 Site-specific analysis of TP53 R337H 2.4% of cases carried the mutation (P = .0442) BRCA1 BRCA2 CHEK2 TP53 Coding introns/exons of BRCA1/2, TP53, and site-specific analysis of CHEK2 (c.1100delC) 22% carried mutations mostly in BRCA1/2 2% (n = 1) had TP53 mutation PCR of each exon of BRCA1 Site-specific analyses of BRCA2 (c.5946_5946delT; c.156_157insAlu), CHEK2 (c.1100delC; c.444+1G>A; p.I157T), and TP53 (p.R337H) 2.8% carried mutations (BRCA = 2, TP53 = 1) Single-site analysis for p.R337H p.R337H identified in 3.4% (group 1) and 8.6% (group 2) Higher prevalence when diagnosed ≤ 45 y (12.1%) vs 55 y (5.1%; P < .001) Coding introns/exons of BRCA1/2 Site-specific analysis of CHEK2 (c.1100delC) and TP53 (p. R337H) Array comparative genomic hybridization for CNVs in other 14 genes 26% (n = 31) mutations (BRCA1/2 = 27, CHEK2 = 1, TP53 = 3) BRCA1/2 CHEK2 TP53 TP53 ATM BRCA1/2 BRIP1 CDH1 CDKN2A CTNNB1– CHEK2 MLH1 MSH6 NBN PALB2 PTEN RAD50 RAD51 TP53 Continued on next page 362 Cancer Control October 2016, Vol. 23, No. 4 Table 1. — Select Non-BRCA Genes Observed in Latina Populations, continued Study GonzálezHormazábal72 Country Chile Jara80 Leyton73 Cohort Gene Analysis Findings No. of Patients Inclusion Criteria 137 (BRCA – = 126, BRCA+ = 11) ≥ 2 family members with breast cancer ≥ 2 family members with ovarian cancer Family history of male breast cancer Early-onset breast cancer with no family history ATM PCR-based analysis of coding sequence and exon/ intron boundaries of ATM Analysis of ATM 5557G>A, IVS38-8T>C, IVS24-9delT 5557G>A, IVS38-8T>C, IVS24-9delT associated with elevated risk of breast cancer if BRCA – Identification of composite genotype that confers 3.19-fold risk for breast cancer 143 (BRCA – = 131, BRCA+ = 12) ≥ 2 family members with breast cancer ≥ 2 family members with ovarian cancer Family history of male breast cancer Early-onset breast cancer with no family history RAD51D PCR-based analysis of coding sequence and exon-intron boundaries of RAD51D Analysis of RAD51D, c.135G>C No mutations detected in RAD51D c.135G>C associated with elevated breast cancer risk if BRCA – 436 BRCA+ ≥ 2 family members with breast cancer ≥ 2 family members with ovarian cancer Single case of early-onset diagnosed ≤ 50 y PALB2 Full gene sequencing in 100 “high-risk” cases Analysis of identified variants No pathogenic mutations identified 3 variants identified (c.1676A>G a , c.2993C>Ta , c.1861C>A) PCR-FLP of 3 specific mutations (IVS24-9delT, IVS38-8T>C, 5557G>A) 5557G>A (13%) IVS24-9delT (21% vs 8% controls; P = .0122) IVS38-8T>C (< 1%) CalderónZúñiga74 Mexico 94 Familial breast cancer Early-onset breast cancer ATM Bell76 United States 362b Early-onset breast cancer CHEK2 169 cases diagnosed ≤ 40 y had sequencing of coding region of CHEK2 Specific analysis of 1100delC, H143Y, and 8 other CHEK2 variants/mutations Data not reported by ethnicity, but reported “infrequency” of c.1100delC among Latinas Bretsky75 101b Personal history of breast cancer ATM 20 specific ATM missense mutations or polymorphisms L546V had modest but not significant predictor of risk; almost exclusive to African American women (found in 2 Latinas) Damiola77 158 b Breast cancer diagnosed ≤ 45 y MRE11 RAD50 NBN PCR-based analysis of coding sequence and exon/ intron boundaries of MRE11, RAD50, NBN Data not reported by ethnicity MRE11, RAD50, NBN are intermediate-risk genes aThese variants play a role in risk of breast cancer. bLatinas were part of a larger multiethnic cohort. CNV = copy number variation, FLP = fragment length polymorphism, HBOC = hereditary breast and ovarian carcinoma, PCR = polymerase chain reaction. counseling and testing. Among those who had not previously undergone genetic counseling (53 of the 120), Latinas were more unaware than their white counterparts of the availability of testing (56.9% vs 34.8%, respectively).108 Vadaparampil et al109 reported on a sample of Latinas with a personal or family history of breast cancer, all of whom reported an awareness of genetic risk for breast cancer (ie, family history). However, none of the Latinas had a clear understanding of October 2016, Vol. 23, No. 4 what genetic testing was and had not received physician referral for genetic testing.109 Findings did differ based on country of origin — an important area to consider in future work, given the diversity of Hispanic populations across the United States.109 In another report, Kaplan et al110 reported differences in awareness of genetic testing by race and ethnicity, such that 19.4% of Latinas had heard of genetic testing compared with 59.4% of whites, 26.1% of Asian Americans, and 31.0% Cancer Control 363 of black women. In a study of more than 2,400 patients completing a family cancer history form, Mays et al111 found that, overall, despite low levels of initial awareness, 65 patients (2.7%) met criteria for cancer risk assessment; of those, 72.3% expressed interest in receiving genetic counseling. Furthermore, no differences in interest in genetic services were reported across all racial and ethnic groups.111 Among 1,536 women with nonmetastatic breast cancer, Jagsi et al112 found that Latinas had a greater desire for genetic counseling than other groups (58.8% of Spanish-speaking Latinas; 36.7% of English-speaking Latinas; 27.1% of non-Latina whites; and 28.1% of blacks). In addition, Lagos et al113 examined social, cognitive, and cultural variables among Latinas prior to an appointment for genetic counseling. Fifty low-income, underserved Latinas completed the assessment, and the results demonstrated their readiness (having the necessary skills for the genetic-counseling process), low fatalism, and high rate of self-efficacy, and social support.113 However, this study was conducted in women who showed up to their genetic counseling appointments, thus representing a unique group of women.113 Vadaparampil et al114 studied a group of Puerto Rican women (living in Puerto Rico or central Florida) with a family or personal history of breast cancer and found that the vast majority of participants said they would undergo genetic testing within the next 6 months if it was available. Barriers included the potential physical pain associated with the test. Uptake of Services Given lower levels of patient awareness, physician recommendations may provide a critical approach to increasing the utilization of genetic counseling and testing for hereditary risk of breast cancer. However, available studies suggest a missed clinical opportunity, because both English- and Spanish-speaking Latina survivors of breast cancer may be more likely to have unmet needs for discussion with a health care professional about genetic testing for cancer than their non-Hispanic white counterparts. For example, Jagsi et al112 reports that minority patients were the most likely to express an unmet need for a discussion about genetic testing, although they also showed a strong desire for such testing. Preliminary studies support the uptake of genetic counseling when services are offered.115-118 One study of predominantly Latina patients (71.4%) offered genetic counseling at a safety-net hospital found that 88.0% kept their appointments.115 Another study of women (69.6% were Latinas) seen in a safety-net hospital setting reported that 96.4% of them underwent BRCA testing when it was recommended to them.116 Once Latinas were referred, Olaya et al117 found that they are equally likely as the general population to complete BRCA test364 Cancer Control ing. Overall, 52% completed genetic testing, and no differences by race and ethnicity were observed.117 Woodson et al118 reported on the utilization of group pretest genetic counseling in a community clinic made up of mostly Latinas (62.3%) with breast cancer; the majority (86.7%) underwent BRCA genetic testing when offered. Overall, these studies have focused on the delivery of genetics services for cancer to majority Latina cohorts, demonstrating that genetic counseling and testing is likely well-received by Latinas with breast cancer; however, these studies were all conducted in safety-net hospitals or in community, low-resource settings and were aimed at the provision of service to low-income, uninsured patients.115-118 Although Latinas continue to be disproportionally uninsured or underinsured, these study findings might not generalize to other health care settings. Thus, further studies are needed across various clinical settings and in a wider representation of Latinas with breast cancer to better understand the utilization of genetic testing as well as the barriers for referrals. Common Genetic Polymorphisms and Risk of Breast Cancer Genome-Wide Association Studies Progress in the discovery of germline genetic polymorphisms associated with breast cancer risk changed pace when technological advances in genotyping made it possible to characterize genome-wide genetic variation at a relatively low cost.119 In 2007, the first breast cancer genome-wide association studies were published, and they reported a handful of single nucleotide polymorphisms (SNPs) associated with a modest increase in risk.120-122 Since then, more than 100 common variants that either increase risk for or are protective against developing breast cancer have been discovered and, including replication efforts, data from more than 120,000 women have been analyzed.120-143 A small proportion of samples included in these major initiatives are from minority populations in the United States (eg, Latinas, African Americans),120-143 and the first results of genome-wide association studies of Latinas with breast cancer were published in 2014.144 This latter study represents important but limited progress, considering that the sample size was one-tenth of that available for genome-wide association studies involving women of European origin.120-122,144 Until the first genome-wide association studies of breast cancer in women of European origin were published, the search for risk-predisposing genetic variants was focused on finding polymorphisms within genes that, for known or hypothesized involvement in the biology of the disease, were likely to contribute to breast cancer risk.120-122 These studies in US Latinas or Latin American women typically consisted of the replication of previously associated polymorphisms reported in Europeans, with few of these studies looking for variaOctober 2016, Vol. 23, No. 4 tion in samples of Latinas before further testing specific polymorphisms for associations in larger samples.145,146 Compared with the hundreds of genome-wide association studies in non-Hispanic white women, we identified 13 case-control studies or cohorts that include US Latina or Latin American women.147-160 These studies include populations of women of no more than 100 and up to approximately 5,000 women of Latin American origin; combined, the study populations tally approximately 5,000 Latina women with breast cancer and 11,000 Latina healthy controls.147-160 Candidate Gene or Pathway Studies Multiple breast cancer–association studies of candidate genes or pathways have been reported for US Latina and Latin American women during the last 20 years. Genes or pathways studied have included those related to hormone metabolism, hormone receptors, hormone coactivators or supressors,145,161-166 growth factors,146,167-173 matrix metalloproteinases,174,175 inflammation and energy balance,149,176-181 metabolism of xenobiotic compounds and oxidative stress,150,182-184 DNA repair,151,152,154,186 and angiogenesis.187 Results reported in these publications should be interpreted with caution, given that approximately 60% of the candidate gene analyses included did not adjust for genetic ancestry, which is a known confounder in genetic association studies in admixed populations.188,189 In addition, no associations in candidate gene or pathways studies, nor any of the interactions with risk factors, genetic ancestry, or tumor characteristics, have been replicated in independent samples of Latinas. Replication of Identified Single Nucleotide Polymorphisms Few studies have included Latinas and tested the association between SNPs discovered in genome-wide association studies of breast cancer conducted in samples of European or Asian women.190-195 The first study genotyped previously reported SNPs in the 2q35 region and FGFR2, TOX3, and MAP3K1, reporting statistically significant replications for the polymorphisms in FGFR2 and 2q35.190 Two different studies published the results of analyses conducted in the same sample of high-risk families from Chile and healthy controls, testing associations between previously reported variants in FGFR2, MAP3K1, and TOX3 and the 2q35 and 8q24 regions and breast cancer risk.194,195 They replicated the associations for FGFR2, MAP3K1, TOX3, and 2q35 but not for 8q24.194,195 An analysis conducted in a pooled sample of Latina cases and controls from the FourCorners study, San Francisco Bay Area Breast Cancer Study, and a study in Mexico, investigated the association between 10 identified polymorphisms in genomewide association studies (in region 2q35 and in or near RELN, MRPS30, RNF146, FGFR2, TOX3, LSP1, TLR1, October 2016, Vol. 23, No. 4 MAP3K1, and RAD51L1) and breast cancer risk.192 They replicated associations for the polymorphisms in RELN, FGFR2, TOX3, and TLR1 and 2q35 and found heterogeneity by ancestry for the RELN, 2q35, and TLR1 SNPs.192 A follow-up study reported that the heterogeneity by ancestry for the 2q35 polymorphism was likely due to the association between genetic ancestry, use of hormone therapy, and breastfeeding.191 Another analysis of the FGFR2 polymorphism in the Mexican study reported an interaction between the FGFR2 polymorphism and alcohol intake.193 The first genomewide association study of breast cancer in US Latinas also replicated previous associations, with most of the SNPs being concordant in terms of direction and magnitude of association with those reported in European or Asian populations.144 Twenty-three of the 83 variants tested had probability values below .05.144 Ancestry Admixture mapping leverages the demographical history of admixed populations to find genomic regions that may carry trait-associated variants.196-204 An admixed population results from the combination of 2 or more ancestral groups.200 The principle of admixture mapping is to identify genomic regions in which cases share more of the same genetic ancestry than either population-based controls (case-control analysis) or compared with the average ancestry of the rest of the genome among cases (case-only analysis).202 This approach has identified risk variants or risk regions for multiple complex traits, including obesity, hypertension, and cancer.196-199,201,203,204 The incidence of breast cancer varies across different racial and ethnic groups in the United States, and Latinas have lower incidence rates than non-Latina whites but higher rates than American Indian women.205 Genetic ancestry has also been associated with breast cancer risk in US Latinas and Mexican women after adjusting for nongenetic risk factors, suggesting that a genetic component could be responsible for the difference in risk.149,206,207 An admixture mapping study in Latinas reported a statistically significant association between a region in the long arm of chromosome 6 (6q25) near ESR1 and risk of breast cancer and a suggestive association on chromosome 11.208 Higher Indigenous American ancestry at chromosome 6q25 was associated with lower risk of breast cancer.208 This finding was concordant with the previous reports of lower rates of risk of breast cancer among Latinas with high American Indian ancestry compared with women with high European ancestry after adjusting for possible risk factors such as socioeconomic status, number of full-term pregnancies, and breast feeding.206-208 One included a discovery phase and replication in 3 additional studies.144 The study reported genome-wide results that were statistically significant Cancer Control 365 for 2 linked SNPs 56kb upstream of ESR1 (rs140068132 and rs147157845).144 These SNPs have a frequency of between 5% and 23% in Latin American populations and are absent in most all other groups.144 The minor allele was protective, with an associated odds ratio (OR) of 0.60 (95% CI: 0.53–0.67) per allele and was more protective for ER-negative disease than for ER-positive disease (OR for ER-negative disease 0.34; 95% CI: 0.21–0.54).144 Treatment Tumor Genomics A growing body of evidence suggests differences in the tumor biology of breast carcinoma across various races and ethnicities. Several studies have evaluated the prevalence of phenotypic subtypes of breast cancer in Latinas compared with other population groups.209-215 Most data have shown a higher proportion of HR-negative disease types among Latinas when compared with non-Hispanic whites (Table 2).4,209-213 However, those results have not always been concordant, and the differences seen across these studies could represent small sample sizes, patient age, or unadjusted rates for genetic ancestry. Although studies based on data from the California Cancer Registry indicated a higher proportion of triple-negative tumors,214 this finding was not confirmed in a Colorado study.209 In a retrospective study performed in Brazil, patients in the southern regions with a higher percentage of European ancestry and higher socioeconomic status presented with the highest proportion of luminal tumors, whereas the more aggressive subtypes were seen in the northern parts of Brazil, an area with a higher African ancestral influence.215 Approximately 15% of breast cancer types over- express human epidermal growth factor receptor 2 (ERBB2; formerly HER2 or HER2/neu) protein.216 High levels of ERBB2 expression identify those women who benefit from treatment with ERBB2-targeted agents, which have been shown to increase survival in the adjuvant and metastatic settings.217,218 Most studies with ERBB2-targeted therapies have enrolled majority populations of non-Hispanic whites, although consistent evidence demonstrates that a higher proportion of ERBB2-positive tumors exist among Latinas, even after adjusting for other tumor characteristics (eg, grade, stage, ER status) and breast cancer risk factors (eg, number of children, alcohol consumption).209 Further tumor characterization has been made possible due to advances in molecular tumor profiling. Oncotype DX (Genomic Health, Redwood City, CA) is a 21-gene breast cancer assay — known as a recurrence score — that provides prognostic and predictive information regarding the benefits of adjuvant chemotherapy in patients with ER-positive tumors. Use of Oncotype DX is part of several guidelines from professional medical organizations, including the National Comprehensive Cancer Network, the American Society of Clinical Oncology, and the European Society for Medical Oncology.219-221 The characteristics of this assay and the impact of its results on treatment decisions among Latinas with breast cancer are lacking in the medical literature. Kalinsky et al222 studied 74 Latinas and 145 non-Hispanic white women matched for age, disease stage, and nodal status, and they observed no differences in the overall recurrence score, ER or PR status, or ERBB2 expression by Oncotype DX. However, Latinas had a higher expression of CCNB1 and AURKA, 2 genes that are part of the proliferation score and heavily weighted in the calculation of the Table 2. — Comparison of ER and ERBB2 Status in Latina, Black, and White Women Study No. of Patients Latina White Black Chlebowski211 N = 3,800 n = 103 Latinas ER+: 83.0% ER+: 87.0% ER+: 71.0% Dunnwald212 N = 209,276 n = 5,585 Latinas ER+: 70.2% ER+: 78.4% ER+: 60.5% Hausauer 213 N = 243,906 n = 15,355 Latinas ER+: 53.2% (unknown ER status: 29.4%) ER+: 63.5% (unknown ER status: 22.3%) ER+: 46.4% (unknown ER status: 29.4%) Hines209 N = 285 n = 69 Latinas ER+: 63.8% ERBB2 +: 31.9% TNBC: 17.4% ER+: 77.3% ERBB2 +: 14.3% TNBC: 15.1% Li210 N = 124,934 n = 7,219 Latinas ER+: 68.7% ER+: 78% ER+: 53.4% Parise 4 N = 143,184 n = 24,078 Latinas ER+: 74.6 % ERBB2 +: 22.2% TNBC: 15.9% ER+: 82.7% ERBB2 +: 17.2% TNBC: 11.2% ER+: 66.5% ERBB2 +: 20.1% TNBC: 24.5% — TNBC = triple-negative breast cancer. 366 Cancer Control October 2016, Vol. 23, No. 4 recurrence score. Multiple trials whose study populations were mostly comprised of non-Hispanic white women have shown that use of Oncotype DX affects treatment recommendations and leads to an increase in physician and patient confidence in treatment decisions.223-226 A small study of 96 patients with breast cancer treated in Mexico showed that use of the Oncotype DX changed treatment decisions for 32% of patients, a finding suggesting that its use has a meaningful impact on recommendations for adjuvant treatment.227 Results from cost-effectiveness analyses indicated that use of the Oncotype DX assay was projected to improve rates of life expectancy when compared with the current standard of care.228 Pharmacogenomics Several factors cause variations in an individual’s response to drugs, including age, body mass index, diet, and genetic variation.229-231 SNPs in genes related to drug-metabolizing enzymes have been recognized as important determinants of variability to drug response.232 Most studies have not been sufficiently powered to determine whether specific chemotherapy agents used to treat breast cancer have different rates of effectiveness and toxicities based on race or ethnicity.233 However, differences in the metabolism of endocrine therapies have been well documented according to race and ethnicity.234-237 In a study that evaluated clinical data and blood samples from patients with breast cancer undergoing adjuvant tamoxifen therapy, mostly non-Hispanic white women (68%) and Latinas (26%) had significantly higher serum levels of tamoxifen and 4-hydroxytamoxifen, one of the tamoxifen metabolites (P = .02 and P = .007, respectively).234 In 2 other studies, genetic polymorphisms in CYP2D6 associated with lower plasma concentrations of the active metabolites of tamoxifen were described in Mexican, Puerto Rican, and Spanish patients.235,236 A higher prevalence of this poor metabolizer phenotype has also been observed in non-Hispanic whites.237 In an attempt to clarify whether CYP2D6 allele status influences outcomes from tamoxifen, investigators assessed data from 2 large prospective trials and found that CYP2D6 allele status did not predict clinical benefit of adjuvant tamoxifen in terms of risk of recurrence.238,239 Therefore, changes in treatment decisions based on CYP2D6 allele status alone are not recommended. Differences in the incidence of polymorphisms of the aromatase gene among different ethnic groups have also been reported and could potentially lead to different outcomes and toxicities among populations.240 One trial evaluated the benefit of extended hormonal therapy with an aromatase inhibitor after 5 years of tamoxifen treatment in non-Hispanic whites (n = 4,708) and minority women (n = 352; 1.5% were October 2016, Vol. 23, No. 4 Latinas).241 In general, the researchers found that, compared with non-Hispanic whites, minorities had fewer associated toxicities and no definitive survival benefit with aromatase inhibitors.241 However, these results should be cautiously interpreted, because the minority participants were less adherent to hormonal therapy and the study was not powered to detect survival benefit in the subgroups.241 Conclusions Several genetic and genomic factors are related to the health disparities of breast cancer in Latinas. Increasing our knowledge about the contribution of high- and moderate-penetrance mutations to the risk of breast cancer among Latinas overall and for subgroups based on country of origin is an important priority. Although genetic counseling and testing for inherited susceptibility to breast cancer has been clinically available for nearly 20 years, disparities in awareness, referral to services, and access persist. Therefore, interventions to address barriers related to low levels of awareness and lacking physician referrals are critical.105-110 Even though multiple candidate gene studies have been conducted in this population, only identified variants in genome-wide association studies have been systematically replicated. Much larger sample sizes will be required if we expect to discover similar results in Latinas as would be identified for the European genome in view of their Indigenous American component. We cannot assume that overlapping variants alone between different ancestral genomes will be associated with rate of risk, so our efforts should be focused on reducing research disparities by expanding available resources to include large cohorts and case-control studies of diverse populations in and outside the United States. Latinas remain systematically underrepresented in pharmacogenomics studies and the current studies were not powered to detect outcome differences. They are also underrepresented in clinical treatment trials and other patient-reported outcomes research. Future research should draw from the few models of success in prior studies that have recruited sufficient numbers of Latinas.242-245 Lessons can also be learned from successful examples of recruiting other racial and ethnic minority patients who have survived breast cancer.246 Elements that appear to bolster success include partnering with community-based organizations that provide services to Latinas and the provision of languageconcurrent clinical care.247-249 The heterogeneity of the US Latina population must also be considered, because different cultural influences, levels of awareness of, and interest in genetic and genomic services appear to vary by country of origin.109 An urgent need exists to ensure that existing genomic research considers the unique needs of this Cancer Control 367 Latina population. As the US population continues to diversify with up to one-third identifying as Hispanics by 2060,1 extending genetic and genomic research into this underserved and understudied population will be critical. By understanding the risk of breast cancer among diverse populations, we will be better positioned to make advancements in the number of women diagnosed at earlier stages, identify more effective and less toxic treatment regimens, and increase rates of survival. Meeting these goals will contribute to reducing the current health disparities in these patients with breast cancer. Acknowledgment: The authors wish to thank Lindsay Salem for her assistance in the literature review for this manuscript. References 1. Colby SL, Ortman JM. Projections of the size and composition of the US population: 2014 to 2060. Curr Pop Rep. 2014:1-13 https://www.census.gov/ content/dam/Census/library/publications/2015/demo/p25-1143.pdf. Accessed September 14, 2016. 2. Pew Research Center. 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Rush CL, Darling M, Elliott MG, et al. Engaging Latina cancer survivors, their caregivers, and community partners in a randomized controlled trial: Nueva Vida intervention. Qua Life Res. 2015;24(5):1107-1118. 249. Detz A, Mangione CM, de Jaimes FN, et al. Language concordance, interpersonal care, and diabetes self-care in rural Latino patients. J Gen Intern Med. 2014;29(12):1650-1656. October 2016, Vol. 23, No. 4 Various clinical and treatment factors differently affect sexual minorities with breast cancer. Stag Horn. X-Ray image courtesy of Bryan Whitney. www.x-rayphotography.com. Clinical Considerations of Risk, Incidence, and Outcomes of Breast Cancer in Sexual Minorities Anne E. Mattingly, MD, John V. Kiluk, MD, and M. Catherine Lee, MD Background: Breast cancer is a leading cause of cancer-related mortality in women. Limited research exists on the impact of sexual orientation on overall risk of and mortality from breast cancer. We sought to summarize the medical literature on breast cancer in sexual minority women and identify possible disparities in this population. Methods: A comprehensive literature search was conducted for English-language studies in peer-reviewed medical journals that referenced breast cancer and sexual minority, lesbian, bisexual, or transgender individuals. Articles published between January 2000 and November 2015 were included. They were reviewed for relevance to breast cancer risk stratification, breast cancer mortality, breast reconstruction, and transgender issues. Results: Behavioral risks, reproductive risks, and risks associated with decreased access to health care may all affect outcomes for sexual minorities with breast cancer. Limited studies have mixed results regarding mortality associated with breast cancer in sexual minorities due to an inconsistent reporting of sexual orientation. Conclusions: Overall, the research examining breast cancer in sexual minority women remains limited. This finding is likely due to limitations in the reporting of sexual orientation within large databases, thus making broader-scale research difficult. Introduction For American women, breast cancer remains the most common cancer and second most common cause of cancer-related mortality.1 In 2016, the estimated incidence of new breast cancer cases will be 246,660, or 29.0% of all new cancer cases, and 72,160 cancer-related deaths are estimated to be due to breast cancer.1 Approximately 1 in 8 women (12.3%) will be diagnosed with breast cancer during their lifetime, and nearly From the Comprehensive Breast Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida. Submitted February 19, 2016; accepted May 11, 2016. Address correspondence to M. Catherine Lee, MD, Comprehensive Breast Program, Moffitt Cancer Center, 109201 North McKinley Drive, MKC-BR PROG, Tampa, FL 33612. E-mail: [email protected] No significant relationships exist between the authors and the companies/organizations whose products or services may be referenced in this article. October 2016, Vol. 23, No. 4 3 million women in 2012 were living with breast cancer in the United States.2 Research has been performed on racial disparities in the screening, diagnosis, treatment, and survival rates of breast cancer, as well as disparities due to insurance status and socioeconomic position.3 Disparity in the risk and mortality rates of breast cancer are likely to continue until we better understand the underlying reasons for the divergence.3,4 According to US Census data, 1.2 million individuals live in a household with a same-sex partner.5 The Surveillance, Epidemiology, and End Results (SEER) Program collects demographical data, including age, race, sex, income, education, and geographical location, but it does not collect data on sexual orientation.2,4 This fact makes research on the disparities in breast cancer among women who identify as lesbian, bisexual, or sexual minority women difficult. Sexual minority women are infrequently the focus of studCancer Control 373 ies in breast cancer, and controversy exists on whether sexual minority women are at increased risk for breast cancer compared with women in the general population.6 Methods The goal of this article is to provide health care professionals with a discussion framework for their patients who are sexual minorities. This is a general overview of the limited published research on breast cancer in sexual minority patients focusing on clinical considerations. Within the medical literature we identified recent and comprehensive studies to address the following clinical questions: • Are sexual minority women at increased risk for developing breast cancer? • Do sexual minority women have an increased frequency of breast cancer related to a potential increase in risk factors? • Can health care professionals influence patient behavior to mitigate the risk of breast cancer in these sexual minority patients? • Does any identified increased risk lead to a difference in outcomes for sexual minority women, specifically breast cancer–related mortality? • How do sexual minority women react to breast reconstruction after completing their course of treatment? • How does the risk of breast cancer change in the transgender population, specifically when taking cross-sex hormone therapy? Risk Factors Risk factors for breast cancer have been extensively researched, and studies evaluating risk factors for breast cancer in sexual minority women have been published. However, whether sexual minority women are at an increased risk of breast cancer is still a controversial topic. For example, Cochran et al7 reviewed data from 7 surveys of women who have sex with women and self-reported bisexual women 18 to 75 years of age and compared their responses to 2 large national surveys of women similar in age (N = 19,000). Case et al8 also examined sexual orientation and general health risk factors, comparing self-reported sexual minority women to heterosexual female participants in a prospective cohort of 116,671 registered nurses 25 to 43 years of age who were followed with biennial surveys starting in 1989. Sexual orientation was added to the surveys in 1995, and demographical information was collected as well as risk factors for breast cancer, other cancers, and cardiovascular disease. Sexual orientation was reported by 98% of respondents, of whom 0.8% identified as lesbian and 0.3% identified as bisexual — thus making the sexual minority respondents a smaller subset of the larger cohort.8 It is diffi374 Cancer Control cult to generalize data as all the respondents were premenopausal registered nurses, and their work likely affected their interaction with the health care system and may not have been reflective of other sexual minority women. Breast cancer is much more common in persons as they age, and a premenopausal cohort does not give a complete picture of breast cancer either in sexual minority or heterosexual women.1 In 2012, Austin et al9 used the same prospective cohort data as Case et al8 to estimate risk of breast cancer in premenopausal women using a modified Rosner–Colditz risk model and compared sexual minority women with heterosexual women. Similar to the Gail model, which uses current age, age of menarche, age at first birth, family history, previous benign results on breast biopsy, history of biopsy with atypia, and race to estimate risk of breast cancer, the Rosner–Colditz model also includes subsequent births following first live birth, type and age of menopause, height, current weight, weight at 18 years of age, and alcohol consumption. Austin et al9 calculated a 1-year breast cancer incidence rate per 100,000 person-years and compared sexual minority women with the heterosexual group. However, these studies have limitations. The self-reported nature of sexual orientation makes objective study inherently difficult. Oftentimes sexual orientation is not included in large databases of breast cancer research.10 Sexual minority women may be less likely to disclose sexual orientation to their health care professional for fear of discrimination.11 As the stigma of sexual minority status has lessened over the decades, it is likely that, as the years go on, more respondents than those who initially self-reported would have come forward as a sexual minority in large national surveys of women. For health care professionals, understanding the risk of breast cancer in sexual minority women could help them to educate their patients, thereby improving rates of screening for breast cancer, or to modify behaviors that could have numerous impacts on patient health in general. From these studies, the risk factors examined can be categorized as behavioral risks (obesity, alcohol use, tobacco use), reproductive risks (parity, use of oral contraceptives), and access to health care (health insurance status, screening).7-9 A summary of selected increased risks in sexual minority women are outlined in the Table.7-9 Behavioral Risks Obesity is associated with an increased risk of breast cancer in postmenopausal women and a higher risk of breast cancer recurrence in premenopausal and postmenopausal women.12 Cochran et al7 observed that 28% of sexual minority women were classified as obese, suggesting that a significantly larger percentage of sexual October 2016, Vol. 23, No. 4 minority women were obese than expected (P < .05). Despite this, sexual minority women were significantly less likely to consider themselves obese than women in the general population (P < .05).7 Compared with heterosexuals, lesbians and bisexuals have higher prevalence rates of obesity (50% and 40%, respectively),8 and both premenopausal groups have a significantly higher mean body mass index (P < .0001 and P = .0004, respectively).9 These data suggest that sexual minority women are more likely than heterosexual women to have challenges with obesity, which is a risk factor for breast cancer as well as other health problems. Evidence also suggests that smoking can cause breast cancer.13 Cochran et al7 reported that sexual minority women were more likely to be current or pre- vious smokers than those in the general population (P < .05). Case et al8 found that lesbians and bisexuals reported higher rates of former smoking (60% and 50%, respectively), and twice as many sexual minority women were current smokers. Increased smoking in women, including sexual minority women, likely increases their risk for breast cancer as well as other medical conditions.1 Alcohol has been considered a carcinogen to humans and has been shown to increase the risk of many cancers, including female breast cancer.14 Cochran et al7 did not note any significant differences in current alcohol use among sexual minority women compared with heterosexual women, but they did find an increased prevalence of alcohol-related problems, such Table. — Comparison of Select Studies Evaluating Risk Factors for Breast Cancer in Sexual Minority Women Author Cochran7 Case8 Austin9 Range 1986–1997 1989–1995 1989–2005 Age, y 18–75 25–43 25–42 Type of participant Heterosexual women = 19,000 Sexual minority women = 11,886 Heterosexual women = 89,812 Lesbian = 694 Bisexual = 317 Heterosexual women = 87,392 Lesbian = 665 Bisexual = 309 Risk factor Heterosexual Sexual minority Heterosexual Lesbian Bisexual Heterosexual Lesbian Bisexual Body mass index 18.3 kg/m2 27.7 kg/m2 (P < .05) 19.8%a PR: 1.0 28.1%a PR: 1.5 (95% CI: 1.4–1.7) 28.2%a PR: 1.4 (95% CI: 1.1–1.6) 22.04 kg/m2b 23.28 kg/m2b (P < .0001) 23.11 kg/m2b (P = .0004) 4.0%c 12.4%c (P < .05) 4.1%d PR: 1.0 9.2%d PR: 1.9 (95% CI: 1.5–2.3) 11.2%d PR: 2.7 (95% CI: 2.1–3.5) 3.56 ge 6.18 ge; (P < .0001) 5.18 ge; (P < .0001) Current smoker, % 16.1 21.2 (P < .05) 10.6 f PR: 1.0 18.9 f PR: 2.0 (95% CI: 1.7–2.3) 20.6 f PR: 2.2 (95% CI: 1.8–2.7) Former smoker, % 20.1 34.0 (P < .05) 23.9 g PR: 1.0 33.5 g PR: 1.6 (95% CI: 1.4–1.7) 31.5 g PR: 1.5 (95% CI: 1.3–1.8) Nulliparity Pregnancy h: 66.7% Live birthi: 56.9% Pregnancy h: 28.1% (P < .05) Live birthi: 16.0% (P < .05) 22.1% PR: 1.0 76.5% PR: 3.3 (95% CI: 2.9–3.6) 49.5% PR: 2.1 (95% CI: 1.8–2.6) No. of births: 1.71 No. of births: 0.38 (P < .0001) No. of births: 0.98 (P < .0001) History of OCP use, % 79.7 36.2 (P < .05) — — — — — — Alcohol intake NA a BMI ≥ 30.0 kg/m2 compared with < 25.0 kg/m2. BMI premenopause. c History of self-reported alcohol-related problems. d Alcohol intake ≥ 15 g/d vs none. e Alcohol intake/d (g) during premenopause. f Current smoker vs never smoker. g Former smoker vs never smoker. h History of pregnancy. iHistory of live birth. BMI = body mass index, CI = confidence interval, NA = not applicable, OCP = oral contraceptive pills, PR = prevalence ratio. b Mean October 2016, Vol. 23, No. 4 Cancer Control 375 as history of alcoholism, in sexual minority women compared with heterosexual women (P < .05). By contrast, 2 other studies found significantly increased rates of alcohol consumption: Twice as many sexual minority women drank at least 15.0 g of alcohol every day, and a significantly greater mean daily intake of alcohol during premenopause was seen among lesbians (P < .0001) and bisexuals (P < .0001) compared with heterosexual women.8,9 Thus, increased alcohol intake in sexual minority women increases the potential risk of breast cancer as well as other health problems in this population.1 Reproductive Risks Nulliparity has been associated with an increased risk of breast cancer, and increased parity can reduce a woman’s risk of breast cancer, particularly HR-positive breast cancer.15 Cochran et al7 demonstrated that sexual minority women had lower lifetime rates of pregnancy and live births when compared against national data (P < .05 for both). Furthermore, subsequent studies demonstrate that nulliparity is 3 times more likely in lesbians and twice as likely in bisexual women, with significantly reduced number of births in lesbian and bisexual women compared with heterosexual women (P < .0001 for both).8,9 These data suggest that sexual minority women are significantly more likely to be nulliparous, thus increasing their risk of breast cancer. If sexual minority women did have children, Case et al8 found that they were twice as likely to have given birth before 19 years of age, a factor associated with a decreased risk of breast cancer,16 conferring up to a 50% risk reduction compared with nulliparous women.17 However, Austin et al9 found no significant difference in age at first birth between lesbian and bisexual women compared with heterosexual women. This is a confounding factor when attempting to elucidate reproductive risk factors for breast cancer in sexual minority women. Use of oral contraceptives is associated with a decreased risk of HR-positive breast cancer.15 Cochran et al7 noted that sexual minority women reported significantly lower rates of oral contraceptive pill use than the general female population (P < .05). Although Austin et al9 did not specifically look at this factor, they did study age of menarche and found a 20% increase rate of menarche at 11 years of age or younger in lesbian women; however, subsequent data found no significant difference between lesbian and bisexual women compared with heterosexual women. Thus, these reproductive risk factors deserve further study. Access to Health Care Health insurance status is important when discussing preventive care such as screening for breast can376 Cancer Control cer. At the time of publication, most sexual minority women are unable to marry their partners by law and may have had impaired access to a partner’s employer health insurance.7 Cochran et al7 indicated lower prevalence rates of health insurance coverage (P < .05) among sexual minority women compared with standardized estimates, and sexual minority women had lower rates of previous mammograms when standardized for demographics across all age groups (P < .05). Current health insurance coverage was associated with a positive history for mammography among sexual minority women in their 40s, with 77% of insured sexual minority women vs 64% of uninsured sexual minority women having undergone mammography at least once (P < .05).7 This finding suggests that health insurance coverage could improve access to screening mammography in sexual minority women, and that sexual minority women are less likely to have health insurance coverage. However, Case et al8 found no significant difference between sexual minority women compared with heterosexual women in regard to history of mammography. Likely, this is an evolving issue. With the recent legalization of same-sex marriage, access to employer-sponsored health care insurance may change for sexual minority women. Despite the increased individual risk factors for breast cancer described in sexual minority women, no definitive studies have demonstrated an increased prevalence of breast cancer in sexual minority women.7-9 Using the Rosner–Colditz risk model, Austin et al9 predicted an incidence rate of breast cancer significantly elevated in both lesbian and bisexual women (P < .0001 for both), and this rate was consistently predicted across all age groups. Regression analysis found lesbian and bisexual women were more likely to be at higher risk than heterosexual women of similar age, race, geography, and income. However, sexual minority women have not been shown to have an increased rate of breast cancer when compared with the general population. Cochran et al7 were unable to link sexual minority women with an increased prevalence of breast cancer compared with US women in general. A self-reported history of breast cancer among sexual minority women was 0.9%, which was concordant with expected standardized estimates, and no statistically significant difference in self-reported prevalence of breast cancer between the study sample of sexual minority women and US estimates for women was observed.7 Therefore, sexual minority women may not have an increased incidence or prevalence rate of breast cancer despite their increased predicted risk. Modulating Risk Based on identified individual risk factors, attempts are warranted by health care professionals to modify paOctober 2016, Vol. 23, No. 4 tient behavior in the hopes that doing so will improve the health of sexual minority patients. It is important to note that many of the risk factors for breast cancer identified in sexual minority women are modifiable behavioral risks.7-9,12,14 Bowen et al18 attempted to modulate risk by increasing screening participation in sexual minority women using group counseling. This prospective study randomized sexual minority women to a counseling (n = 69) or control group (n = 81). The intervention included psychosocial counseling with education, group discussion, and skills training during 4 weekly 2-hour sessions led by a trained health counselor specializing in sexual minority women. Weekly sessions had themes that included a personalized breast cancer risk assessment, discussions of mammography, recommendations for self-examinations and clinical breast examination, stress management, progressive muscle relaxation and guided imagery, and social support in 4 main areas (emotional, informational, instrumental, and companionship) focused on devising strategies for increasing support where needed.18 At 6 and 24 months, participants were evaluated on perceived risk of breast cancer, worry of cancer, mental health, “outness,” and identification with the lesbian community.18 At 24 months, the intervention group reported a higher rate of breast cancer screening in the past 2 years compared with the control group (87% vs 75%; P < .05). The intervention group also had a significantly higher rate of breast self-examinations at 6 (P < .01) and 24 months (P < .05) than the control group.18 The intervention group changed more over time in perceived risk (P < .001), cancer worry (P < .001), and mental health (P < .01).18 Regression analysis showed identification with the lesbian community and feelings of outness were predictors of participation in screening mammography and a feeling of outness was also a significant predictor of performing a breast self-examination. With education and group counseling structured for sexual minority women, these researchers demonstrated that trained health counselors can successfully increase participation of sexual minority women in breast cancer screening.18 However, it is worth noting that this study has limitations because it studied 1 volunteer group in a single community, thus making it difficult to generalize to all sexual minority women. It is encouraging to think that an intensive, demographical directed counseling intervention can improve the participation of sexual minority women in breast cancer screening.18 However, without a heterosexual cohort, it is difficult to know whether behavior modification is specific to sexual minority women or generalizable to others. Although it is not reasonable to assume that a health care professional would have the resources to educate his or her sexual minority patients to such a degree that this study entails, improvOctober 2016, Vol. 23, No. 4 ing participation in breast cancer screening for sexual minority women is important. Sexual minority women have consistently lower lifetime prevalence rates of screening mammography than expected across all age groups, although this is likely confounded by their decreased access to health care.7 Improving the participation rates of breast cancer screening among sexual minority women are important, but opportunities still exist to modulate other modifiable high-risk behaviors identified in sexual minority women, such as alcohol intake, obesity, and smoking.7-9 Health care professionals should be aware of these modifiable risk factors associated with breast cancer and other health problems, as they may present an educational opportunity to promote healthy behaviors. Clinicians should also be encouraged that intensive education is successful at promoting behavioral change in sexual minority women and improving their participation with breast cancer screening.18 Mortality The goals of reducing risk and modifying behavior should be to lower the mortality rate associated with breast cancer and promote healthy living. Cochran and Mays6 examined the mortality risk of breast cancer among sexual minority women using the National Health Interview Survey, which is an annual population-based, household interview of married or cohabitating women 18 to 80 years of age that was conducted between 1997 and 2003. Of the 155,427 respondents, 693 reported having female partners (0.5%).6 Sexual minority women were younger (P < .001), had higher levels of education (P < .001) and higher family incomes (P < .05), were less likely to have health insurance (P < .05), and were more likely to be in a cohabitating relationship rather than be married (P < .001).6 The mortality rate of breast cancer was identified using the National Death Index: Of the 4,396 identified deaths, 274 (3.1%) were attributed to death from breast cancer.6 Age, race, education, family income, and health insurance coverage were strongly associated with death from any cause (P < .001 for all).6 After adjusting for confounding variables, sexual minority women were not at increased risk of overall mortality; however, sexual minority women had an elevated risk for breast cancer–related mortality compared with heterosexual women (P < .05).6 Overall, sexual minority women were 3 times more likely to die from breast cancer after adjusting for age, although the researchers did not evaluate the prevalence of breast cancer in the sexual minority population. The data are limited because they only include women who were in a defined relationship and, thus, the data cannot be generalized to sexual minority women without partners. In interpreting potential reasons for this difference in mortality rates, a review of the risk facCancer Control 377 tors previously discussed is important. Is there an increased rate of incidence or prevalence of breast cancer not yet identified in sexual minority women because of reproductive and behavioral risks that leads to this increased mortality risk of breast cancer? Perhaps the increased mortality risk of breast cancer among sexual minority women could be due to later diagnoses because of decreased access to health care due in part to lack of insurance or decreased rates of screening. Cochran and Mays19 attempted to validate their findings by reviewing mortality risks associated with sexual orientation both in women and in men using data from the General Social Surveys and comparing mortality status using the same National Death Index. Respondents were interviewed face-to-face in their household and then were self-administered questionnaires or computer-assisted self-interviews; these responses were matched to National Death Index records.19 Sexual orientation was classified based on lifetime numbers of male or female sexual partners and the gender of those sexual partners in the year prior to the interview. Of the 17,886 respondents who completed the interview/questionnaire, 853 (4.8%) reported a history of same-sex partners. Results were then subdivided by race, education, income, geographical region, overall self-rated health status, and generalized self-reported happiness. Similar to the previous study, sexual minority women were younger and reported higher education6; however, in this cohort, sexual minority women had lower household incomes and, geographically, more sexual minority women lived in western states.19 All-cause mortality among women was significantly associated with older age, non-white race, and lower education (P < .001 for all), but sexual minority status was not significantly correlated with all-cause mortality or breast cancer, even after multivariate survival analysis (all-cause mortality, P = .72; breast cancer mortality, P = .27).19 Overall, 9.1% of sexual minority women died from breast cancer vs 4.4% of heterosexual women.19 Thus, Cochran and Mays19 were unable to replicate their 2013 findings,6 and it is unclear whether sexual minority women have an increased risk of mortality from breast cancer. The later study benefited from a much broader definition of sexual orientation (it included lifetime partners), which helped capture people not in current same-sex relationships.19 However, sexual orientation remains difficult to objectively measure due to inherent self-reporting bias in identifying sexual minority status. Overall, the later study reported more same-sex partners (4.8% vs 0.5%), but this is still a relatively low percentage of respondents — possibly underpowering the study.6,19 Thus, further research is necessary. 378 Cancer Control Breast Reconstruction A unique aspect of the treatment for female breast cancer is the impact that surgery, including breast reconstruction, can potentially have on a patient’s self-identity.20 In general, breast cancer treatment is dictated by tumor biology, particularly with regard to systemic therapy; sexual orientation has no impact on chemotherapeutic or hormonal therapy recommendations.1 However, surgery for breast cancer is the cornerstone of breast cancer management in many American women.1 Decision-making regarding breast reconstruction in these patients is not well understood, but it has the potential for disparate care among women.20 In particular, breast reconstruction is scrutinized because of the presumed heterosexual focus of the breast, as well as an example of health care access.20 A paucity of literature exists on use of reconstruction options in sexual minority women. It is possible that sexual orientation and self-identity could have significant impact on decisions regarding type of oncological surgery and whether or not a patient would desire reconstruction. Sexual minority women may perceive that health care professionals are not always considering sexual orientation when making recommendations for surgery or reconstruction. The scientific literature on sexual minority women and their decisions to undergo breast reconstruction is limited: A single, retrospective, qualitative study has explored decisions by sexual minority women for or against reconstruction.20 A total of 15 self-reported sexual minority women diagnosed with nonrecurrent and nonmetastatic breast cancer who completed invasive treatment within the past 5 years completed demographical surveys and a disclosure scale. These participants were separated into breast reconstruction and no breast-reconstruction groups. Semi-structured interviews covered diagnosis, treatment course, treatment decision-making, sources of social support, and adjustment; participants identified support persons who were then interviewed covering similar topics. Comparisons of demographics, clinical stage, receipt of adjuvant therapy, and time since diagnosis revealed that the groups were similar. All support persons were female, and the majority of support persons were partners. Mastectomy was recommended for some, whereas others opted for mastectomy to avoid radiotherapy; one-half of participants underwent breast conservation before undergoing mastectomy.20 Of those in the reconstruction group (n = 8), 3 had autologous reconstruction, 5 had implant-based reconstruction, 3 received chemotherapy, 3 received radiotherapy, and 6 received hormonal therapy; of those in the no-reconstruction group (n = 7), 4 received chemotherapy, 2 received radiotherapy, and 4 received hormonal therapy.20 The researchers discovered that breast size was a consideration among the participants when deciding October 2016, Vol. 23, No. 4 whether to accept or reject reconstruction.20 Sexual minority women with small breasts felt more comfortable rejecting reconstruction, whereas sexual minority women with larger breasts feared being unbalanced and having a heavy prosthesis. Both groups mentioned the importance of the breast for their self-image but emphasized physical functioning and body strength over aesthetics. Sexual minority women emphasized that their sexual minority status contributed to them not being defined by the presence of their breasts, and they noted a discrepancy between their values and body image and those of mainstream society — this was especially true when communicating with specialists in breast cancer. Sexual minority women who decided against reconstruction emphasized strength, long-term health, and survival; they complained less of physical problems but did discuss having to adjust to their changed body shape; they did not voice doubts or regrets about their choice. Their partners emphasized body image and their value system as motivators, and they confirmed the same satisfaction with respect to body image. They characterized making the decision jointly, and they reported attraction and desire being present as before.20 Sexual minority women who underwent reconstruction reported physical issues, including numbness and limited range of motion; 1 woman reversed her reconstruction completely.20 The group expressed doubt or regret about their choice and lack of information about potential complications. Some opted for reconstruction to cover the physical effects of the cancer and regain a “normal” appearance, although some chose to forego formal nipple reconstruction.20 Their partners confirmed that outcomes of the reconstruction had not been thoroughly explained by the plastic surgeon, and they echoed doubts about reconstruction; their partners were characterized as more passive in the decision-making process, and these couples displayed discordance in values and body image.20 Women without a partner at the time of their decision were influenced by their relationship status, and support persons not in a partner relationship were more reluctant to express reconstructive preferences. Overall, sexual minority women who underwent reconstruction expressed doubt and regret; by contrast, sexual minority women who elected against reconstruction did not, and this finding was echoed by their support persons.20 However, this study has limitations, including its small convenience sample, retrospective recall bias, and, thus, low applicability to the general population.20 This study also has no comparison to a heterosexual control, making it difficult to define the themes as unique to sexual minority women, but it did outline potential themes that may arise for sexual minority women as they embark on their decision for or against reconstructive surgery.20 October 2016, Vol. 23, No. 4 It is also worth underscoring that the notion that women may regret undergoing reconstruction after mastectomy may not be limited to the sexual minority community. Metcalfe et al21 prospectively followed patients after mastectomy with and without delayed breast reconstruction and found that psychosocial functioning improves over time in patients following mastectomy. During the long-term follow-up, women with delayed breast reconstruction had significantly higher levels of total distress (P = .01), obsessiveness (P = .03), and cancer-related distress (P = .02) compared with those who underwent mastectomy alone, although no differences were seen in quality of life between the 2 groups.21 Metcalfe et al22 published another report that demonstrated no difference in body image for women with mastectomy alone compared with mastectomy and immediate breast reconstruction. They further found that women with delayed breast reconstruction had higher levels of body stigma (P = .01), body concerns (P = .002), and concerns regarding the obviousness of mastectomy-related changes in appearance (“transparency”; P = .001) than mastectomy alone or mastectomy with immediate reconstruction.22 Another study reported on women who underwent breast-conserving surgery, mastectomy alone, and mastectomy with reconstruction, and it found that women who underwent mastectomy with reconstruction had greater mood disturbance and poorer well-being (P = .002 for both) compared with those who underwent mastectomy alone.22 This finding persisted up to 18 months after surgery. All of these studies suggest the potential for selection bias for women who undergo breast reconstruction — in particular, delayed breast reconstruction — as pursuing that option because of their underlying distress regarding their body image.20-22 It is difficult to generalize this information to sexual minority women, but these issues of dissatisfaction may not be unique to either population. It is important for health care professionals to understand that sexual minority women may have a different perspective on breast reconstruction after mastectomy regardless of their surgical choice for or against reconstruction. Boehmer et al22 described sexual minority women as not being defined by having breasts, emphasizing body strength and physical functioning over aesthetics, and “otherness,” described as a discrepancy of values and body image among sexual minority women when compared with the general population. Overall, health care professionals must be aware of a patient’s sexual orientation and include the patient’s support persons or partners in discussions regarding treatment. Health care professionals should also consider how the presence or absence of the breast might affect the patient’s body image, understanding that sexual minority women may not feel emotionally attached to the physical Cancer Control 379 presence of their breasts. Health care professionals should also discuss physical functioning after breast reconstruction and not limit the discussion to aesthetics alone. Reconstructive options should be clearly and comprehensively presented, elucidating realistic expectations for patients. Transgender Persons The term transgender defines a person whose self-identity does not conform to gender norms, and many patients may choose to use medical or surgical means to live as another gender. The risk of breast cancer is particularly relevant due to cross-sex hormone therapy for many patients who desire to feminize or masculinize their appearance. In general, research on breast cancer in the transgender community is limited, and our understanding is also limited with regard to how hormonal therapy affects a person’s risk of breast cancer. Sattari et al23 summarized the cases of male-to-female transgender patients with breast cancer published in the literature since 1968. The authors identified 10 cases of breast cancer in male-to-female transgender persons, all of whom received long-term cross-sex hormone treatment; 7 of the cases had ER status reported (n = 5 negative, n = 2 positive).23 Thus, breast cancer in general appears to be rare among male-to-female transgender persons, although it is difficult to make any generalizations about the risks of cross-sex hormone therapy in this transgender population. Understanding the risk of breast cancer in femaleto-male transgender persons who take testosterone for masculinization is important, because it is likely different from the risk of breast cancer in male-to-female transgender persons. Circulating testosterone is converted to estradiol by aromatase enzyme, and higher levels of circulating testosterone could increase peripheral estrogen. Shao et al24 described 2 cases of female-to-male transgender persons, both of whom took testosterone for masculinization. One patient was postmenopausal (aged 48 years) when testosterone was initiated, was also taking an aromatase inhibitor for symptoms of endometriosis, and was diagnosed with breast cancer 5 years later; the other case patient was premenopausal (aged 21 years) when testosterone was initiated and then diagnosed with breast cancer 6 years later. Both patients had ER-positive breast cancer, and both tested negative for a deleterious BRCA mutation.24 These cases are worth noting, but they do not provide conclusive evidence for an increased risk of breast cancer in transgender persons receiving cross-sex hormone therapy. A study by the US Veterans Health Administration (VHA) is the largest and most comprehensive research on breast cancer in the transgender community (as of publication).25 This research has evaluated the inci380 Cancer Control dence of breast cancer in transgender men and women treated within the VHA. Using encounter and prescription data from 1996 to 2013, transgender-related diagnosis and breast cancer events were identified within the VHA system.25 Medical records were reviewed for any patients with both a transgender-related diagnosis and a breast cancer event; cross-sex hormone therapy prescribed by a VHA physician was classified as androgen/anabolic or estrogen. The incidence rates of breast cancer were compared with Surveillance, Epidemiology, and End Results data from 2007 to 2011 using overall observed and expected rates.25 Of approximately 6 million veterans seen every fiscal year, 5,135 had a transgender-related diagnosis, 1,579 were female at birth, and 3,556 were male at birth.25 No statistically significant difference was observed in breast cancer incidence among women, men, and in the overall population. For the entire sample, 10 confirmed cases of breast cancer were found in transgender veterans (0.2%), 7 in female-to-male veterans, 2 in male-to-female veterans, and 1 in a natal male veteran with transvestic fetishism.25 The average age at diagnosis was 63.8 years and all participating veterans racially self-identified as non-Hispanic white. Breast cancer surgery was performed in 8 transgender veterans; 4 patients died. Of those patients not receiving cross-sex hormone therapy, breast cancer was diagnosed in 3 transgender men and 1 transgender woman. For those patients receiving cross-sex hormone therapy breast cancers occurred in 3 transgender women, and 3 cases of female breast cancer occurred in transgender veterans who received cross-sex hormone therapy many years following their diagnosis of breast cancer.25 More than one-half (52%; n = 2,645) of transgender veterans received at least 1 prescription for cross-sex hormone therapy, with the average duration of treatment being 6.5 years and the average age at initial treatment being 48.9 years.25 None of the males prescribed crosssex hormone therapy developed breast cancer, suggesting that male breast cancer is rare in the transgender population receiving cross-sex hormone therapy. Breast cancers occurred in 3 transgender female veterans receiving cross-sex hormone therapy (n = 2 received estrogen products, n = 1 received testosterone products) prior to diagnosis.25 In general, no significant difference was observed for transgender patients receiving estrogen, testosterone, or cross-sex hormone therapy when compared with the overall cohort.24 Transgender veterans receiving cross-sex hormone therapy had no increased risk of breast cancer, and the overall incidence of breast cancer in transgender persons was low; however, late presentations in the 3 male patients with breast cancer and the high mortality rate seen in transgender veterans are concerning.25 Clinicians should consider breast and chest examinations and possible mammography, if indicated, in this October 2016, Vol. 23, No. 4 subset of patients. History of chest-contouring surgery or mastectomy does not preclude the development of breast cancer, as observed in 1 female-to-male transgender patient in this study.25 This study did not include gene mutation data because they were not readily available, but it is the largest series of transgender patients with breast cancer reported in the literature to date.25 Interpretation of the use of cross-sex hormone therapy may be limited because the study required that at least 1 prescription was obtained through the VHA system to identify the patient as receiving cross-sex hormone therapy.24 For example, if a patient received cross-sex hormone therapy outside of the VHA system, then the therapy may not have been recorded.25 Typically, male breast cancer is hormonally sensitive (92%).2,26 As data have emerged and are now associating female breast cancer with use of perimenopausal estrogen-based hormone replacement therapy, concern exists about the potential risks of estrogen therapy in male-to-female transgender persons.27 However, male breast cancer is rare in the transgender population.25 At this time, the evidence is insufficient to support an increased incidence of breast cancer in transgender male-to-female persons, even when taking cross-sex hormone therapy. Risk of breast cancer may be different in the female-to-male transgender population compared with the general population. In female-to-male persons receiving testosterone cross-sex hormone therapy, theoretical concern of breast cancer is extrapolated from the data on perimenopausal estrogen-based hormone therapy.27 The theory postulates that the metabolism of testosterone could increase peripheral estrogen levels, and, as reported in Shao et al,24 2 such patients both developed ER-positive breast cancer. However, only 1 female-to-male patient receiving testosterone crosssex hormone therapy in the VHA transgender cohort developed breast cancer.25 Although transgender females are at an increased risk of breast cancer due to their sex at birth compared with male-to-female transgender patients, the data are lacking for us to conclude whether an increased risk of breast cancer exists in transgender female-to-male patients receiving cross-sex hormone therapy compared with the general female population. Moreover, the data do not support an increased incidence of breast cancer in transgender persons receiving cross-sex hormone therapy, and, in general, breast cancer in transgender persons is rare or under-reported.23 However, the scientific research related to transgender persons is lacking, making conclusions difficult to draw. It does highlight the fact that more research is needed. Conclusions Breast cancer is the most common cancer and second most common cause of cancer-related death in American women.1 Given the pervasive nature of breast canOctober 2016, Vol. 23, No. 4 cer, many researchers have looked into specific groups of women in an effort to identify and reduce disparities in breast cancer among different populations of women. Numerous racial and socioeconomic disparities have already been identified, but research on sexual orientation and disparities in breast cancer is still limited and the data contradictory.3 Some evidence supports that sexual minority women have higher rates of risk factors associated with breast cancer.6,7 Studies are conflicting on which risk factors are more common in sexual minority women, but such risk factors consistently noted to be increased in sexual minority women include nulliparity, a history of smoking, and increased alcohol consumption.7-9 Published data also showed lower rates of health insurance coverage and decreased rates of breast cancer screening in sexual minority women.6,7 Despite an increase in risk factors, no clear increased incidence or prevalence rate for breast cancer in sexual minority women has been identified,7,8 and research on breast cancer in the transgender population remains limited. Utilizing education and structured support groups for sexual minority women help to improve rates of participation in breast cancer screening,18 and health care professionals should consider breast and chest examinations as well as mammography in transgender patients. Clinicians should also be aware of the sexual orientation of their patients and the potential association with disparities in breast cancer and differences in related outcomes. Recent legislation supporting same-sex marriage may improve the documentation of sexual orientation, so health care professionals should be aware of their patient’s sexual orientation and include support persons in treatment discussions, as needed, to ensure they understand the patient’s goals while counseling them on treatment options, including breast reconstruction. Consistent documentation of gender preferences as part of the medical record could improve the delivery of personalized care. Large-scale databases should consider adding sexual orientation to their demographical data to allow for more robust research. With these considerations in mind, researchers should consider standardizing terminology regarding sexual minority patients to allow for more cohesive dialogue in the scientific literature. References 1. American Cancer Society. Cancer Facts & Figures 2016. http://www. cancer.org/acs/groups/content/@research/documents/document/acspc047079.pdf. Accessed October 3, 2016. 2. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. SEER Stat Fact Sheets: Female Breast Cancer. http://seer.cancer. gov/statfacts/html/breast.html. Accessed July 1, 2016. 3. Bigby J, Holmes MD. Disparities across the breast cancer continuum. Cancer Causes Control. 2005;16(1):35-44. 4. Brown JP, Tracy JK. Lesbians and cancer: an overlooked health disparity. Cancer Causes Control. 2008; 19(10):1009-1020. 5. Mayer KH, Bradford JB, Makadon MD, et al. Sexual and gender minority health: what we know and what needs to be done. Am J Pub Health. 2008;98(6):989-995. Cancer Control 381 6. Cochran SD, Mays VM. Risk of breast cancer mortality among women cohabiting with same sex partners: findings from the National Health Interview Survey, 1997-2003. J Womens Health (Larchmt). 2012;21(5):528-533. 7. Cochran SD, Mays VM, Bowen D, et al. Cancer-related risk indicators and preventative screening behaviors among lesbians and bisexual women. Am J Public Health. 2001;91(4): 591-597. 8. Case P, Austin SB, Hunter DJ, et al. Sexual orientation, health risk factors, and physical functioning in the Nurses’ Health Study II. J Womens Health (Larchmt). 2004;13(9):1033-1047. 9. Austin SB, Pazaris MJ, Rosner B, et al. Application of the RosnerColditz risk prediction model to estimate sexual orientation group disparities in breast cancer risk in a U.S. cohort of premenopausal women. Cancer Epidemiol Biomarkers Prev. 2012;21(12):2201-2208. 10. Meads C, Moore D. Breast cancer in lesbians and bisexual women: a systematic review of incidence, prevalence and risk studies. BMC Public Health. 2013;13:1127. 11. Hart SL, Bowen DJ. Sexual orientation and intentions to obtain breast cancer screening. J Womens Health (Larchmt). 2009;18(2):177-185. 12. Jain R, Strickler HD, Fine E, et al. Clinical studies examining the impact of obesity on breast cancer risk and prognosis. J Mammary Gland Biol Neoplasia. 2013;18(3-4):257-266. 13. Reynolds, P. Smoking and breast cancer. J Mammary Gland Biol Neoplasia. 2013;18(1):15-23. 14. Scoccianti C, Lauby-Secretan B, Bello PY, et al. Female breast cancer and alcohol consumption: a review of the literature. Am J Prev Med. 2014;46(3 suppl 1): S16-S25. 15. Anderson KN, Schwab RB, Martinez ME. Reproductive risk factors and breast cancer subtypes: a review of the literature. Breast Cancer Res Treat. 2014;144(1):1-10. 16. Hunter DJ, Speigelman D, Adami HO, et al. Non-dietary factors as risk factors for breast cancer and as effect modifiers of the association of fat intake and risk of breast cancer. Cancer Causes Control. 1997;8(1):49-56. 17. Kobayashi S, Sugiura H, Ando Y, et al. Reproductive history and breast cancer risk. Breast Cancer. 2012;19(4):302-308. 18. Bowen DJ, Powers D, Greenlee H. Effects of breast cancer risk counseling for sexual minority women. Health Care Women Int. 2006;27(1):59-74. 19. Cochran SD, Mays VM. Mortality risks among persons reporting same-sex sexual partners: evidence from the 2008 General Social SurveyNational Death Index data set. Am J Public Health. 2015;105(2): 358-364. 20. Boehmer U, Linde R, Freund KM. Breast reconstruction following mastectomy for breast cancer: the decisions of sexual minority women. Plast Reconstr Surg. 2007;119(2):464-472. 21. Metcalfe KA, Zhong T, Narod SA, et al. A prospective study of mastectomy patients with and without delayed breast reconstruction: long-term psychosocial functioning in the breast cancer survivorship period. J. Surg. Oncol. 2015;111(3):258-264. 22. Metcalfe KA, Semple J, Quan ML, et al. Changes in psychosocial functioning 1 year after mastectomy alone, delayed breast reconstruction, or immediate breast reconstruction. Ann Surg Oncol. 2012;19(1):233-241. 23. Sattari M. Breast cancer in male-to-female transgender patients: a case for caution. Clin Breast Cancer. 2015;15(1):e67-e69. 24. Shao T, Grossbard ML, Klein P. Breast cancer in female-to-male transsexuals: two cases with a review of physiology and management. Clin Breast Cancer. 2011;11(6): 417-419. 25. Brown GR, Jones KT. Incidence of breast cancer in a cohort of 5,135 transgender veterans. Breast Cancer Res Treat. 2015;149(1):191-198. 26. Ruddy KJ, Winer EP. Male breast cancer: risk factors, biology, diagnosis, treatment, and survivorship. Ann Oncol. 2013;24(6):1434-1443. 27. Women’s Health Initiative Study Group. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-333. 382 Cancer Control October 2016, Vol. 23, No. 4 A large racially and ethnically diverse database was created and TMAs of IDC were constructed to represent African American, Hispanic, and non–Hispanic-white patient populations. Proteus. X-Ray image courtesy of Bryan Whitney. www.x-rayphotography.com. Construction and Validation of a Multi-Institutional Tissue Microarray of Invasive Ductal Carcinoma From Racially and Ethnically Diverse Populations Edward Seijo, MS, Diana Lima, MPH, Egiebade Iriabho, MS, Jonas Almeida, PhD, Jesus Monico, MPH, MS, Margarita Echeverri, PhD, Sylvia Gutierrez, MD, Idhaliz Flores, PhD, Ji-Hyun Lee, PhD, Kate Fisher, MA, William E. Grizzle, MD, PhD, Gabriel L. Sica, MD, PhD, Charles Butler, Chindo Hicks, PhD, Cathy D. Meade, PhD, RN, Stephen Olufemi Sodeke, PhD, Krzysztof Moroz, MD, Domenico Coppola, MD, and Teresita Muñoz-Antonia, PhD Background: The scarcity of tissues from racial and ethnic minorities at biobanks poses a scientific constraint to research addressing health disparities in minority populations. Methods: To address this gap, the Minority Biospecimen/Biobanking Geographic Management Program for region 3 (BMaP-3) established a working infrastructure for a “biobanking” hub in the southeastern United States and Puerto Rico. Herein we describe the steps taken to build this infrastructure, evaluate the feasibility of collecting formalin-fixed, paraffin-embedded tissue blocks and associated data from a single cancer type (breast), and create a web-based database and tissue microarrays (TMAs). Results: Cancer registry data from 6 partner institutions were collected, representing 12,408 entries from 8,279 unique patients with breast cancer (years 2001–2011). Data were harmonized and merged, and deidentified information was made available online. A TMA was constructed from formalin-fixed, paraffin-embedded samples of invasive ductal carcinoma (IDC) representing 427 patients with breast cancer (147 African Americans, 168 Hispanics, and 112 non-Hispanic whites) and was annotated according to biomarker status and race/ethnicity. Biomarker analysis of the TMA was consistent with the literature. Conclusions: Contributions from participating institutions have facilitated a robust research tool. TMAs of IDC have now been released for 5 projects at 5 different institutions. From the Tissue Core Facility (ES), Departments of Thoracic Oncology (DL), Health Outcomes and Behavior (CM), and Pathology (CD), Biostatistics and Bioinformatics Core (KF), and Tumor Biology Program (TM-A), H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, Pathology Informatics Core (EI, JA) and Pathology Program for Translational Research in Neoplasia (WEG), University of Alabama at Birmingham, Birmingham, Alabama, Departments of Pathology (JM) and Medicine and Cancer Institute (CH), University of Mississippi Medical Center, Jackson, Mississippi, Center for Minority Health and Health Disparities Research and Education, Xavier University of Louisiana (ME) and Department of Pathology, Tulane University School of Medicine (KM), New Orleans, Louisiana, Department of Anatomy (SG) and Department of Microbiology (IF), Ponce Health Sciences University, Ponce, Puerto Rico, Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico (J-H L), Department of Pathology and Laboratory Medicine, Winship Cancer Institute and Emory School of Medicine, Atlanta, Georgia (GLS, CB), and Tuskegee University National Center for Bioethics in Research and Health Care, Tuskegee, Alabama (SOS). Submitted March 3, 2016; accepted May 31, 2016. Address correspondence to Teresita Muñoz-Antonia, PhD, Tumor Biology Program, Moffitt Cancer Center, 12902 Magnolia Drive, MRC-3 WEST, Tampa, FL 33612. E-mail: [email protected] This work was supported in part by the Tissue Core Facility and Bioinformatics and Biostatistics Core at Moffitt Cancer Center, a National Cancer Institute–designated Comprehensive Cancer Center (P30-CA076292). October 2016, Vol. 23, No. 4 Cancer Control 383 Introduction The burden of cancer disparities on African American and Hispanic populations has been well documented.1-8 It is our opinion that discoveries in precision medicine and basic science with the potential to improve the prognosis or treatment of cancer in affected individuals might be limited by the scarcity of research biospecimens from racial/ethnic minority populations. The availability of diverse samples is key to inclusive precision medicine.9 For example, the triple-negative breast cancer subtype, defined by the absence of ER, PR, and ERBB2 (formerly HER2 or HER2/neu) expression, accounts for 10% to 20% of all breast cancer cases, with an uneven distribution among ethnicities.10 In African American women, triple-negative breast cancer is nearly twice as prevalent as it is in European Americans, with some studies reporting triple-negative subtypes in up to 40% of all breast cancer cases among premenopausal African Americans.10,11 Consistent with this observation, epidemiological studies have shown substantial differences in rates of breast cancer mortality between racial groups.5,8,12 For example, premenopausal African American women have a lower 5-year breast cancer–related survival rate than European American women (79.0% vs 91.0%, respectively), placing them at a higher risk of mortality despite an overall lower incidence of breast cancer.12 This disparity may be due to the increased frequency of triple-negative breast cancer observed in African American women who typically present at a later disease stage and are more likely to have lymph-node metastases at similar tumor sizes.13 Study findings have revealed that Hispanic women have a higher prevalence of ER-negative tumors compared with non-Hispanic women (36.2% vs 22.7%; P = .05) and an unexpectedly high proportion of ERBB2-positive tumors compared with non-Hispanic women (31.9% vs 14.3%; P < .01).14 These findings, coupled with more recent data, suggest that considerable molecular differences in cancers may exist in various ethnic groups.10 Because molecular features can be used for predicting cancer prognosis and therapeutic response, research focused on understanding the molecular features of cancers occurring in ethnic minorities is important. Purpose To address the lack of tissue-based studies for ethnic minorities with cancer, the Biospecimen/Biobanking Geographic Management Program (BMaP) was initiated by the National Cancer Institute’s Center to Reduce Cancer Health Disparities. BMaP coordinated regional efforts focused on health disparities in cancer research, training, and care and was organized into 6 geographical regions within the United States. BMaP region 3 (BMaP-3), which makes up the south384 Cancer Control eastern region, consists of Alabama, Florida, Georgia, Louisiana, Mississippi, and Puerto Rico, and it included 9 partner institutions that created a collaborative network. A key goal for BMaP-3 was to develop a stateof-the-art network that could provide a foundation and infrastructure to adequately and continuously supply high-quality, multiethnic, human biospecimens for cancer research. Since 2015, the National Cancer Institute has reorganized and consolidated the regions into 6 regions, and the institutions previously in region 3 are now, at the time of publication, in Geographical Management of Cancer Health Disparities region 2.15 In 2014, members of the participating BMaP-3 institutions completed a comprehensive assessment tool that revealed a diversity of samples by race/ethnicity and cancer site were available as formalin-fixed, paraffin-embedded (FFPE) tumor samples or fresh-frozen samples (from 6 of 9 institutions).16 In addition, 5 of the institutions had a tissue advisory/steering committee, thus providing the necessary infrastructure and expertise to build a network approach. This provided the basis for the design of a BMaP-3 pilot study to test the feasibility of developing and implementing a regional, web-based database of available biospecimens and collecting FFPE blocks to create unique tissue microarrays (TMAs) for health disparities in cancer research. This pilot study represents a regional team, science-oriented approach for constructing and validating multi-institutional breast cancer TMAs from a racially and ethnically diverse population. Using the construction and validation of a breast cancer TMA as an example, we illustrate how a regional team, science-oriented approach can effectively leverage the tissue and database resources of multiple institutions to facilitate tissue-based studies for a minority cohort — a difficult challenge for single institutions alone. Materials and Methods The research conducted in this study was performed with tissue samples and patient data unlinked from patient identifiers. Approval or waiver of informed consent was obtained by the Institutional Review Boards of the 6 institutions contributing FFPE biospecimens and data to support this pilot study. Collection and Management of Data Cancer registry coding discrepancies were harmonized by adopting a standardized coding for each variable and systematically replacing prior coding with current coding using software R v2.15.2 (R Foundation for Statistical Computing, Vienna, Austria). Patient cases were removed from the data sets for any of the following reasons: younger than 18 years of age at diagnosis (n = 1), tumor marker and site-specific factor did not agree for either ER or PR status (n = 157), had a Spanish surname and unknown “Spanish Hispanic” variOctober 2016, Vol. 23, No. 4 able (n = 17), or assigned a study identification number that already existed (n = 1). The original site-specific factor 16 was captured after the year 2010; therefore, the site-specific factor was manually derived from the tumor marker 1 ER assay, tumor marker 2 PR assay, and ERBB2 variables, with assignments of either HR+/ ERBB2+, HR+/ERBB2–, PR–/ER–/ERBB2+, or PR–/ER–/ ERBB2–. If the original site-specific factor 16 disagreed with the derived site-specific factor, then the entry was deemed unreliable and was deleted (n = 19). Multi-Institutional, Web-Based Database To ensure no changes were made to the data set originally merged by the biostatistician, the web-based data set was exported and a comparison of the webbased data set against the original merged data set was executed. Counts were also verified between both data sets. The aggregated data were posted on a website (http://labpages.moffitt.org/bmap3/Cancer%20Database/Cancer_Database.html [access restricted]) in the form of an output of descriptive statistics generated by SPSS (IBM, Armonk, NY). BMaP-3 public access database (PAD) has logging features enabled so that, in the event of improper data modification, the user account responsible, the data that were changed, and the time of the change can be identified and corrected in a timely manner. The governance model for the BMaP-3 PAD consists of 3 hierarchical user-access levels (administrator, data manager, and investigator), ranging from full to search access. Archival Case Selection and Tissue Microarray Construction Each archival tissue sample was categorized according to tumor expression of ER, PR, and ERBB2. For each case, optimal areas for inclusion as cores in the TMA were marked on the slides stained with hematoxylin and eosin by pathologists. When sufficient tumor tissue was available, 3 or fewer 1-mm cores from each selected donor block were punched and put into 8 TMAs 60 × 10 mm in size using Tissue Arrayer (Beecher Instruments, Sun Prairie, WI). Each TMA also included 1 sample of normal breast tissue. Cores from kidney, spleen, and tonsil, as well as melanoma, human breast cancer lines (MCF-7 and MDA231), human prostate adenocarcinoma cells (LNCaP), and human ovarian carcinoma cells (SK-OV-3), were included as reference cells/tissues. Immunohistochemical Staining and Evaluation All TMA slides were stained with hematoxylin and eosin and processed for whole-slide imaging. Each TMA slide was scanned using ScanScope XT (Aperio, Vista, CA) with a 20×/0.8 numerical aperture objective lens at a rate of 10 minutes per slide. Image analyses for stained TMAs were performed using Nuclear v9.1 (Aperio) to segment nuclei of various intensities. The October 2016, Vol. 23, No. 4 captured hematoxylin and eosin stained images were made available to investigators at all participating institutions. The biomarker status obtained from cancer registry data was validated with immunostains for estrogen receptor (ER), progesterone receptor (PR), and erb-b2 receptor tyrosine kinase 2 (ERBB2) using the following antibodies from Ventana Medical Systems (Tucson, AZ): 790-4324 CONFIRM anti-ER (SP1), 7902223 CONFIRM anti-PR (1E2), and 790-100 PATHWAY anti-HER2/Neu (4B5). Antigen retrieval and incubation times were optimized for each antibody as follows: 60-minute retrieval for ER and PR antibodies; 30-minute retrieval for ERBB2 antibodies; 32-minute incubation for the ER antibody; and 16-minute incubation for the PR and ERBB2 antibodies. The Ventana Benchmark XT (Tucson, AZ) platform was used for all immunohistochemistry analyses. The Allred scoring system was used to score the ER and PR stains.17 ERBB2 stains were scored in accordance with guidelines from the College of American Pathologists, which defines ERBB2-positive status by immunohistochemistry as protein overexpression.18 The HR rules for the categorization of cases were: if either ER or PR is positive, then HR+; if both are negative, then HR–; and if both ER and PR are missing, or if one is missing and the other is negative, then it was labeled as “missing.” Results Building an Infrastructure To ensure equitable governance for issues concerning human biospecimen research sponsored by BMaP-3, a Tissue Advisory Board was formed with representatives from all 9 BMaP-3 institutions. A collaboration agreement, signed by members of each of the 9 partner institutions, allowed data and tissue sharing between the partner institutions regardless of the ability of any individual institution to contribute samples. Once the infrastructure was established, the goal was to evaluate the feasibility of collecting FFPE tissue blocks and associated data and creating a web-based database and TMAs. The first step in this pilot study was to choose a tumor type for the TMA. The BMaP-3 investigators chose breast cancer as the highest priority to address health disparities related to cancer in the southeastern United States and Puerto Rico. This decision was based on a variety of factors, including unpublished observations on the scarcity of breast TMAs from diverse populations described in the literature, lack of commercially available breast TMAs with associated patient data on race and ethnicity, the observed rates of incidence and mortality associated with breast cancer at the 6 contributing cancer sites, and the unpublished results of a multi-institutional survey of researcher needs for TMAs.16 In addition, researchers specializing in breast cancer were surveyed to determine what type of breast cancer TMA is most needed for research. As Cancer Control 385 shown in Fig 1, 29 of the 61 respondents (47.5%) expressed greatest need for a TMA based on biomarker status between different racial/ethnic groups, followed by a TMA based on 1 histological type of breast tissue in different racial/ethnic groups (26%), and a TMA based on 1 tumor, node, and metastasis pathology stage group in different racial/ethnic groups (14%). Collection and Management of Cancer Registry Data Deidentified American College of Surgeons cancer registry data from each institution served as the basis for the web-based database and for the selection of cases to be included in the TMA. Requests for data from cancer registries at each of the 9 partner institutions specified the following criteria for selecting cases: date range, 2001 to 2011 (to avoid using biospecimens that might be needed for clinical care), age at diagnosis (≥ 18 years of age), primary breast cancer only (no metastasis), and first-course surgery at the institution. In addition, because cases from minority populations were a priority for inclusion in the TMA, members at partnering institutions were asked to specifically retrieve patient data from African Americans and Hispanics/Latinos. The 17 data elements requested are described in Table 1. Cancer registry data sets were retrieved from 6 institutions, and a biostatistician harmonized the data sets. A total of 12,408 entries from 8,279 unique patients with breast cancer pathology were confirmed after merging the data sets. Deidentified information about breast cancer cases collected from the different cancer registries is available in BMaP-3 PAD (https:// apps.mathbiol.org/bmap [access restricted]). Archival Case Selection and Tissue Microarray Construction The data set was further analyzed for cases with invasive ductal carcinoma (IDC; histology selected by the Tissue Advisory Board) and then cross-tabulated by race/ethnicity and biomarker status (triple-negative, TMA based on 1 TNM stage group in different racial/ethnic groups TMA of 1 histological type of breast tissue in different racial/ethnic groups TMA based on biomarker status between different racial/ethnic groups Other 0 5 10 15 20 25 30 35 40 45 50 HR+/ERBB2 –, HR+/ERBB2+, ER –/PR –/ERBB2+). The demographical and clinical characteristics of the data from the breast cancer cases obtained from the 6 institutions are presented in Table 2. Because cancer registry standards for ERBB2 were largely adopted from 2006 onward, many of the archival cases (collected from 2001 to 2005) were categorized as missing for ERBB2 status. Therefore, the Tissue Advisory Board decided that the 3 biomarker categories for selecting cases would be as follows: (1) triple negative, (2) HR+/ ERBB2–, and (3) ERBB2+ (HR+/ERBB2+ and ER–/PR–/ ERBB2+ grouped together). All unique cases of female Table 1. — Data Elements and Their Descriptions Data Element Study identifier Unique code used by honest broker for reidentification Year first seen Year of first patient contact (inpatient or outpatient), with the reporting facility for the diagnosis of the tumor, its treatment, or both Site primary Code for the primary site of the tumor being reported using ICD-O (2nd or 3rd ed.) Age at diagnosis Records the age of the patient in complete years at his or her last birthday before diagnosis Sex Identifies the sex of the patient Race Identifies the primary race of the patient Spanish/Hispanic origin Identifies patients of Spanish or Hispanic origin Histology (ICD-O [3rd ed.]) First 4 digits of the morphology code that describe the tumor/cell type Behavior (ICD-O [3rd ed.])a Code for the behavior of the tumor being reported Year of surgery Year in which a surgical procedure was performed Surgery of primary site, at hospital Type of surgery performed to breast aimed at modifying, controlling, removing, or destroying cancerous tissue Systemic/surgery sequence Records the sequencing of systemic treatment and surgical procedures given as part of first-line therapy Surgery/radiation sequence Records the sequencing of radiation and surgical procedures provided as part of firstline therapy Collaborative stage, site-specific factor 16 Combinations of ER, PR, and ERBB2 results Tumor marker 1 ER assay Tumor marker 2 PR assay ERBB2 Interpretation of results (not the same as the laboratory value) for the ERBB2 test used to determine the status of ERBB2 TNM, pathology, stage group The anatomical extent of disease based on TNM elements of the tumor following surgery Respondents, % Fig 1. — Results of the breast cancer researcher survey (N = 61). A multiinstitutional, web-based poll was distributed to investigators in region 3 (currently region 2) institutions to assess the research interest regarding different kinds of breast TMAs. Survey responses were anonymous. As can be seen, the greatest need was for TMA based on biomarker status between different racial and ethnic groups. TMA = tissue microarray, TNM = tumor, node, metastasis. 386 Cancer Control Description a Behavior is the fifth digit of the ICD-O (3rd ed.) morphology code. ICD-O = International Classification of Diseases for Oncology, TNM = tumor, node, metastasis. October 2016, Vol. 23, No. 4 IDC were tabulated according to biomarker status (site-specific factor 16) and by race/ethnicity (Table 3). Although a large portion of cases were missing data, this analysis revealed that, in this cohort, African American women have a higher incidence of triplenegative breast cancer compared with white women, and Hispanic women have a higher incidence of HRnegative breast cancer compared with non-Hispanic women. These data, as well as data on breast cancer cases not included in the TMA, were incorporated into the BMaP-3 PAD web-based database. FFPE blocks were requested from participating Table 2. — Characteristics of Patients at the Contributing Institutions (N = 8,279) Variable No. of Patients, n (%) Sex Male Female 59 (0.72) 8,219 (99.30) Race American Indian 2 (0.02) Asian Indian 1 (0.01) Asian Other Black/African American 1 (0.01) 2,012 (24.30) Filipino 2 (0.02) Pacific Islander 3 (0.04) Vietnamese 3 (0.04) White 5,904 (71.30) Other 80 (0.97) Unknown 271 (3.30) Ethnicity institutions, and 427 blocks from 427 unique patients with breast cancer were obtained. Tumor expressions of ER, PR, and ERBB2 were annotated based on cancer registry data in the following manner: (1) HR+ (ER+, PR+, or both) and ERBB2–, (2) HR+ (ER+, PR+, or both) and ERBB2+, and (3) HR– (ER– and PR–) and ERBB2–. These 427 FFPEs were used to construct the TMA blocks, of which 8 blocks were constructed. TMA slides from each of the blocks were stained for ER, PR, and ERBB2 to confirm the biomarker status of the samples. Fig 2 shows a sample representation of tumors from each of the 3 types of breast TMAs (ERBB2+, ERBB2–, and triple negative) for each stain. Thereafter, the cancer registry data were reviewed, and 4 samples originally classified as triple negative were reclassified as either ERBB2+ or HR+. Several discrepancies were found between the cancer registry data and the TMA immunohistochemistry results. Specifically, for all racial/ethnic groups, the biomarker status obtained from the cancer registry data was 100% in concordance to the staining results for ERBB2– cases. However, this was not true for the triple-negative cases (86.8% and 85.7% rates of accuracy for African Americans/whites and Hispanics, respectively), and concordance was much lower in the case of ERBB2+ staining (43.6% and 30.6% for African Americans/whites and Hispanics, respectively). This finding could be due to different factors such as tumor heterogeneity or loss of antigenicity (eg, some donor blocks were several years old).19 These stains were scanned and quantified, and links to the images were made available upon request. Detailed information on the samples included on the TMA is posted on http://labpages.moffitt.org/bmap3/Cancer%20Database /Cancer_Database.html. Cuban 43 (0.52) Dominican Republic 7 (0.08) Discussion Mexican 24 (0.29) Puerto Rican 248 (3.00) South/Central American 66 (0.80) Spanish (not otherwise specified) 368 (4.40) This pilot study successfully accomplished the following goals: • Creation of a regional infrastructure with an organizing framework for communications, processes for memorandums of understanding and Institutional Review Board approval from multiple institutions, and an established Tissue Advisory Board and related guidelines • Processes for retrieval and synchronization of data from multiple cancer registries into a single data set • Development of a collaborative model for optimizing TMA design considerations • Development and implementation of a web-based database of cancer registry cases All of these accomplishments demonstrate the overall feasibility of creating a unique, centralized, public resource for multiethnic biobanking and the collection of biospecimens. Given the large number of cases included in the web-based database and the Other Spanish 9 (0.12) Non-Spanish 7,370 (89.00) Spanish surname only Unknown 2 (0.02) 142 (1.70) Age, y < 25 23 (0.28) 25–34 222 (2.70) 35–44 1,126 (13.60) 45–54 2,217 (26.80) 55–64 2,267 (27.40) 65–74 1,588 (19.20) ≥ 75 October 2016, Vol. 23, No. 4 836 (10.10) Cancer Control 387 Table 3. — Site-Specific Factor 16 for Invasive Ductal Carcinoma by Race and Ethnicity for Women in All Institutions Combined HR+/ERBB2– HR+/ERBB2+ PR–/ER–/ERBB2– PR–/ER–/ ERBB2+ Missing Totals African American 169 (15) 58 (5) 130 (11) 33 (3) 755 (66) 1,145 White 585 (18) 91 (3) 163 (5) 43 (2) 2,295 (72) 3,177 Race, n (%) Other/missing Totals 99 (36) 15 (6) 58 (21) 26 (9) 77 (28) 275 853 (19) 164 (3) 351 (8) 102 (2) 3,127 (68) 4,597 Ethnicity, n (%) Hispanic 128 (25) 21 (4) 97 (19) 28 (6) 234 (46) 508 Non-Hispanic 711 (18) 139 (3) 251 (6) 73 (2) 2,835 (71) 4,009 Other/missing Totals 14 (17) 4 (5) 3 (4) 1 (1) 58 (73) 80 853 (19) 164 (3) 351 (8) 102 (2) 3,127 (68) 4,597 amount of TMAs, this model demonstrates that no institution could have accomplished these outcomes alone. A primary benefit of this approach is that members of all the partner institutions are eligible to access the data and tissue resources regardless of their capabilities to contribute to the database or TMA. The first step in this pilot study was to select a tumor type for creation of the TMAs. We chose to focus on breast cancer as the highest priority to address health disparities related to cancer in the southeastern United States and Puerto Rico for a variety of reasons.16 This decision was based on1,10,13,14,20-22: • Analysis of the literature on TMAs from patients with different racial/ethnic backgrounds showing a scarcity of breast TMAs from diverse populations • Lack of commercially available breast TMAs that provide associated data on race and ethnicity • Observed incidence and mortality rates associated with breast cancer at each of the 6 contributing cancer sites by race/ethnicity • Data from the comprehensive assessment tool on FFPE biospecimens for 6 cancer types available for study at the 9 study institutions • Survey results of researcher needs for TMAs This pilot study demonstrated the feasibility of collecting cancer registry data for more than 12,000 breast cancer cases and creating a web-based database. We were successful in creating a racially/ethnically diverse TMA from FFPEs representing 427 breast cancer cases. For validation of the TMAs, we focused on studying the characteristics of IDC among different racial/ethnic groups because the investigators from the BMaP3 institutions identified these as an important area of investigation, given the known differences in incidence of triple-negative IDC among diverse populations. The results of the biomarker analysis showed a higher incidence rate of triple-negative breast cancer among African American women compared with white women and a higher incidence rate of HR-negative 388 Cancer Control Biomarker Status Antibodies ERBB2 PR ER Triple negative ERBB2+ ERBB2– Fig 2. — Sample representation of immunostaining according to biomarker status. TMA slides were immunostained with anti-ER, anti-PR, and anti-ERBB2 antibodies. ER = estrogen receptor, ERBB2 = erb-b2 receptor tyrosine kinase 2, PR = progesterone receptor, TMA = tissue microarray. breast cancer among Hispanic women compared with non-Hispanic women. These observations are consistent with the literature.10,14 However, our analysis is compromised by a large amount of missing data. Hines et al14 showed that breast cancer among Hispanic women comprises a distinct spectrum of tumor subtypes compared with non-Hispanic white women. In that study, a diverse TMA based on biomarkers was created, allowing researchers to study potential molecular differences in triple-negative breast cancer in different racial/ethnic groups.14 Although most institutions had compatible bioinformatics systems for the management of biospecimen data, these systems were used for fresh frozen samples. No single institution had a direct database for associated FFPE tissue data; thus, cancer registry data and pathology reports were the sources of data for cases likely to have tissues stored at the respective institution. When needed, data would have had to be abstracted October 2016, Vol. 23, No. 4 from pathology reports — which was beyond the resources of this project. Our findings suggest that the idea of synchronizing pathology reports with cancer registry data should be pursued because pathology reports offer more complete and accurate information on biomarker data than is currently provided by a cancer registry. Conclusions We have created a model for collaboration. Through the contribution of formalin-fixed, paraffin-embedded blocks from the Minority Biospecimen/Biobanking Geographic Management Program for region 3 (BMaP-3) institutions, this project facilitated the creation of a robust research tool that would not be readily available if each institution worked independently. Moreover, each institution benefited from the collaboration and from the team approach to tackle a research/clinical issue common to all team members. It is expected that investigators at the partner institutions will utilize the web-based database on an ongoing basis for data analysis. This database is freely available with open access for the BMaP-3 investigators. We fully expect that the model and process for the work described herein could be applied and exported to other multi-institutional networks focused on a participatory approach to biobanking. We also demonstrated the feasibility of creating tissue microarrays from racially and ethnically diverse populations through the BMaP-3 partnership. This work was made possible by the infrastructure of this partnership, and it can serve as a model for other multiinstitutional networks focused on research utilizing human biospecimens. To date, these tissue microarrays of invasive ductal carcinoma have been released for 5 projects at 5 different institutions. Acknowledgments: The authors would like to thank Ivana Sehovic and Zena Sayegh for managing and constructing the BMaP-3 TMA blocks. Marithea Goberville, PhD, provided editorial support. Substantial support was provided by Region 3 GMaP/BMaP partner institutions: Emory Winship Cancer Center, Moffitt Cancer Center, Morehouse School of Medicine, Ponce Health Sciences University, Tulane University, Tuskegee University, University of Alabama at Birmingham, University of Mississippi Medical Center, and Xavier University of Louisiana. This work was supported in part by National Cancer Institute grants 3U56 CA118809-14S2; 3U54 CA153509-02S3 and 3U54 CA153509-03S1 (Moffitt Cancer Center). 2011;127(3):729-738. 3. Partridge EE, Fouad MN, Hinton AW, et al. The deep South network for cancer control: eliminating cancer disparities through community-academic collaboration. Fam Community Health. 2005;28(1):6-19. 4. Ward E, Jemal A, Cokkinides V, et al. Cancer disparities by race/ ethnicity and socioeconomic status. CA Cancer J Clin. 2004;54(2):78-93. 5. Ademuyiwa FO, Edge SB, Erwin DO, et al. Breast cancer racial disparities: unanswered questions. Cancer Res. 2010;71(3):640-644. 6. Evens AM, Antillón M, Aschebrook-Kilfoy B, et al. Racial disparities in Hodgkin’s lymphoma: a comprehensive population-based analysis. Ann Oncol. 2012;23(8):2128-2137. 7. Fedewa SA, Ward EM, Stewart AK, et al. Delays in adjuvant chemotherapy treatment among patients with breast cancer are more likely in African American and Hispanic populations: a national cohort study 2004-2006. J Clin Oncol. 2010;28(27):4135-4141. 8. Tamimi RM, Hughes ME, et al. Racial and ethnic differences in breast cancer survival: mediating effect of tumor characteristics and sociodemographic and treatment factors. J Clin Oncol. 2015;33(20):2254-2261. 9. Tian Q, Price ND, Hood L. Systems cancer medicine: towards realization of predictive, preventive, personalized and participatory (P4) medicine. J Intern Med. 2012;271(2):111-121. 10.Carey LA, Perou CM, Livasy CA, et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA. 2006;295(21):2492-2502. 11. Kohler BA, Sherman RL, Howlader N, et al. Annual report to the nation on the status of cancer, 1975-2011, featuring incidence of breast cancer subtypes by race/ethnicity, poverty, and state. J Natl Cancer Inst. 2015;107(6):djv048. 12. U.S. Department of Health and Human Services; National Institutes of Health; National Cancer Institute. Surveillance, Epidemiology, and End Results (SEER) 2010. http://seer.cancer.gov/. Accessed March 24, 2016. 13. McBride R, Hershman D, Tsai WY, et al. Within-stage racial differences in tumor size and number of positive lymph nodes in women with breast cancer. Cancer. 2007;110(6):1201-1208. 14. Hines LM, Risendal B, Byers T, et al. Ethnic disparities in breast tumor phenotypic subtypes in Hispanic and non-Hispanic white women. J Womens Health (Larchmt). 2011;20(10):1543-1550. 15. National Cancer Institute. Geographical Management of Cancer Health Disparities (GMaP). Updated August 1, 2016. http://www.cancer. gov/about-nci/organization/crchd/inp/gmap. Accessed August 19, 2016. 16. Wells KJ, Lima DS, Meade CD, et al. Assessing needs and assets for building a regional network infrastructure to reduce cancer related health disparities. Eval Program Plann. 2014;44:14-25. 17. Allred DC, Carlson RW, Berry DA, et al. NCCN task force report: estrogen receptor and progesterone receptor testing in breast cancer by immunohistochemistry. J Natl Compr Canc Netw. 2009;(7 suppl 6):S1-S21. 18. Wolff AC, Hammond ME, Schwartz JN, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 2007;25(1):118-145. 19. Miller RT, Swanson PE, Wick MR. Fixation and epitope retrieval in diagnostic immunohistochemistry: a concise review with practical considerations. Appl Immunohistochem Mol Morphol. 2000;8(3):228-235. 20. Wu Y, Sarkissyan M, Elshimali Y, et al. Triple negative breast tumors in African-American and Hispanic/Latina women are high in CD44+, low in CD24+, and have loss of PTEN. PLoS One. 2013;8(10):e78259. 21. Lindner R, Sullivan C, Offor O, et al. Molecular phenotypes in triple negative breast cancer from African American patients suggest targets for therapy. PLoS One. 2013;8(11):e71915. 22. Winter JL, Stackhouse BL, Russell GB, et al. Measurement of PTEN expression using tissue microarrays to determine a race-specific prognostic marker in breast cancer. Arch Pathol Lab Med. 2007;131(5):767-772. References 1. Lisovicz N, Johnson RE, Higginbotham J, et al. The Deep South Network for cancer control. Building a community infrastructure to reduce cancer health disparities. Cancer. 2006;107(8 suppl):1971-1979. 2. Ooi SL, Martinez ME, Li CI. Disparities in breast cancer characteristics and outcomes by race/ethnicity. Breast Cancer Res Treat. October 2016, Vol. 23, No. 4 Cancer Control 389 Data suggest that immediate action must be taken to improve the time between diagnosis and treatment for disadvantaged patients. Lily. X-Ray image courtesy of Bryan Whitney. www.x-rayphotography.com. Determinants of Treatment Delays Among Underserved Hispanics With Lung and Head and Neck Cancers Evelinn A. Borrayo, PhD, Katie L. Scott, PhD, Ava R. Drennen, PhD, Tiare MacDonald, PhD, and Jennifer Nguyen, MS Background: Evidence is lacking to explain the reasons why treatment is delayed among disadvantaged Hispanic patients diagnosed with lung and head and neck cancers. Data indicate that treatment delays beyond 46 days increase the risk of death for individuals with these cancers. Methods: A mixed-methods design was used to explore determinants of treatment delays by analyzing data from the medical records of 40 Hispanic patients and data from interviews with 29 Hispanic patients, caregivers, health care professionals, and patient navigators from a safety-net hospital. Results: Of the 40 Hispanic patients, 35% initiated treatment 46 days or more after being diagnosed, but women experienced longer delays than men (average of 48 days). Women with few comorbid diseases (≤ 4) were more likely to experience treatment delays. Institutional-related determinants at publicly funded hospitals appear to delay treatment for patients at the safety-net hospital, and patient-related determinants common to underserved patients (eg, no health insurance coverage) are likely to further contribute to these delays. Conclusions: Delayed treatment is associated with poor outcomes and low rates of survival in patients with lung and head and neck cancers. Therefore, action should be taken to improve the time between diagnosis and the initiation of treatment for disadvantaged Hispanic patients. From the Department of Psychology (EAB, TM, JN), Colorado State University, Colorado School of Public Health, University of Colorado, Denver, Colorado, Department of Neurology (KLS), Spectrum Health Medical Group, Grand Rapids, Michigan, and the Department of Behavioral Health (ARD), Salud Family Health Centers, Fort Collins, Colorado. Submitted May 5, 2016; accepted July 28, 2016. Address correspondence to Evelinn A. Borrayo, PhD, Department of Psychology, Colorado State University, 1876 Campus Delivery, Fort Collins, CO 80523. E-mail: [email protected] No significant relationships exist between the authors and the companies/organizations whose products or services may be referenced in this article. This work was supported by a grant from the National Cancer Institute at the National Institutes of Health (U01, CA114604). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. 390 Cancer Control Introduction In the United States, lung cancer accounts for more deaths than any other cancer in both men and women.1 Among Hispanics, lung cancer is the leading cause of cancer-related death for men and the secondleading cause for women.2 Those with lung cancer are also at increased risk for developing secondary neoplasms of the head and neck and vice versa.3,4 Lung and head and neck cancers are largely induced by tobacco use, which accounts for 87% and 70% of lung cancer–related deaths for men and women, respectively.5 Approximately 75% of head and neck cancers are attributed to tobacco use, and a 30-fold increased risk is seen among those who smoke and drink alcohol.1,6 Moreover, those with lung and head and neck October 2016, Vol. 23, No. 4 cancers who smoke cigarettes and drink alcohol are at increased risk for developing comorbid conditions, such as chronic bronchitis, emphysema, and cardiovascular disease.7 Although Hispanics have lower incidences of and mortality rates from lung and head and neck cancers than non-Hispanic whites, disparities in timely and quality treatment remain for Hispanics — poverty is typically cited as the explaining factor.1 Mounting evidence demonstrates that worse outcomes (eg, survival, quality of life) for ethnic minorities with cancer are also best explained by their low socioeconomic status (SES).1,8 Similarly, inequalities exist in properly treating medically underserved patients (eg, low-income, uninsured) with lung and head and neck cancers.9-11 In a systemic review and meta-analysis of socioeconomic inequalities and lung cancer treatment, Forrest et al9 found that lower SES was associated with a statistically significant reduced likelihood of receiving any treatment — particularly surgery and chemotherapy. These SES inequalities could not be accounted for by differences in stage at presentation or by differences in health care systems (ie, publicly funded vs private health care systems).9 Choi et al10 conducted a longitudinal study to examine disparities as predictors of survival among patients with head and neck cancers and found that low income, low education, and advanced age were significant independent predictors of poor survival (ie, 5-year overall, cancer-specific, and disease-free survival rates; P < .001). Similarly, Yang et al11 found in a population-based study that significant independent predictors of worse survival rates among patients with lung cancer were older age and severe poverty. The effects of ethnicity were statistically significant: A higher percentage of Hispanic patients resided in the highest poverty areas, were less likely to receive radiotherapy, and had shorter survival rates if they smoked compared with their non-Hispanic white counterparts.11 Treatment Initiation More than 10 years ago, the Institute of Medicine recommended improving the timeliness of treatment by reducing wait times that can potentially result in harmful delays for patients.12 Timeliness in the treatment of lung and head and neck cancers is important, because delaying the start of treatment has been associated with disease recurrence,13-16 lower rates of survival,17 and poor patient outcomes (eg, distress).18,19 Using the US National Cancer Database, Murphy et al20 found that the interval from diagnosis to the start of treatment has been increasing since 1985 for Americans diagnosed with head and neck cancers. Their examination of predictors found that patients with advanced-stage disease who underwent chemoradiotherapy, were treated at academic facilities, and October 2016, Vol. 23, No. 4 who received transitional care had the greatest increases in time to treatment initiation.20 In a follow-up study using the same database, Murphy et al17 found that the time to treatment initiation of 46 to 52 days was associated with a significant increased risk of death — a risk that was consistently detrimental beyond 60 days. After examining covariates, the researchers also found that the effect of time to treatment initiation on mortality risk was greater for early-stage (stage I/II) than advanced-stage disease (stage III/IV) and for radiotherapy and surgery than for chemoradiotherapy.17 To assess the impact of delayed treatment for lung cancer on an international level, Vinas et al21 conducted a systemic review of multinational studies and found that long delays were predictive of better survival rates than shorter delays, but patients who experienced longer delays had fewer symptoms — possibly explaining a better prognosis. Instead, short delays in lung cancer treatment had a negative prognostic meaning because urgent treatment was provided to patients with more advanced disease.21 Patients with lung and head and neck cancers increasingly experience longer delays between their diagnoses and subsequent treatment.20,21 Delays are more prevalent for patients with early-stage disease, thus increasing their disease progression, their wait times (if candidates for surgical treatment), and their level of distress.18,19,22-25 Instead, shorter delays are experienced by patients with more advanced-stage disease for whom treatment is urgently initiated without clear benefits in their disease progression or rate of survival.17,21 A paucity of evidence explains what factors drive the treatment delays experienced by patients with lung and head and neck cancers. Murphy et al20 contend that the delay in the start of treatment is due to increases in more sophisticated, pretreatment diagnostics, complex multimodal therapies, and transitions in care for patients treated at academic cancer centers. However, these factors are not as likely to explain treatment delays for patients treated at community-based hospitals.20 Community-Based Facilities Few studies have compared the intervals from diagnosis to treatment among academic and public hospitals that treat head and neck cancers; however, among those that have, significantly longer treatment delays have been observed at public hospitals.26,27 In a study by Yorio et al,26 age, sex, race, and type of insurance coverage were not significantly associated with a longer time to treatment. The single significant factor they found for the delay of lung cancer treatment was receiving that care at a public hospital. Patel et al28 suggest that the factors that affect the timely delivery of cancer treatment are likely institution-related factors Cancer Control 391 that generally apply to public institutions, including availability of specialty services, adequacy of equipment, timely pathological analysis, and lack of imaging and surgical procedures — this is particularly true for patients with head and neck cancers. Patient Factors Less is known about patient-related factors that might contribute to delays in cancer treatment, but they are likely related to low SES, limited access to transportation, lack of paid leave from work, language barriers, comorbid medical conditions, and homelessness.28 Purpose To our knowledge, no studies have investigated the factors at the institutional and patient levels that are likely to contribute to treatment delays among underserved Hispanic patients with lung and head and neck cancers treated at community-based hospitals, let alone studies that have focused on underserved Hispanic patients who experience high rates of morbidity from these cancers. We conducted this exploratory study to better understand the institution- and the patient-level determinants associated with the timely initiation of cancer treatment among underserved Hispanic patients diagnosed with lung and head and neck cancers. variables that procure or impede a patient’s initiation of treatment (eg, health insurance, income); and predisposing factors include personal propensities to access treatment (eg, age, sex, language).30,31 Measures Data were extracted from the medical records of Hispanic patients with a primary diagnosis of lung cancer or head and neck cancer treated at a “safety-net” hospital in Colorado across a 1-year period. The patient data included sociodemographic variables (eg, age, sex), diagnosis (eg, cancer type, stages I–IV), cancer treatment (eg, chemotherapy, surgery), number of comorbid diseases (using the Charlson Comorbidity Index), date of cancer diagnosis (by diagnostic biopsy), and date when the patient began any type of cancer treatment.32 The interval between the initial diagnosis and the start of treatment was calculated as the number of days between the date when patients were diagnosed and the date when they began their first curative treatment. For patients diagnosed at the time of resection and surgery was their first treatment, the number of days was coded as 1 day. Study Design A triangulation, mixed-method design (ie, quantitative and qualitative data linked to the literature) was used for breadth and depth of understanding and corroboration from multiple angles to determine the initiation of cancer treatment among the study population.29 We collected quantitative data from medical records to assess the magnitude of the influence of patient variables and diagnostic factors on treatment initiation as well as qualitative research to explore stakeholder perspectives and other influential factors not captured by the data in the medical records. One-on-one interviews were also conducted with patients who had lung cancer and head and neck cancers and their health care professionals (HCPs), while focus-group interviews were conducted with the caregivers and patient navigators who assisted the study patients. Data Analysis For medical record data, a stepwise, multiple regression method was used to evaluate whether predisposing, enabling, and need factors were necessary to predict the range of days between initial diagnosis and initiation of treatment. Data were centered by converting age, cancer stage at diagnosis, and comorbid diseases into z scores. Regression assumptions and diagnostics were satisfactory, except for homoscedasticity, which led to the removal of a single influential case. Ethnographical content analysis was utilized to extract relevant themes from the semi-structured and focusgroup interviews.33 The goal of the analysis was to identify factors that detail the delays in receiving cancer treatment from the perspective of patients, caregivers, HCPs, and patient navigators. Five analysts were trained and employed in this study to follow the content analysis methods of Krippendorff.34 All analysts independently coded each transcript and then met to corroborate the codes, broaden the subject categories, and identify quotes to illustrate the themes. Theoretical Framework The Behavioral Model for Vulnerable Populations was used as the guiding theoretical framework.30,31 The model proposes that need, enabling, and predisposing factors facilitate or block the use of health services by vulnerable populations. Need factors include the vulnerabilities that make patients necessitate medical treatment (eg, cancer type and stage, comorbid diseases); enabling factors include social or environmental Participants The patients included in this study were treated at a safety-net hospital that serves impoverished community neighborhoods. Medical Records: Medical records were reviewed for 53 Hispanic patients with a primary diagnosis of lung or head and neck cancer; of those, 40 patients had medical records of the number of days from diagnosis to treatment. Table 1 displays the characteristics Methods 392 Cancer Control October 2016, Vol. 23, No. 4 for all 40 patients. Patients were an average of 57 years of age (standard deviation [SD] 16.3; range, 23–88); 57% were diagnosed with head and neck cancers and 43% were diagnosed with lung cancer. The average number of days from diagnosis to treatment was 40 (SD 33.2; range, 1–141); 65% received treatment in less than 42 days, 18% between 46 and 59 days, and 17% received treatment after more than 60 days. The number of comorbidities in the study patients ranged from 2 to 17 conditions (mean [SD] = 5 [3.84]), with the most common being hypertension (58%), chronic obstructive pulmonary disease (43%), tobacco use (40%), and depression (33%). Men and women were significantly different in their cancer stage at diagnosis: Men were more likely to have advanced cancer (79%) and women were more likely to have less-advanced cancer (stages I/II; 69%). Moreover, men were significantly more likely to have received chemotherapy than women (65% vs 31%, respectively). Interviews In-depth interviews were conducted in 29 participants: 4 with lung cancer, 5 with head and neck cancers, 6 caregivers, 7 HCPs, and 7 patient navigators. The patients interviewed were an average of 62 years of age (SD 9.64; range, 49–75). Five were men and 4 were women. Five patients were diagnosed with head and neck cancers and 4 with lung cancer; 3 patients were diagnosed at stage I/II disease and 6 at stage III/IV disease. Of the 6 caregivers, two cared for patients with head and neck cancers and 4 cared for patients with lung cancer. The ages of the caregivers ranged from 34 to 59 years (mean [SD] = 46.67 [10.31]). One was a man and 5 were women. October 2016, Vol. 23, No. 4 Table 1. — Select Characteristics of Study Patients Variable Men (n = 23) Women (n = 17) All Participants F (N = 40) Statistic Mean (SD) Age, y 61 (14.5) 52 (17.6) 57 (16.3) Diagnosis to treatment delay, dª 34 (23.1) 48 (42.8) 40 (33.2) 1.76 5 (4.4) 4 (2.9) 5 (3.8) 0.51 n (%) n (%) n (%) X² United States 13 (57) 9 (53) 22 (55) Latin America 10 (43) 8 (17) 18 (45) No. of comorbid diseases 2.95 Sociodemographic Characteristics Place of Birth 0.05 Language 0.06 English 14 (58) 11 (56) 25 (62) Spanish 9 (42) 6 (44) 15 (38) 9 (39) 7 (41) 16 (40) 14 (61) 10 (59) 24 (60) Marital Status Married Not married (eg, single, widow) 4.36 Insurance Coverage 0.27 Insured (Medicaid/Medicare) 10 (43) 6 (44) 16 (40) Uninsured (no health insurance) 13 (57) 11 (56) 24 (60) 12 (57) 6 (40) 18 (50) 6,240–13,908 3 (14) 6 (40) 9 (25) 14,248–33,192 6 (29) 3 (20) 9 (25) Head/neck 11 (48) 12 (71) 23 (57) Lung 12 (52) 5 (29) 17 (43) Income, $ < 6,144 4.25 Cancer Diagnosis Cancer Site 2.07 Cancer Stage at Diagnosis 13.38* I 4 (17) 11 (69) II 1 (4) 0 (0) 15 (38) 1 (3) III 3 (13) 3 (19) 6 (15) IV 15 (66) 2 (12) 17 (44) Yes 11 (50) 13 (76) 24 (60) No 11 (50) 4 (24) 15 (40) Yes 15 (65) 5 (31) 20 (51) No 8 (36) 11 (69) 19 (49) Cancer Treatment Surgery 2.84 Chemotherapy 4.36** Radiotherapy 1.12 Yes 16 (73) 9 (56) 25 (66) No 6 (27) 7 (44) 13 (34) Numbers in the group categories do not sum to the total number of participants because of missing data for certain variables. ªAssessed as the number of days from the time patients received a cancer diagnosis until their first treatment. *P < .01. **P < .05. Cancer Control 393 Results Medical Records Predisposing (ie, age, sex), enabling (ie, health insurance), and need (ie, cancer site, stage at diagnosis, comorbid conditions) variables were entered as predictors of days from diagnosis to the initiation of treatment. The prediction model contained 4 of the 6 predictors and was reached in 4 steps with 2 variables removed (ie, age, health insurance). As shown in Table 2, the model was significant (F [4, 36] = 2.58; P < .05, R: 0.482; R²: 0.233 [adjusted R²: 0.142]). The variables of sex and comorbid conditions were significant predictors of the time from diagnosis to treatment initiation. Compared with men, women were significantly more likely to experience more days between diagnosis and the start of treatment. Patients with fewer comorbid conditions also experienced significantly more days from diagnosis to treatment initiation than those with more comorbidities. Specifically, with each additional comorbid condition, a patient’s time from diagnosis to treatment initiation decreased by nearly 17 days. Sex accounted for 9% of the variance and comorbidities accounted for 17% of the variance of diagnosis to treatment initiation (see Table 2). Inspection of the structure coefficients suggests that women and patients with fewer comorbidities experienced significantly more days between their initial diagnosis and the start of treatment. Although we examined the interaction effect of all the predictors in the model, the interaction alone between sex and comorbidities was found to be significant (F [2, 21] = 3.68; P = .04). As seen in the Fig, compared with men, women with fewer comorbidities experienced the longest delay from their initial diagnosis to the start of cancer treatment. Interviews Overall, HCPs and patient navigators had more years of experiences to draw upon when discussing how various factors influenced the time from initial diagnosis to treatment initiation among underserved Hispanic patients with lung and head and neck cancers. Thus, patient and caregiver responses were organized around the responses of their HCPs and navigators. Need Factors: All participating HCPs conveyed that lung and head and neck cancers are usually diagnosed at a later stage of disease, thus decreasing survival rates among patients with these cancers. They recognized that reducing delays in treatment is impor- 100 Estimated Marginal Mean (Diagnosis to Treatment, d) The 7 HCPs included a pulmonologist, medical oncologist, oncology nurse, oncology pharmacist, otolaryngologist, pulmonology surgeon, and radiation oncologist. Five HCPs identified as being white and 2 self-identified as ethnic minorities; 2 were women and 5 were men. Their time at the safety-net hospital ranged from 9 months to 10 years (mean [SD] = 5.46 [3.28]). Of the 7 patient navigators, 5 were women and 2 were men. Six self-identified as Hispanic and 1 as nonHispanic white. Their employment at the safety-net hospital ranged 2 to 9 years (mean [SD] = 3.43 [2.57]). Sex Men Women 80 60 40 20 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Sum of Charlson Comorbidity Status Fig. — Interaction between the sexes and number of comorbidities. Table 2. — Coefficients for Predictors of Diagnosis to Treatment Delay (N = 40) Model Unstandardized Coefficient B Value Standard Error Standardized Coefficient β Level T test sr ² Structured Coefficient (Constant) 24.87 9.35 — 2.55 — — Sex 24.49 12.30 .369 1.99* .09 .52 Cancer site 12.42 12.04 .187 1.03 .02 –.21 7.88 6.63 .238 1.19 .03 –.27 –16.53 6.07 –.523 .17 –.77 Cancer stage at diagnosis Comorbid diseases –2.73** R = 0.482; R² = 0.233 (adjusted R² = 0.142). Sex coded as 0 = men, 1 = women. Cancer site coded as 0 = head and neck cancer, 1 = lung cancer. Cancer diagnosis stage coded as 1 = stage 0/1, 2 = stage II, 3 = stage III, and 4 = stage IV. *P < .05. **P < .01. 394 Cancer Control October 2016, Vol. 23, No. 4 tant to reduce the high rates of morbidity from these cancers. The pulmonologist said: Lung cancer is a progressive disease and cancer grows. My fear with patients is always that this is a particular cancer that can be treated with surgery and cured. If it advances to the point where it can no longer be taken care of in time for surgery, then it’s impossible to cure, and the only thing we can do is give people radiation or drugs to slow it down, but not cure it. The HCPs acknowledged lengthy delays in treatment, similar to what the pulmonology surgeon reported: Well, ultimately, the care is good. It’s just the delay from one step to the next. They’re getting the appropriate treatments and procedures done — it’s just the delay [of 8 months]. Delays in treatment were viewed as being influenced by systems-level factors. At the systems level, most patients and caregivers said that a missed diagnosis of cancer by their primary care physician was the factor that contributed to receiving delayed treatment. When 1 caregiver explained the reasons her relative with head and neck cancer experienced a lengthy delay of treatment, she said: Just maybe look to see if it was cancer before. Before they thought it was a blister or fever blister. She had it for a long time, and it was probably growing. HCPs identified lack of coordinated care as a systems-level factor that contributed to delays in treatment. Although underserved patients receive affordable care at the safety-net hospital, they recognized that the process of coordinating these patients’ treatment is difficult. HCPs believed that enrolling for services was an obstacle to patients because of the amount of paperwork needed and the requirements that they must meet before the coordination of these patients’ treatment can begin. The clinical oncology pharmacist summarized it as such: Getting them enrolled is the biggest gap. I think that, if they can get through that hurdle, everything else goes a lot smoother [to begin their treatment]. HCPs also reported that the coordination of care for lung and head and neck cancers is complex and can delay treatment. Medical care from various departments (eg, medical oncology, surgery, radiation) and specialty clinics (eg, otolaryngology) must be coordinated prior to the start of treatment as well as during the various procedures necessary for the treatment of October 2016, Vol. 23, No. 4 these cancers. The oncology nurse also reported on the complications of coordinating care among the different specialties: Oh, yeah, particularly the head and neck patients because they have to go between radiation, medical oncology, and otolaryngology, so their care is more complicated. The complex coordination of care was also believed to result in negative treatment outcomes, as illustrated by the radiation oncologist: If the patient at [my institution] had surgery that I’m not aware of, and the patient comes to me, and really there was a long gap, a long interval … I actually had quite a few patients when they had surgery who, when they came to me, their tumor had recurred already. Related to lack of care coordination was lack of communication across departments, among HCPs, and with patients. Communication was seen as lacking between different constituents and related to treatment delays and to difficulties tracking patients during follow-up or transitional periods. The pulmonology surgeon said: I think the gaps — the major ones — are the communication between clinics and providers. So, we have a gap there that results in delays, and sometimes we don’t have all the information transmitted. It’s only what was written down in the chart. If you don’t look in the right place, you might not find it. That’s the biggest issue. Lack of communication between HCPs and patients was also recognized as contributing to delays in treatment. The patient navigators stated that HCPs should better communicate with their patients about the proper expectations of treatment. Patient navigators believed that when the explanation of the HCP is only verbally communicated, without written instructions or drawn diagrams, then patients forget the instructions given to them — which, in turn, results in patients delaying treatment or not adhering to treatment instructions. Enabling Factors: Patients, caregivers, HCPs, and patient navigators agreed that the enabling factors that generally apply to procuring or impeding patient access to health care were also contributors to delays in cancer treatment. Factors related to low SES mentioned by the study participants included financial barriers. All the respondents highlighted that patients at the safety-net hospital generally lacked the finances to cover basic expenses for housing, food, and transportation, as well as health insurance or, if they had insurance, the ability to cover their co-pays. Thus, the access barrier most directCancer Control 395 ly related to low SES was lack of health insurance or of sufficient health insurance to cover the cancer treatment (eg, radiotherapy) they needed. Patients who did have health insurance were, in general, covered through Medicaid or Medicare; few had sufficient private health insurance. Instead, a majority of patients, similar to other underserved Hispanic patients, had no health insurance, which significantly impeded their access to treatment. The medical oncologist summarized it by saying: People [who] do not have good health coverage have a hard time accessing the system. There are some things we cannot do for people who do not have good coverage at [this hospital], eg, positron emission tomography, which is used for staging lung cancer to see how advanced it is. Delays in proper cancer staging may then lead to delays in timely treatment for these underserved patients. Due to the significant financial barriers that disadvantaged Hispanic patients at the safety-net hospital face to initiate and complete their cancer treatment, statefunded programs are available for select patients, such as the Colorado Indigent Care Program, or some hospitals can assist them by finding resources that could help them cover some treatment costs. For example, some patients received assistance with medications they could not afford, as mentioned by the oncology nurse: There is an indigent formulary at this hospital, so that means certain folks [with no financial resources] come and get certain drugs. However, the oncology nurse explained that the process of finding resources for underserved patients makes the treatment of these patients difficult: We have our hands tied in a lot of situations or have a number of hurdles to jump through to provide the best care that we can for patients, and we absolutely do everything that we can to make sure we are providing the best care possible. The HCPs believed that the process of assisting patients was also a lengthy process that contributed to treatment delays. Although the safety-net hospital staff has administrative difficulties in providing care to this underserved population, these patients also face the hurdles of navigating the health care system themselves. Patients encountered system difficulties throughout the treatment process, from scheduling appointments to receiving timely and proper treatment. Navigation hurdles that delayed treatment tended to exist at the system level, as the pulmonology surgeon indicated: 396 Cancer Control The routine times to get appointments in some clinics can be pretty long. I think that’s why we see 8-month delays. It’s not surprising when we see it. We see it frequently. Patients with cancer may receive care at a hematology/oncology clinic that functions within the overall hospital structure, which further contributes to treatment delays, as the oncology nurse explained: The patient can call and get scheduled into the wrong clinic. There are issues with having central scheduling that handles all the appointments for all the outpatient clinics, as opposed to having someone dedicated to oncology who knows the patients, understands how our clinic works, and why patients need to be seen in a timely fashion. At the study hospital, the hematology/oncology clinic does not offer radiation oncology services but refers patients to a partnering academic cancer center when patients require radiotherapy. Navigating between separate treatment clinics was problematic and resulted in further treatment delays, particularly when care coordination was lacking, as the radiation oncologist explained: I just had a patient — he had surgery done, he’s late already, he’s like close to 4 weeks — so I saw the patient. I did the treatment planning the same day, so I want to start the treatment really quick. [Results from] computed tomography were not there [with the patient file from the safety-net hospital]. Treatment delays that result from difficulties navigating the health care system are also patient-dependent, and they generally originate from patients not understanding their HCPs’ follow-up instructions or not understanding how the health care system works. The pulmonologist made the observation: Part of the problem is the patients don’t understand how to get where they need to be. Sometimes they need help filling out forms to get their tests done in a timely fashion. Lack of patient understanding is likely linked to lack of care coordination at the systems-level, and difficulties navigating the health care system then contribute to delays in treatment, as the pulmonology surgeon explained: I think the major barriers are delays related to the process of getting from one clinic to the next in our system. Some of them may be language-related and some of them are just the way our system has been set up. October 2016, Vol. 23, No. 4 Predisposing Factors: Personal, social, cultural, and psychological propensities were noted as predisposing factors that contribute to a patient’s ability to access cancer treatment. Influential personal factors were related to patient immigration status and included lack of language proficiency and lack of legal status. Most Hispanic patients at the safety-net hospital spoke only Spanish — a barrier to timely treatment: The patient showed up late with the tumor recurred. … I think just for the Spanish patients — I think there are things … they probably had more difficult than the other patient population. Well, once, for whatever reason, they missed the appointment; they had [a] language barrier. Similarly, patients who lacked documentation of their legal immigration status encountered problems accessing treatment care, as the oncology pharmacist explained: If they [patients] are undocumented and there is a patient-assistance program available through pharmaceutical companies to provide drugs at low cost or free, undocumented patients don’t qualify. Language and legal status barriers impeded access to care, and, if they eventually accessed resources, their treatment was significantly delayed. Another predisposing factor to timely treatment is a patient’s social support system. Patients who have a caregiver or family members to assist them with navigating the medical system and support them through treatment are more successful at obtaining timely and proper treatment, as noted by the otolaryngologist’s report of the important role of a caregiver: I have one man who lost his larynx from laryngeal cancer, and his sister — his wicked sister — brings him in and she’s just a riot, but she keeps on this guy like you can’t believe. She has him here on time, all the time. An HCP also emphasized how a social support system can help patients overcome other barriers that imped timely treatment: My Latino patients who have done well have Englishspeaking families who have been here, and then they bring mom and dad in. By contrast, patients without caregivers or family members to care for them have a more difficult experience: A lot of our patients have no support system. So, if they get sick, they have no one to help them. And that’s tough, really tough. October 2016, Vol. 23, No. 4 Thus, social support appears to impact patients’ timely access and adherence to treatment. Lack of health literacy was another predisposing factors that played an important role in whether Hispanic men experienced treatment delays. We found that these underserved patients have difficulties understanding medical information related to their diagnosis and treatment, and, consequently, do not follow-up with their treatment regimen, as explained by the medical oncologist: Sometimes patients have no idea that they have to come back. Even though we tell them we want them back, they have no idea why. … And also there is lack of understanding from the patients of what is required to be successful when they’re in treatment. Misconceptions about cancer treatment were also reported as stemming from lack of health literacy. For example, when the pulmonologist was asked to expand on how he believed lack of health literacy contributed to treatment delays, he said: Well, so, I think one of the things I’ve heard from a lot of immigrants when we talked about surgery for lung cancer is that they don’t want to have surgery because they’ve heard that will cause the cancer to spread. Other similar diagnosis and treatment misconceptions also appeared to contribute to treatment delays. Mental health propensities were identified as directly and indirectly influencing a patient’s ability to initiate treatment. Substance abuse was related to treatment delays, which the medical oncologist explained: Yeah, well, that’s a problem because, number one, they sometimes have to actually quit these other complications [before treatment], … and, you know, sometimes that doesn’t happen. Similarly, emotional distress (eg, depression, anxiety, fear) affects patients’ ability to participate in treatment. The otolaryngologist illustrated: People who drink have depression. Uh, either it’s generated by the alcoholism or it’s preceding the alcoholism — where they drink because they’re depressed. I would think that’s an impediment [to treatment] that begins, you know, with the patient itself. Patients and their caregivers also recognized the role of emotional distress in the patient’s ability to initiate treatment and attend follow-up visits, as 1 woman with head and neck cancer explained: Yup, it was the first [round of] chemotherapy, after we found out. I missed my first — I was scared — I missed Cancer Control 397 my first appointment because I was scared. Same with radiation. I missed the first appointment. Discussion Our exploratory study findings help to understand the systems- and patient-level determinants of treatment delay among underserved Hispanic patients diagnosed with lung and head and neck cancers. Such contributing evidence was unavailable prior to this study. The literature that does exist suggests that socioeconomic inequalities negatively impact the ability of underserved patients to receive treatment for lung and head and neck cancers, and, when ethnicity is included, impoverished Hispanic patients are at a particular disadvantage.9-11 A paucity of evidence explains what factors determine the treatment delays experienced by this patient population, but the available data indicate that the time interval between the initial diagnosis and the start of treatment continues to increase and that delays beyond 46 days increase the risk of death.17,20 Treatment delays among patients with lung and head and neck cancers occur more often in those with early-stage disease,17,21 placing them at a higher risk for disease progression,22-25 disease recurrence,13-16 increased emotional distress,18,19 and lower rates of survival.17 Thus, assessing the determinants of treatment delays is important, because such understanding could lead to interventions that effectively target the factors that influence treatment inequalities among vulnerable populations, such as underserved Hispanic patients with lung and head and neck cancers. We used the Behavioral Model for Vulnerable Populations to frame our study design and analysis because it includes domains relevant to understanding the factors that influence access and the utilization of health care services among vulnerable populations.30,31 Thus, the Behavioral Model for Vulnerable Populations guided the choice of variables to include in the prediction model, from the medical records and the questions to ask patients and their caregivers, HCPs, and patient navigators. Institutional-Related Factors The literature and our findings unequivocally point to the need to decrease the treatment delays for lung and head and neck cancers because the timely initiation of treatment is likely to result in improved outcomes and survival for patients with these types of cancer. In our study, 35% of patients had treatment delays longer than 46 days, at a point when these patients have a significant increased risk of death.17 Series of institution-level factors common to publicly funded hospitals appear to be associated with such treatment delays in the underserved patients of our study. At the safety-net hospital where we conducted the study, lack of care coordina398 Cancer Control tion was common, either from enrolling patients for services to coordinating the specialty treatments they need — all of which were believed to result in treatment delays. In our study, communication was lacking across various clinics, providers, and patients when coordinating care, and it was consistent with the intuitive notion that the multidisciplinary coordination of care is complex and takes time, particularly if specialty care services are limited.28 Creating and encouraging the participation of HCPs in multidisciplinary tumor boards at public hospitals may help improve communication and contribute to better care coordination among oncologists and other HCPs. Use of tumor review boards has been associated with improved care and increased rates of survival among patients with cancer, although this association is controversial, and limitations still exist for those living in rural, low-resource areas, as well as in other suboptimal settings.35,36 Undergoing curative surgery among patients with early-stage lung and head and neck cancers is also likely to be improved when their HCPs participate in weekly tumor board meetings.37 The patients and caregivers interviewed did not attribute poor treatment outcomes to treatment delays due to lack of care coordination or lack of communication; rather, they attributed treatment delays to an initial missed diagnosis of cancer by their primary care physician. They implied that this initial missed diagnosis resulted in a delayed referral to an oncologist. One meta-analysis found that delayed referrals to specialists predicted a 3-fold mortality risk for patients with head and neck cancers, likely resulting from treatment delays and advanced disease.38 In our study, patients and caregivers believed that, after being diagnosed, the safety-net hospital provided patients with the care that they needed and viewed any treatment delays as being less consequential. The 7 patient navigators interviewed recognized that delays in treatment were overall related to lack of care coordination and miscommunication across hospital clinics. They were particularly concerned that patients with lung and head and neck cancers need system-navigation services to decrease delays in treatment, but they noted that patients were not receiving such services at the hospital. If the systems-level factors are not addressed, our findings suggest that treatment delays are likely to continue — and possibly increase disparities in treatment outcomes — among underserved Hispanic patients with lung and head and neck cancers. An evidence-based solution that can improve communication and care coordination may well be a patientnavigation program for this underserved patient population.39,40 October 2016, Vol. 23, No. 4 Patient-Related Factors As is characteristic of other patients at the safety-net hospital, the Hispanic patients in our study were medically underserved, with the majority of participants (60%) being uninsured and all of them being poor (annual income < $36,000).41 Due to lack of variability in income and health insurance status, this factor did not contribute to the prediction of treatment delays in our study. Instead, sex and number of comorbidities had independent effects on treatment delay, but these variables were also intertwined. Compared with men whose treatment was, on average, delayed by 34 days, disparities in treatment delays were more pronounced for women whose treatment was delayed by, on average, 48 days (above the critical 46-day delay17) from initial diagnosis to treatment initiation. Moreover, women with fewer comorbidities (≤ 4) were more likely to have increased delays in treatment compared with women who had more comorbidities or men who had a similar lower number of comorbid conditions. Compared with men, women were also more likely to be diagnosed with early-stage disease. Thus, our findings suggest that healthier women might be at high risk for treatment delays and patients whom safety-net hospital staff should follow-up more closely to avoid disparities in poor treatment outcomes,13-16,22-25 distress,18,19 and low rates of survival.17 Some published data indicate that the time from first diagnosis to treatment initiation does not significantly vary by comorbidity among patients treated at academic facilities.17 For patients treated at high-burden, safety-net hospitals, it is possible that a greater number of comorbidities means that these patients are better integrated into the system and, consequently, experience fewer treatment delays. If this is the case, then we think it appropriate to assume that patients who receive care for comorbid conditions are likely to have already enrolled in hospital services, medication programs, and be adept at navigating the health care system. Thus, having more than 4 comorbid conditions could be a proxy for patients having had some institution-level barriers addressed, possibly resulting in a more timely initiation of cancer treatment. Lack of legal status in the United States and lack of English-language proficiency are determinants of treatment delays that disadvantage medically underserved Hispanic patients, although the effects of these factors on treatment delays among these patients have not been quantified. As found in our study, patients with undocumented status are unable to qualify for resources that other underserved patients are able to access to cover their cancer treatment, and, if they eventually do, their treatment is likely to be significantly delayed. Similarly, our findings indicate that immigrant Hispanic patients who do not communicate in English face barriers to acOctober 2016, Vol. 23, No. 4 cessing care that may result in treatment delays. An adequate social support system that can assist patients with language barriers and to navigate the health care system could facilitate the ability of patients to obtain proper and timely treatment. A factor common to underserved patients is the lack of health literacy that, in this study, was reported to be associated with lack of proper and timely adherence to recommended treatment.42 For patients who lack adequate social support — particularly those with limited proficiency in English — or adequate health literacy, the presence of language translators or of patient navigators can help to engage patients and caregivers during physician visits, thereby increasing their ability to understand and follow the required steps in the cancer treatment process.39,40 A barrier to individuals with lung and head and neck cancers is substance abuse, which, in our study, was anecdotally linked to delays for patients unable to initiate treatment if they continued to smoke tobacco or drink alcohol. In particular, substance-abuse problems place underserved Hispanic patients with these types of cancers at a higher risk for emotional distress and mortality.1,11,43 Because mental health disparities are present among underserved Hispanic patients with cancer, affordable mental health services can assist them in addressing these problems and improve treatment delays.44 Limitations This exploratory study used a convenience sample to explore some possible determinants of treatment delays among underserved Hispanic patients with lung and head and neck cancers. A randomly selected sample followed longitudinally would strengthen the generalizability of the study results to this population of patients with cancer. The categorization of patients as Hispanics also limits generalizations to how determinants of treatment delays may differ by other ethnic groups (eg, country of origin, acculturation levels). Methodologically, we were limited by the data available in the medical records of the study patients, and we were unable to assess their reliability. Because the incomes of all of our study participants fell below the poverty level at the beginning of the study,14 we could not examine the effects of SES on the number of days from the initial diagnosis to treatment initiation as reported in their medical records. Instead, in-depth interviews with the HCPs suggested that low SES contributed to treatment delays via the patients’ lack of health insurance. We also could not explore the effects of health insurance coverage, because most patients were uninsured or lacked proper health insurance through Medicaid or Medicare. However, the Affordable Care Act that expands the coverage of public health inCancer Control 399 surance for underserved patients may now improve their access to timely and proper treatment; however, its effects on cancer disparities remains to be demonstrated.45 Conclusions Data suggest that delays in cancer treatment are associated with poor outcomes and lower rates of survival for patients with lung and head and neck cancers. Thus, immediate action should be taken to improve the time between diagnosis and treatment initiation for these disadvantaged patients. Future studies should assess the effects of the determinants that our interviewees believed influence delays in treatment initiation among underserved Hispanic patients with cancer treated at a safety-net hospital. Our findings could be used to guide future research as well as interventions for underserved patient populations. Acknowledgment: The authors wish to thank Drs Estevan Flores, Paula Espinoza, Al Marcus, and Tim Byers for their generous advice. References 1. American Cancer Society. Cancer Facts and Figures 2016. http://w w w.cancer.org/acs/groups/content /@research/documents/ document/acspc-047079.pdf. Accessed September 6, 2016. 2. American Cancer Society. Cancer Facts & Figures for Hispanics/ Latinos: 2015-2017. http://www.cancer.org/acs/groups/content/@research/ documents/document/acspc-046405.pdf. Accessed September 6, 2016. 3. Ries LAG, Melbert D, Krapcho M, et al, eds. SEER Cancer Statistics Review, 1975-2005, National Cancer Institute. Bethesda, MD. http://seer. cancer.gov/csr/1975_2005. Based on November 2007 SEER data submission. Accessed July 29, 2016. 4. Kuriakose MA, Loree TR, Rubenfeld A, et al. Simultaneously presenting head and neck and lung cancer: a diagnostic and treatment dilemma. Laringoscope. 2002;112(1):120-123. 5. Centers for Disease Control and Prevention. Smoking-attributable mortality, years of potential life lost, and productivity losses – United States, 2000-2004. MMWR Morb Mortal Wkly Rep. 2008;57(45):1226-1228. 6. Blot WJ, McLaughlin JK, Winn DM, et al. Smoking and drinking in relation to oral and pharyngeal cancer. Cancer Res. 1988;48(11):3282-87. 7. Centers for Disease Control and Prevention. Cigarette smokingattributable morbidity -- United States, 2000. MMWR Morb Mortal Wkly Rep. 2003;52(35):842-844. 8. Agency for Healthcare Research and Quality (AHRQ). 2014 National Healthcare Quality & Disparities Report. Rockville, MD: AHRQ; 2015. http://www.ahrq.gov/sites/default/files/wysiwyg/research/findings/nhqrdr/ nhqdr14/2014nhqdr.pdf. Accessed September 6, 2016. 9. Forrest LF, Adams J, Wareham H, et al. Socioeconomic inequalities in lung cancer treatment: systematic review and meta-analysis. PLoS Med. 2013;10(2):e1001376. 10. Choi SH, Terrell JE, Fowler KE, et al. Socioeconomic and other demographic disparities predicting survival among head and neck cancer patients. PloS one. 2016;1;11(3):e0149886. 11. Yang R, Cheung MC, Byrne MM, et al. Do racial or socioeconomic disparities exist in lung cancer treatment? Cancer. 2010;116(10):2437-2447. 12. Committee on Quality of Health Care in America; Institute of Medicine. Crossing the Quality Chasm: A New Health System for the 21st Century. Washington, DC: National Academy Press; 2001. 13. Ang KK, Trotti A, Brown BW, et al. Randomized trial addressing risk features and time factors of surgery plus radiotherapy in advanced headand-neck cancer. Int J Radiat Oncol Biol Phys. 2001;51(3):571-578. 14. Fortin A, Bairati I, Albert M, et al. Effect of treatment delay on outcome of patients with early-stage head-and neck carcinoma receiving radical radiotherapy. Int J Radiat Oncol Biol Phys. 2002;52(4):929-936. 15. Hansen O, Larsen S, Bastholt L, et al. Duration of symptoms: impact on outcome of radiotherapy in glottis cancer patients. Int J Radiat Oncol Biol Phys. 2005;61(3):789-794. 16. Chen Z, King W, Pearcey R, et al. The relationship between waiting time for radiotherapy and clinical outcomes: a systematic review of the 400 Cancer Control literature. Radiother Oncol. 2008;87(1):3-16. 17. Murphy CT, Galloway TJ, Handorf EA, et al. Survival impact of increasing time to treatment initiation for patients with head and neck cancer in the United States. J Clin Oncol. 2016;34(2):169-178. 18. Haisfield-Wolfe ME, McGuire DB, Soeken K, et al. Prevalence and correlates of depression among patients with head and neck cancer: a systematic review of implications for research. Oncol Nurs Forum. 2009;36(3):E107-E125. 19.Hess CB, Chen AM. Measuring psychosocial functioning in the radiation oncology clinic: a systematic review. Psychooncology. 2014;23(8):841-854. 20. Murphy CT, Galloway TJ, Handorf EA, et al. Increasing time to treatment initiation for head and neck cancer: an analysis of the National Cancer Database. Cancer. 2015;121(8):1204-1213. 21. Vinas F, Ben Hassen I, Jabot L, et al. Delays for diagnosis and treatment of lung cancers: a systematic review. Clin Respir J. 2016;10(3):267-271. 22. Waaijer A, Terhaard CHJ, Dehnad H, et al. Waiting times for radiotherapy: consequences of volume increase for the TCP in oropharyngeal carcinoma. Radiother Oncol. 2003;66(3):271-276. 23. Jensen AR, Nellemann HM, Overgaard J. Tumor progression in waiting time for radiotherapy in head and neck cancer. Radiother Oncol. 2007;84(1)5-10. 24. Kowalski LP, Carvalho AL. Influence of time delay and clinical upstaging in the prognosis of head and neck cancer. Oral Oncol. 2001;37(1):94-98. 25. Laroche C, Wells F, Coulden R, et al. Improving surgical resection rate in lung cancer. Thorax. 1998;53(6):445-449. 26. Yorio JT, Xie Y, Yan J, et al. Lung cancer diagnostic and treatment intervals in the United States: a health care disparity? J Thoracic Oncol. 2009;4(11):1322-1330. 27. Munck K, Ali MJ, Murr AH, et al. Impact of socioeconomic status on the diagnosis to treatment interval (DTI) in Waldeyer’s ring carcinoma. Laryngoscope. 2005;115(7):1283-1287. 28. Patel UA, Brennan TE. Disparities in head and neck cancer: assessing delay in treatment initiation. Laryngoscope. 2012;122(8):1756-1760. 29. Creswell JW, Plano Clark VL. Designing and Conducting Mixed Methods Research. 2nd ed. Thousand Oaks, CA: Sage Publications; 2007. 30. Gelberg L, Andersen RM, Leake BD. Healthcare access and utilization. The Behavioral Model for Vulnerable Populations: application to medical care use and outcomes for homeless people. Health Serv Res. 2000;34(6):1273-1302. 31. Bazargan M, Bazargan SH, Farooq M, et al. Correlates of cervical cancer screening among underserved Hispanic and African American women. Prev Med. 2004;39(3):465-473. 32. Singh B, Bhaya M, Stern J, et al. Validation of the Charlson Comorbidity Index in patients with head and neck cancer: a multi‐institutional study. Laryngoscope. 1997;107(11 pt 1):1469-1475. 33.Altheide DL. Ethnographic content analysis. Qualitat Sociol. 1987; 10(1):65-77. 34. Krippendorf K. Content Analysis: An Introduction to its Methodology. 2nd ed. Beverly Hills, CA: Sage Publications; 2004. 35. Keating NL, Landrum MB, Lamont EB, et al. Tumor boards and the quality of cancer care. J Natl Cancer Inst. 2013;105(2):113-121. 36. Krasna M, Freeman RK, Petrelli NJ. Re: Tumor boards and the quality of cancer care. J Natl Cancer Inst. 2013;105(23):1839-1840. 37. Kehl KL, Landrum MB, Kahn KL, et al. Tumor board participation among physicians caring for patients with lung or colorectal cancer. J Oncol Pract. 2015;11(3):e267-e278. 38.Seoane J, Takkouche B, Varela-Centelles P, et al. Impact of delay in diagnosis on survival to head and neck carcinomas: a systematic review with meta-analysis. Clin Otolaryngol. 2012;37(2):99-106. 39. Pasket ED, Harrop PJ, Wells KJ. Patient navigation: an update on the state of science. Cancer. 2011;61(4):237-249. 40. Raich PC, Whitley EM, Thorland W, et al. Patient navigation improves cancer diagnostic resolution: an individually randomized clinical trial in an underserved population. Cancer Epidemiol Biomarkers Prev. 2012;21(10):1629-1638. 41. US Department of Health and Human Services; Office of The Assistant Secretary for Planning and Evaluation. 2013 poverty guidelines. Published December 1, 2013. http://aspe.hhs.gov/poverty/13poverty.cfm. Accessed September 6, 2016. 42. Shaw SJ, Huebner C, Armin J, et al. The role of culture in health literacy and chronic disease screening and management. J Immigr Minor Health. 2009;11(6):460-467. 43.Glazier KA. Tobacco-induced diseases: an emphasis on mental health conditions that may result from cigarette use. N Sch Psychol Bulln. 2010;8(1):56-61. 44. Luckett T, Goldstein D, Butow PN, et al. Psychological morbidity and quality of life of ethnic minority patients with cancer: a systematic review and meta-analysis. Lancet Oncol. 2011;12(13):1240-1248. 45. Moy B, Polite BN, Halpern MT, et al. American Society of Clinical Oncology policy statement: opportunities in the patient protection and Affordable Care Act to reduce cancer care disparities. J Clin Oncol. 2011;29(28):3816-3824. October 2016, Vol. 23, No. 4 Geographical analysis can be used to respond to select barriers that contribute to disparities in prostate care. Orchid. X-Ray image courtesy of Bryan Whitney. www.x-rayphotography.com. Geographical Factors Associated With Health Disparities in Prostate Cancer Scott M. Gilbert, MD, Julio M. Pow-Sang, MD, and Hong Xiao, PhD Background: Treatment variation in prostate cancer is common, and it is driven by clinical and clinician factors, patient preferences, availability of resources, and access to physicians and treating facilities. Most research on treatment disparities in men with prostate cancer has focused on race and socioeconomic factors. However, the geography of disparities — capturing racial and socioeconomic differences based on where patients live — can provide insight into barriers to care and help identify outlier areas in which access to care, health resources, or both are more pronounced. Methods: Research regarding treatment patterns and disparities in prostate cancer using the Geographical Information System (GIS) was searched. Studies were limited to English-language articles and research focused on US populations. A total of 43 articles were found; of those, 30 provided information about or used spatial or geographical analyses to assess and describe differences or disparities in prostate cancer and its treatment. Two additional GIS resources were included. Results: The research on geographical and spatial determinants of prostate cancer disparities was reviewed. We also examined geographical analyses at the state level, focusing on Florida. Overall, we described a geographical framework to disparities that affect men with prostate cancer and reviewed existing published evidence supporting the interplay of geographical factors and disparities in prostate cancer. Conclusions: Disparities in prostate cancer are common and persistent, and notable differences in treatment are observable across racial and socioeconomic strata. Geographical analysis provides additional information about where disparate groups live and also helps to map access to care. This information can be used by public health officials, health-systems administrators, clinicians, and policymakers to better understand and respond to geographical barriers that contribute to disparities in care. From the Departments of Genitourinary Oncology (SMG) and Health Outcomes and Behavior (SMG, JP), H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, and the Department of Pharmaceutical Outcomes and Policy (HX), College of Pharmacy, University of Florida, Gainesville, Florida. Submitted May 2, 2016; accepted September 20, 2016. Address correspondence to Scott M. Gilbert, MD, Departments of GU Oncology & Health Outcomes and Behavior, Moffitt Cancer Center, 12902 Magnolia Drive, XCB-GU Program, Tampa, FL 33612-9416. E-mail: [email protected] No significant relationships exist between the authors and the companies/organizations whose products or services may be referenced in this article. October 2016, Vol. 23, No. 4 Introduction Prostate cancer is the most common nondermatological cancer diagnosed among American men, accounting for approximately 180,000 new cases each year in the United States.1 Although it is typically characterized by a protracted clinical course, prostate cancer is also one of the most common causes of cancer-related death (fourth most common overall following lung, colorectal, and breast cancers) and accounts for more than 26,000 deaths related to cancer each year in the United States alone.2 Cancer Control 401 Although most prostate cancers (80%) are detected at an early stage and 10-year survival rates surpass 90%, 16% of men present with either locally advanced or metastatic disease.3 Metastatic prostate cancer is an incurable disease despite advances in treatment.3 Early-stage prostate cancer is also a heterogeneous disease defined by variable clinical behavior and outcomes.4 Following local treatment, prostate cancer recurs in up to 40% of men with early-stage disease.5,6 An estimated 2.85 million American men are living with prostate cancer, making this patient group the second largest group of cancer survivors.3 With health care expenditures surpassing an estimated $9.8 billion each year, prostate cancer is also one of the most costly cancers in the United States.7 Although these figures underscore the personal and public health burdens associated with prostate cancer, not all men fare equally. Disparities in risk of aggressive disease and differences in treatment and outcomes are consistently observed.3-11 For example, incidence rates among black men (214.5 per 100,000 persons) are significantly higher compared with their white counterparts (130.0 per 100,000 persons), and death rates from prostate cancer are more than double for black men compared with their white counterparts (46.3 per 100,000 persons vs 19.8/100,000 persons, respectively).3 Several factors may contribute to observed racial disparities, including biological determinants (differences in genetic polymorphisms related to testosterone metabolism and the androgen receptor) differences in health behaviors, and access to health care resources.8 Beyond racial factors, men with lower social status and educational level are also more frequently diagnosed with more aggressive, clinically significant forms of prostate cancer than men from higher socioeconomic backgrounds, and prior research indicates that health seeking and literacy issues, as well as access to health care resources, may partially explain why some men have poorer outcomes than others.9-11 Certainly social and demographical factors may be signals for other yet-to-be identified sources that drive divergent outcomes, or they may be principal factors that explain why some men die from prostate cancer and others do not. Disparate risk factors and outcomes can be defined by geographical boundaries, and there may be a geographical component to health disparities. Methods In addition to studying broader reviews of racial and sociodemographic disparities, our search of available literature databases focused on geographical factors associated with health and outcome disparities, and use of spatial analyses, including the Geographical Information System (GIS), in disparity research studies related to prostate cancer. Additional, nonindexed prostate cancer treatment and outcome reports using the GIS were searched online, 402 Cancer Control and reports were examined and included if they were related to geographical and health disparities. Studies were limited to research focusing on US populations and those published in the English language. A total of 43 publications were identified, 30 of which were relevant and included in our review. Results The geographical and prostate cancer factors found in selected disparity studies have been summarized in the Table.12-25 Racial and Sociodemographic Disparities Disparities in treatment and survival between black and non-black men have long been observed. Research has shown that black men are at significantly higher risk of dying from prostate cancer than white men, they are less likely to receive curative local therapy for intermediate- and high-risk disease than their white counterparts, and small but significant differences in 5-year survival rates have been documented.26,27 Mahal et al27 reported that black men are 12% more likely to die from prostate cancer than white men (hazard ratio 1.12; 95% confidence interval [CI]: 1.01–1.25), corresponding to an absolute risk of death of 4.5% for blacks (95% CI: 4.1–4.9) compared with 3.4% for whites (95% CI: 3.3–3.6). They also found that black men were 18% less likely to receive curative treatment than their white counterparts.27 Other studies have also reported lower rates of screening and appropriate staging rates among black men compared with white men.28,29 Black men less frequently receive curative therapy, they may receive treatment later after diagnosis, and they are less likely to be treated with adjuvant therapy than white men.29 Increased risk of mortality has been observed in black men as well as in men from disadvantaged social, educational, and economic backgrounds: these men have higher rates of death from prostate cancer, regardless of race.30 Inequity in mortality related to prostate cancer is generally ascribed to 1 of 3 factors: disease factors (eg, differences in biology, risk of more aggressive disease in some groups), patient factors (eg, health behaviors), and issues endemic to the health care system (eg, differences in access to health care facilities and resources, screening and detection practices, treatment variation).31-33 Social, economical, and education disparities may be linked to significant differences in disease management and outcomes.34-39 Several studies have shown that men from disadvantaged groups (eg, those with lower socioeconomic status) are less likely to receive aggressive local treatment, such as radical surgery or radiotherapy, than those of higher socioeconomic status.34-37 Screenings are also less commonly performed in poorer and less-educated communities, possibly leading to diagnoses at a later-stage disease when fewer treatment options October 2016, Vol. 23, No. 4 Table. — Summary of Select Disparity Studies With Geographical and Prostate Cancer Factors Study Geographical Unit Disease Phase Key Finding Aneja12 United States, county Mortality 3.91%–5.45% reduction in mortality in counties with ≥ 1 radiation oncologist compared with counties lacking radiation oncologists Antwi13 Kentucky, Appalachian region Survival Black men had lower survival rates compared with white men (HR 1.41; 95% CI: 1.26–1.65) Cetnar 14 Wisconsin, census tract Primary treatment Likelihood of noncurative treatment no different in rural compared with urban areas (OR 0.96; 95% CI: 0.52–1.77) Cobran15 United States, SEER site Treatment Intensity-modulated radiotherapy more commonly used in white than blacks (53% vs 45%; P < .05) Socioeconomic-, geographic-, and tumor-related factors explained preponderance of variation Cook 16 United States, census divisions Incidence rates Large geographical differences in black-to-white incidence rate ratios DeChello17 Connecticut and Massachusetts, census tract Incidence rates Significant geographical variation observed in age-adjusted incidence rates among white and black men Garg18 United States, state Screening Significant variation in PSA screening among states Men living in urban areas have lower odds of screening (OR 0.8; 95% CI: 0.7–0.9), low physician density, low PSA screening (OR 0.78; 95% CI: 0.63–0.94) Goovaerts19 Florida, county Incidence of late-stage disease Variation noted in temporal decrease in late-stage diagnosis by county and race Gregorio20 Connecticut, census tract Survival Spatial scan statistical analysis of adjusted survival times identified one significant outlier area in the state with significantly lower survival (death hazard 1.39 > state average; P < .05) Meliker 21 Michigan, legislative districts Survival Higher survival rates observed in white men at state level without confirmation of racial disparities at smaller geographical units Onukwugha 22 United States, county Follow-up care Significant variation in follow-up physician visits explained by geographical factors Black men living in low socioeconomic and high-crime areas less likely to receive follow-up care Wagner 23 Georgia, county Incidence rates “Hot spots” identified in several counties in both black and white men in northern and northwestern-central Georgia Xiao24 Florida, county and census tract Incidence of late-stage disease Late-stage diagnosis related to low census tract median income and lower educational attainment Xiao25 Florida, county and census tract Incidence of late-stage disease Late-stage diagnosis associated with lack of insurance, low household income, rural location CI = confidence interval, HR = hazard ratio, OR = odds ratio, PSA = prostate-specific antigen, SEER = Surveillance, Epidemiology, and End Results. may be available or cure is less likely.38,39 Level of health literacy and patient decision-making capacity may also contribute to socioeconomic disparities,40 a hypothesis partly supported by research showing that racial disparities appear to be modified by socioeconomic status.41 This suggests that the gap between white and black men residing in higher-income and higher-level education neighborhoods is narrower than the gap separating residents from low socioeconomic status regions. A systematic review analyzing the association between socioeconomic status and risk of prostate cancer–related death reported that most research supports a significant link between socioeconomic status and prostate cancer–related mortality, even after adjusting for factors such as patient comorbidities and differences October 2016, Vol. 23, No. 4 in treatment.30 In aggregate, these data suggest that low socioeconomic status increases the risk of prostate cancer–related death in men with prostate cancer, even after accounting for differences in health, stage at diagnosis, and treatment. It is worth noting that socioeconomic status disparities do not appear to have decreased in the last 10 years.10 By contrast, average survival rates of prostate cancer have improved during that same time.3 Geographical Disparities Examining nationwide treatment trends, Harlan et al42 noted significant regional variation across definitive treatment modalities among both white and black men. The age-adjusted proportion of men treated with prostatectomy ranged from 22.5% in Connecticut to Cancer Control 403 47.8% in Utah, although use of radiotherapy varied less across Surveillance, Epidemiology, and End Results (SEER) cancer registry sites.42 In addition to confirming widespread variation in treatment modality in another SEER cohort, Krupski et al36 also documented significant racial and socioeconomic variation in care, with black and low-income men receiving surgery for localized disease significantly less commonly than white, higher-income men. The adjusted likelihood of surgical therapy was less than one-half (odds ratio [OR] 0.44; 95% CI: 0.41–0.47) in the lowest utilization region compared with the highest, and the investigators documented that black men were one-half as likely to be treated with surgery than whites (OR 0.52; 95% CI: 0.48–0.56).36 Regional variation in radiotherapy was observed: it was typically more common in regions with low rates of surgery.36 The results of another study examining ecological correlations between variation in prostate cancer–related deaths and surrogate measures of access to medical care (eg, prostate-specific antigen [PSA] screening uptake, late-stage presentation) suggest that between 10% and 30% of observed variations in mortality rates may be attributable to access issues.43 Although regional differences in treatment for prostate cancer have been well described, a paucity of research has focused on the underlying determinants of geographically linked disparities. Access, distance, and travel time to health care facilities are germane when compared with concerns related to disparities in treatment and subsequent outcomes among US residents living in rural areas.44 One review examined the differences in incidence and mortality rates between residents of rural and urban areas.45 Few differences were observed in incidence rates, particular in the post–PSA screening era, but the findings of the review suggested that men living in rural areas are at higher risk of prostate cancer– related death than those living in urban areas, presumably due to issues related to health care accessability.45 Other research has also shown that patients living in rural areas, regardless of their racial/ethnic background, are less likely to undergo PSA screening and more likely to present with more advanced disease, so they may have fewer curative treatment options.43 Another study found that awareness of and knowledge about prostate cancer were lower among rural men,46 and another confirmed that screening and detection practices are significantly less common in rural than urban areas.47 Rates of mortality and survival are also significantly associated with race/ethnicity, socioeconomic status, and accessibility to health care among men with prostate cancer.48,49 Geographical Information System and Its Role in Disparity Research The GIS is a computer system designed to capture, store, analyze, manage, and display spatially referenced data. It was developed in the 1960s by Tomlinson and then 404 Cancer Control further refined and commercialized by Fisher.50 Applying the GIS to visualize and analyze spatial and temporal disease patterns has become more prevalent in health care research in recent years.51 Health conditions such as cardiovascular disease, hepatitis C virus infection, birth defects, and various cancers have been displayed in a spatial context to better understand these disease states.51 By merging health data and geography, the GIS can also help inform decision-making when allocating resources. Thus, research involving GIS brings together several different fields, including medicine, epidemiology, geography, computer sciences, and statistics.50 In recent years, GIS has started to extend to areas of epidemiological and health services research — focusing on health disparities — to examine the availability of health resources, utilization of health care, the geographical distribution and clustering of cancers, treatment, and rates of mortality. For example, health-related GIS studies have increased the ability of public health officials to monitor diseases and to identify areas of need. The National Cancer Institute has an interactive website that uses the GIS for cancer control purposes.52 In the field of prostate cancer, research using GIS approaches has been conducted to investigate diagnoses, management, and treatment outcomes across different geographical levels, such as counties, census division/tracts, cancer registry areas, and other aggregate geographical scales.12-25,53-68 Cockburn et al53 used the GIS to geocode the historical residential addresses of individuals and measured the association between ambient exposure to pesticide and incidence rates of prostate cancer in California. They found a positive relationship between prostate cancer and ambient pesticide exposure in and around homes in intensely agricultural areas.53 Hsu et al56 used a spatial scan statistic to detect counties with increased mortality between 1980 and 2001 in Texas. DeChello et al17 used the same method and found geographical variation in incidence rates of prostate cancer among both white and black men between 1994 and 1998 in Connecticut and Massachusetts. In a subsequent analysis of the Connecticut data, researchers identified an outlier locale with a significantly higher mortality rate (adjusted for age, disease, and race) than other parts of the state. 20 Wagner et al23,62 applied GIS methods to visualize ratios of cancer mortality and incidence and detected large geographical disparities among blacks in Georgia compared with national benchmark data. Antwi et al13 found that men with prostate cancer living in the Appalachian region within Kentucky have lower rates of survival than those living in non-Appalachian regions. Differences in health resources and treatment patterns have also been examined among men with prostate cancer, and they have been linked to outcomes and possible quality-of-care issues. Aneja and Yu12 mapped the density of radiation oncologists for all counties in October 2016, Vol. 23, No. 4 ≥ 17.0% black (top quartile) 30–45 Rural (large and small) > 45 Late-Stage Diagnosis (%) 0.4 15–30 Bla 2006 0.5 ≥ 20% living in poverty (low income) 1982 ck males 0.3 County boundary 0–15 2006 0.1 Travel Time (min) 1982 ales White m 0.2 ≥ High-volume facility temporal trends for whites and blacks were also observed in rural counties of Florida.19 Another study used boundary analysis and reported significant regional differences in relation to when a decline of late-stage cases was seen, suggesting that the introduction of PSA testing and urbanization in several areas of Florida led to fewer late-stage diagnoses than that seen in nonurbanized areas, where uptake of screening practices are likely to have been slower.64 Al- 0.0 the United States and found that a higher density rate of radiation oncologists was associated with lower rates of prostate cancer–related mortality. Cetnar et al14 compared trends in first-line treatment of prostate cancer in rural and urban areas in Wisconsin and found that a person’s place of residence was not associated with treatment choice. GIS projects in other states have also examined disparities related to geography. Research involving men with prostate cancer has shown that the risk of late-stage prostate cancer diagnoses among black men living in Florida consistently exceeds that of white Floridians, although this gap has decreased in recent years.24,25 These studies used geographically weighted regression to account for the geographical variation in racial and sociodemographic composition, which provides estimates more likely to indicate the actual local impact of sociodemographic and clinical characteristics on patient outcomes.24,25 Using multiscale join-point regression analysis to investigate geographical, temporal, and racial/ethnic disparities in the incidence rates of late-stage prostate cancer among men living in Florida, researchers illustrated how the proportion of late-stage incidence can change over time.19,23 They observed striking geographical and racial disparities within a single state (Fig 1).19,23 Although the percentage of late-stage disease was halved between 1980 and 2000, nonmetropolitan areas lagged behind urban parts of the state, suggesting that late-stage presentation is a larger problem in rural areas compared with nonrural areas in Florida.19 Larger differences in Fig 1. — Temporal patterns of late-stage prostate cancer across Florida counties. Reprinted from Goovaerts P, Xiao H. Geographical, temporal and racial disparities in late-stage prostate cancer incidence across Florida: a multiscale joinpoint regression analysis. Int J Health Geogr. 2011;10:63. © Goovaerts and Xiao; licensee BioMed Central Ltd. 2011. Licensed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/2.0. The Northwest Florida CCC is notable for relatively large uncovered (> 45 min to high-volume facilities) rural areas characterized by low income and a high percentage of black residents. Tallahassee is the one area covering a relatively significant area of black residents. Fig 2. — Service area coverage and average travel times to high-volume prostate cancer treatment facilities in the Northwest Florida CCC area. Reproduced from reference 71. CCC = Cancer Control Collaborative. October 2016, Vol. 23, No. 4 Cancer Control 405 though this gap has narrowed across most Florida counand time to high-volume treatment centers.71 Furtherties and the rate of late-stage diagnoses continues to more, low income and rural areas of Florida also appear decrease, some parts of the state still demonstrate perto be characterized by limited resources for prostate sistent disparity.64 The decline in number of late-stage cancer care and specialist health care professionals diagnoses of prostate cancer has been slowest in Flor(eg, urologists, radiation oncologists).71 Treatment faciliida’s Big Bend region.64 In another study, researchers ties are more sparse in the North-Central and Panhandle compared the impact of comorbidities on late-stage diregions of Florida, thus resulting in longer travel times agnoses at the local level with the expected state-level for residents in those regions that appear to disproporrisk and found significant differences in observed-totionately affect disadvantaged men (Fig 2); by contrast, expected results in Tallahassee and Pensacola, where the southeastern and western parts of the state are the local OR was smaller than expected, and in Palm characterized by a greater number and higher density Beach, where the OR was larger than expected.65 of treatment facilities, shorter average travel times Racial/ethnic differences in how prostate cancer is (particularly along the coastal areas and in high-income, treated have also been documented in Florida through low-minority areas).71 However, low income and black GIS-based studies.66,67 These results point to the imporcommunities are still located beyond the close access tance of more granular, local analyses to evaluate potenbands even in those regions of Florida, thus indicating tial disparities and gaps, although the stability of estimata disproportionate and disparate service coverage for ed incidence, treatment, and mortality rates can become disadvantaged men (Fig 3).71 an issue when using small geographical units (eg, zip codes, census tracts), parThe Southwest Florida CCC is characterized ticularly when cases are by clustering of high-volume facilities and further stratified by race, soservice coverage areas along the Gulf Coast cioeconomic status, or both. with large uncovered inland areas that are low income and rural. It is worth noting that empirical research suggests that the census tract is the most reliable unit of analysis for spatial analyses.69,70 Another Florida study examining racial/ethnic and sociodemographic disparities focused on access to health care resources and differences in statewide treatment patterns.71 The Florida Prostate Cancer Atlas Project71 chronicled geographical variation in the burden of disease (eg, High-volume facilities late-stage diagnosis), disCounty boundaries tribution and availability of ≥ 20% living in poverty (low income) health care resources relevant to prostate cancer, ≥ 17.0% black (top quartile) as well as access to those Rural (large and small) resources, as assessed by Travel Time (min) travel times to treatment 0–15 facilities using cancer registry data from 1998 through 15–30 2007. The results of the 30–45 project demonstrate that > 45 low-income areas and areas characterized by a high percentage of black residents Fig 3. — Service area coverage and average travel times to high-volume prostate cancer treatment facilities in the Southwest Florida CCC area. Reproduced from reference 71. were associated with the CCC = Cancer Control Collaborative. greatest distance to travel 406 Cancer Control October 2016, Vol. 23, No. 4 Age-Adjusted Incidence Rate ≥ 15.8% Above state ratio by ≥ 20% 14.5%–15.8% Above state ratio by 10% to < 20% 11.9%–14.4% Within 10% of state ratio mutable factors that contribute to health disparities.52 Responses to actionable geographical health information include outreach and awareness campaigns, community-based health ser vice effor ts, such as screening events, organizing providers and resources into more accessible networks, and creating local infrastructure in underserved communities to allow better access and care to needed health services.52 References 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7-30. ≤ 10.5% Below state ratio by ≥ 20% 2. American Cancer Society. Cancer Facts & Figures 2016. 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Prostate cancer treatment patterns among racial/ethnic groups in Florida. J Natl Med Assoc. 2009;101(9):936-943. 67. Xiao H, Tan F, Goovaerts P, et al. Factors associated with time-totreatment of prostate cancer in Florida. J Health Care Poor Underserv. 2013;24(4 suppl):132-146. 68.Oliver MN, Smith E, Siadaty M, et al. Spatial analysis of prostate cancer incidence and race in Virginia, 1990-1999. Am J Prev Med. 2006;30(suppl):S67-S76. 69. Krieger N, Waterman P, Chen JT, et al. Zip code caveat: bias due to spatiotemporal mismatches between zip codes and US census-defined geographic areas – the Public Health Disparities Project. Am J Pub Health. 2002;92(7):1100-1102. 70. Gregorio DI, Dechello LM, Samociuk H, et al. Lumping or splitting: seeking the preferred areal unit for health geography studies. Int J Health Geogr. 2005;4(1):6. 71. Gilbert SM, Henriksen C, Hutton C, et al. Florida Prostate Cancer Atlas. https://com-uro-advisory-council.sites.medinfo.ufl.edu/files/2014/07/ Atlas_final_with_cover_final.pdf. Accessed September 21, 2016. October 2016, Vol. 23, No. 4 Differences in racial/ethnic, sociodemographical, and economic disparities in penile cancer can influence cancer control and survival-related outcomes. Birds Nest. X-Ray image courtesy of Bryan Whitney. www.x-rayphotography.com. Disparities in Penile Cancer Pranav Sharma, MD, Kamran Zargar-Shoshtari, MD, Curtis A. Pettaway, MD, Matthew B. Schabath, PhD, Anna R. Giuliano, PhD, and Philippe E. Spiess, MD Background: Although penile cancer is a rare malignancy in developed nations, racial and socioeconomic differences exist in the incidence of the disease and its associated survival-related outcomes. Methods: A search of the literature was performed for research published between the years 1990 and 2015. Case reports and non–English-language articles were excluded, instead focusing specifically on large, population-based studies. Results: The incidence of penile cancer is higher in Hispanic and African American men compared with whites and Asians. Men with penile cancer also appear to have a distinct epidemiological profile, including lower educational and income levels, a history of multiple sexual partners and sexually transmitted infections, and lack of circumcision with the presence of phimosis. African American men presented at a younger age with a higher stage of disease and worse survival rates when compared with white men. Rates of cancer-specific mortality increased with age, single marital status, and among those living in regions of lower socioeconomic status. Conclusions: An understanding of sociodemographical differences in the incidence and survival rates of patients with penile cancer can help advance health care policy changes designed to improve access and minimize disparities in cancer care for all men alike. Introduction Penile cancer is rare in the United States, with an estimated 2,030 new cases in the United States and 340 related deaths estimated to occur this year.1 From the Departments of Genitourinary Oncology (PS, KZ-S, PES) and Cancer Epidemiology (MBS, ARG), H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, and the Department of Urology (CAP), University of Texas MD Anderson Cancer Center, Houston, Texas. Submitted January 21, 2016; accepted February 26, 2016. Address correspondence to Philippe E. Spiess, MD, Department of Genitourinary Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, WCB-GU PROG, Tampa, FL 33612. E-mail: [email protected] Dr Sharma is now affiliated with the Department of Urology at Texas Tech University Health Sciences Center in Lubbock, Texas. No significant relationships exist between the authors and the companies/organizations whose products or services may be referenced in this article. October 2016, Vol. 23, No. 4 However, its incidence is higher in some countries of Asia, Africa, and South America, where it represents 10% of all malignancies diagnosed among men.2 Patients with penile cancer appear to have a distinct epidemiological profile consisting of lower income and education levels, poor hygiene, a history of sexually transmitted infections, phimosis, and multiple sexual partners.3 Risk factors for penile cancer include lack of circumcision, presence of phimosis or paraphimosis, poor hygiene, human papillomavirus (HPV) infection, presence of genital warts, chronic inflammatory conditions of the foreskin, glans penis, or penile shaft (eg, balanitis xerotica obliterans, lichen sclerosis), presence of smegma (a whitish substance that accumulates underneath the foreskin), tobacco abuse, or history of psoriasis treatment with ultraviolet light.4,5 Tumor grade and stage, basaloid or sarcomatoid histological Cancer Control 409 features, and the presence and extent of lymph-node (LN) involvement in the groin or pelvis have all been identified as important prognostic factors for penile cancer in determining long-term, cancer-related survival outcomes.6 In addition to disease-specific characteristics, significant demographical, racial/ethnic, social, and economic disparities exist with regard to both the incidence and survival rates of penile cancer.7 This is especially important considering the diverse patient population in which this disease presents.2 These findings also highlight the importance of considering these differences when developing health care policies to help improve access to standard medical care and reduce the treatment gap in cancer management. Methods A search of the medical literature was performed for research published between January 1990 and December 2015. Case reports and non–English-language articles were excluded, focusing instead on large, population-based studies from national or international datasets. A total of 54 studies were initially identified, 30 of which are included in this review. Incidence The incidence of penile cancer varies within specific racial/ethnic and socioeconomic groups, and a summary of the reviewed literature analyzing disparities in penile cancer incidence based on large population-based data sets is shown in Table 1.8-10 Hernandez et al8 examined the burden of invasive squamous cell carcinoma (SCC) of the penis in the United States from 1998 to 2003 based on data from the Surveillance, Epidemiology, and End Results Table 1. — Overview of the Disparities in Incidence of Penile Cancer in Select Population-Based Studies Study Colón-López Data Set Select Findings Puerto Rico Cancer Registry SEER program Puerto Rican men had higher rates of penile cancer than other groups Lower socioeconomic status and educational level associated with higher incidence rates in Puerto Rican men Goodman9 US populationbased registries Hispanic and African American men had highest rates of penile cancer African American men diagnosed at advanced stage with more nodepositive disease Highest incidence in the southern United States Hernandez8 SEER program Penile cancer rates higher in Hispanics and those living in regions of lower socioeconomic status or in the southern United States 10 SEER = Surveillance, Epidemiology, and End Results. 410 Cancer Control (SEER) program of the National Cancer Institute. The annual, average age-adjusted incidence rate of penile SCC was 0.81 cases per 100,000 men, and rates steadily increased with age.8 The incidence of penile SCC was comparable in whites and African Americans, but it was approximately twofold lower in Asians and Pacific Islanders.8 Rates among Hispanics were 72% higher compared with non-Hispanics, which may be attributable to a decreased prevalence of circumcision in this ethnic group.11 From 1993 to 2002, white Hispanics had the highest incidence rates of penile cancer (1.01 per 100,000 men) followed by Alaska Natives/American Indians (0.77 per 100,000 men) and African Americans (0.62 per 100,000 men).11 Incidence of penile SCC was also elevated in the southern United States and in regions of lower socioeconomic status. However, the study had limitations because the education level of participants was not analyzed. Colón-López et al10 compared the incidence of penile cancer in Puerto Rico with other racial and ethnic groups in the United States. Puerto Rican men had a higher incidence of penile cancer than non-Hispanic white men (standardized rate ratio [SRR] 3.33), nonHispanic African American men (SRR 3.04), and other US Hispanic men (SRR 2.59).10 This difference was more pronounced for Puerto Rican men younger than 60 years of age when compared with similarly aged US counterparts.10 Puerto Rican men with the lowest socioeconomic status had a 70% higher incidence rate of penile cancer than Puerto Rican men with the highest socioeconomic status (SRR 1.70).10 Less education (< 12 years of education) was also statistically associated with a higher incidence rate of penile cancer among Puerto Rican men (SRR 2.18).10 However, the overall rate of penile cancer in Puerto Rico declined over time. In other studies, Hispanic and African American men have been reported to have the highest age-adjusted rates of penile cancer compared with whites, Asians, or American Indians.9,12 The highest rates of penile cancer were observed in Hispanic and African American men older than 85 years of age, but penile cancer was rare among males younger than 20 years of age. Analyses to assess temporal trends from 1995 to 2003 revealed a statistically significant decline in the incidence of penile cancer for African Americans and whites. Approximately 60% of penile cancers were diagnosed at a localized stage (≤ pT2) among all racial and ethnic groups, although Hispanic and African American men tended to be diagnosed at an advanced stage (≥ pT3) with a higher incidence of node-positive disease than whites.9 Racial and ethnic differences in tumor grade were not found. The incidence of penile cancer was highest in the southern United States and lowest in the western states. The highest age-adjusted incidence rate of penile SCC was seen in African American men living in the southern United States, and the October 2016, Vol. 23, No. 4 lowest rate was found among Asian-Pacific Islanders living in western states.9 The incidence of primary malignant penile cancer has decreased significantly over time from 1973 to 2002 based on data from SEER; however, the incidence of nodal disease has increased over time.13 The overall incidence of penile cancer in the United Kingdom (England and Wales) is higher than in Australia and the United States, although the incidence of penile cancer in all 3 countries was stable over time.14 Although cancer-specific mortality rates were higher in England and Wales compared with Australia and the United States, the incidence ratios were similar for all 3 countries.14 In Finland, the age-adjusted incidence rate of penile cancer has decreased from the 1960s onward.15 Penile cancer was primarily a disease of elderly men during this time in Finland, and no systematic geographical variation or predilection in terms of incidence was observed.15 The most common predisposing risk factors in Finland were phimosis (44% of cases) and condylomatous genital lesions (20% of cases).15 Human Papillomavirus Infection An estimated 40% to 80% of invasive penile cancers have been linked to HPV infection.16-18 Warty and basaloid penile carcinomas have been associated with HPV infection, particularly HPV types 16 and 18, more so than typical SCC or verrucous carcinoma of the penis.19,20 No significant association between HPV status and pathological tumor stage, grade, or LN status was found in this study.19 The impact of HPV infection on the prognosis of patients with penile cancer is still controversial. Lont et al21 reported an association between high-risk HPV infection and reduced disease-specific mortality from penile cancer (hazard ratio [HR] 0.14), whereas Hernandez et al16 observed no association between HPV status and rate of survival in patients with penile cancer. HPV-associated penile malignancies, similar to other nonviral penile cancers, have been associated with lower education level (incidence density ratio 1.32; P = .0002) and income status (incidence density ratio 1.59; P < .0001).22 Current and former smokers were significantly more likely to have an α-HPV infection than any other type.23 In a study by Chaux et al3 of 103 Paraguayans with penile cancer, patients with penile cancer were generally found to dwell in rural or suburban areas (82%), live below the poverty line (75%), have a lower level of education (91%), and have a significant smoking history (76%). Phimosis (57%), moderate or poor hygienic habits (90%), and a history of sexually transmitted infections (74%) were also observed.3 Patients with more than 10 lifetime female sexual partners were nearly 4 times as likely to present with HPV-positive penile October 2016, Vol. 23, No. 4 tumors when compared with patients who had fewer than 6 lifetime female sexual partners.3 However, this trend was not significant when the number of sexual partners was adjusted for age at first coitus and past history of sexually transmitted infections. HPV-positive tumors were found in 36% of cases studied, and they were characterized by warty or basaloid morphology in addition to a high histological grade in the majority of cases.3 Treatment The management of penile carcinoma has evolved in recent years, resulting in a shift in the treatment of the disease.24 Options for the treatment of localized disease have expanded to organ-sparing therapy, and treatment of advanced disease has developed into a multidisciplinary, team-based approach using multimodal therapies.24 Demographical, racial/ethnic, and socioeconomic disparities can influence the treatments offered for patients with penile cancer in different populations (Table 2).25,26 Zhu et al26 used data from SEER to identify individuals diagnosed with penile SCC from 1998 to 2009 and treated with either local tumor excision or partial or total penectomy for their primary tumor. Of the 1,292 eligible patients, 24.2% underwent local tumor excision for surgical treatment of penile cancer.26 For stage T1 disease, the rates of local tumor excision increased from 29% to 40% within 10 years.26 Following a multivariable analyses, age younger than 65 years, African American descent, tumor size of less than 3 cm, and pathological stage disease of no higher than T1 were reported predictors for the use of local tumor excision as surgical treatment of the primary penile tumor as part of a penile-sparing approach.26 The authors concluded that penile-sparing surgery is underutilized in the general population, and significant age and racial/ethnic disparities exist in its use.26 Other studies have noted that the majority of paTable 2. — Overview of the Disparities in Treatment for Penile Cancer in Select Population-Based Studies Study Data Set Zhu Select Findings 25 SEER program Men < 50 y of age more likely to receive extensive LN dissection (≥ 8 LNs removed) during inguinal LN dissection for high-risk penile cancer Zhu26 SEER program More likely to receive penile-sparing approach for surgical treatment of primary tumor: Age < 65 y African American decent Tumor size < 3 cm Pathological stage ≤ T1 LN = lymph node, SEER = Surveillance, Epidemiology, and End Results. Cancer Control 411 tients identified with penile SCC in the SEER data set were treated with surgical therapy, and a small percentage of patients received radiotherapy alone or as adjuvant therapy.27,28 No statistically significant sociodemographic or racial/ethnic differences were reported with regard to radiotherapy for penile cancer due to small sample size.28 Zhu et al25 also assessed the impact of patient characteristics on the extent of inguinal LN dissection when it is clinically indicated for patients with high-risk penile SCC. Using SEER data, the authors identified 393 patients who underwent regional LN dissection for penile cancer; this study cohort was then stratified into 2 groups, limited LN dissection (< 8 LNs removed) and extensive LN dissection (≥ 8 LNs removed).25 The median number of dissected LNs in this series was 15, and 28% of patients underwent limited LN dissection.25 The prevalence of extensive LN dissection decreased in tandem with increasing age (81% in men aged < 50 years to 65% in men aged ≥ 70 years).25 On multivariable analysis, age alone was the independent predictor of extensive LN dissection (odds ratio 0.98; P = .01).25 Inadequate LN dissection with few LNs removed was observed in some patients with penile cancer, particularly among elderly men, even despite evidence that inguinal lymphadenectomy has a similar morbidity rate in this age group compared with men younger than 65 years of age.25,26 Table 3. — Overview of the Disparities in Survival Rates of Penile Cancer in Select Population-Based Studies Study Data Set Findings Hernandez8 SEER program Penile SCC mortality elevated in: African American men Hispanic men Elderly (age > 80 y) Southern US residents Low-income areas Less-educated populations Rippentrop27 SEER program African American race independent predictor of worse cancer-specific survival Sharma31 NCDB African American race independent predictor of worse OS Private insurance and higher median income independent predictors of better OS Thuret 32 SEER program Single marital status independent predictor of: Locally advanced primary tumor Higher-grade disease Increased overall mortality Tyson30 SEER program Tumors on penile shaft and overlapping lesions increased cancer-specific mortality vs preputial lesions Verhoeven3 SEER program 5-year cancer-specific survival of penile cancer in United States decreased from 1998 to 2011 NCDB = National Cancer Database, OS = overall survival, SEER = Surveillance, Epidemiology, and End Results. Survival Factors affecting health insurance coverage and access to early detection and treatment could influence the cancer-specific mortality rate of penile cancers. A summary of the literature analyzing disparities in penile cancer survival rates based on select, large population-based data sets is shown in Table 3.3,8,27,30-32 Rippentrop et al27 first described the racial and socioeconomic disparity in survival from penile carcinoma based on data from SEER. They reported that African American men presented at a younger age and with a higher stage of disease compared with other racial groups. The disease-specific risk of death for African American men was also nearly twice as high than for whites (P = .0023), and marriage was associated with improved disease-specific rates of survival in the localized (P = .0002) and regional stages (P = .001) of disease.27 Multivariable analysis demonstrated that a higher stage at diagnosis, age older than 65 years, African American race, and positive LNs were all significant independent predictors of cancer-specific survival from penile carcinoma.27 Thuret et al32 also used SEER data to evaluate the association between marital status, tumor stage and grade, overall mortality, and cancer-specific mortality in patients with penile SCC. Multivariable logistic regression models revealed that unmarried men 412 Cancer Control had a 1.5-fold higher risk of having locally advanced (pT3/T4, N+, M+) or higher grade (grade 3/4) disease at the time of surgery (P < .001) and a 1.3-fold higher risk of overall mortality (P = .001); however, marital status had no effect on cancer-specific mortality.32 Age, socioeconomic status (median family income above or below the poverty line within the patient’s county of residence), and race (white vs African American vs other) did not correlate with rates of locally advanced or higher-grade disease and cancer-specific mortality.32 However, the study was limited by its small sample size of African Americans (n = 183). In a multivariable competing-risk model, Thuret et al33 studied a population of patients with cN0T1 penile SCC after primary tumor excision and before initial LN dissection and found no statistically significant association between race and age (≥ 70 vs ≤ 69 years) for cancer-specific mortality after accounting for tumor grade. Tyson et al 30 also found no significant association between age and penile SCC-specific mortality rate after adjusting for tumor grade based on SEER data. Penile tumors on the body of the penis (HR 1.61) and overlapping lesions (HR 1.79; P = .01) had increased cancer-specific mortality compared with preputial lesions.30 Furthermore, the disease-specific 10-year survival rate of those with October 2016, Vol. 23, No. 4 preputial tumors was 89.4% compared with 78.7% for tumors at other locations combined (P < .0001).30 Hernandez et al8 analyzed more than 4,900 cases of histologically confirmed invasive penile SCC in the United States using SEER data, the Centers for Disease Control and Prevention’s National Program for Cancer Registries, and the National Center for Health Statistics. The authors found that the rate of mortality due to penile SCC increased with age (mortality rate at age < 50 years: 0.02 vs age > 80 years: 1.80).8 African American men were also diagnosed at a significantly younger age than white or Asian men (median age, 62 vs 68 vs 68 years, respectively) and had a lower incidence-tomortality ratio than white or Asian men (3.44 vs 5.18 vs 5.63, respectively; P < .01 for all).8 This was also true for Hispanic men compared with non-Hispanic men (median age, 58 vs 69 years; incidence-to-mortality ratio: 4.61 vs 5.25; P < .01).8 Rate of mortality due to penile SCC was also increased among those men living in southern states, in regions of lower socioeconomic status, and among those living in areas with lower levels of educated people.8 Sharma et al 31 used the National Cancer Database (NCDB) to study patients with a diagnosis of penile SCC from 1998 to 2011, and they found that African American and Hispanic men were diagnosed at a younger age (< 55 years: 38.3% vs 25.9% and 51.0% vs 24.5%; P < .01), and African Americans presented with a higher stage of disease (pT3/T4: 16.6% vs 13.2%; P = .027) and had worse median overall survival (OS) rates (68.6 vs 93.7 months; P < .01). The estimated median OS rate in the entire cohort was 91.9 months at a median follow-up period of 44.7 months, and survival did not change over the study period.31 Hispanic ethnicity was not associated with all-cause mortality in the penile cancer population.31 Location and education level also did not have a significant relationship with OS. Patients with private health insurance and a median income of at least $63,000 based on zip code presented with a lower stage of disease (pT3/T4: 11.6% vs 14.7%, P = .002; 12.0% vs 14.0%, P = .042) and had better median rates of OS (163.2 vs 70.8 months, P < .01; 105.3 vs 86.4 months, P = .001).31 Multivariable analysis revealed that African American race (HR 1.39; 95% confidence interval [CI]: 1.21–1.58; P < .01) was independently associated with worse OS, whereas private insurance (HR 0.79; 95% CI: 0.63–0.98; P = .028) and higher median income of at least $63,000 (HR 0.82; 95% CI: 0.72–0.93; P = .001) were independently associated with better OS.31 Colón-López et al10 compared the mortality rates of penile cancer in Puerto Rican men with other racial and ethnic groups in the United States and evaluated the influence of socioeconomics and educational level on the rates of mortality observed in Puerto Rico. From 2000 to 2004, Puerto Rican men had a statistiOctober 2016, Vol. 23, No. 4 cally significant higher mortality rate when compared with non-Hispanic white men (HR 3.32), non-Hispanic African American men (HR 2.51), and other US Hispanic men (HR 1.89).10 A higher rate of mortality related to penile cancer was also observed among Puerto Rican men in the lowest socioeconomic status (HR 1.61) when compared with Puerto Rican men in the highest socioeconomic status, although this difference was not statistically significant.10 An increasing trend in mortality due to penile cancer was observed among men in Puerto Rico due to a possible convergence of early and high levels of sexual activity, low circumcision rates, and high prevalence rates of sexually transmitted infections in Puerto Rico — particularly among the medically underserved. Paiva et al34 reported an increased cancer-specific mortality rate in patients younger than 40 years of age at a mean follow-up period of 22.4 months (19%) compared with patients aged between 40 and 60 years (11%) and those older than 60 years of age (13%; P < .05). Younger patients also had an increased likelihood of perineural invasion (26% vs 13%) and infiltrative growth pattern (70% vs 50%) on pathological review, and they had a higher risk of recurrence (45% vs 25%; P < .05 for all).34 Study findings from Sharma et al31 similarly showed an increased prevalence of node-positive disease in patients younger than 55 years of age compared with those older than 75 years (21.5% vs 13.1%; P < .01) but a decreased prevalence of pT3 to T4 disease (12.0% vs 15.4%; P = .007). Others have also shown younger men (< 50 years) were more likely to receive more extensive LN dissection (> 8 LNs removed) than older men (> 70 years; 81% vs 65%; P = .01) with better rates of cancer-specific survival (P = .006).25 These findings remained true even in the subgroup of study patients with node-positive penile cancer (P = .01).25 Older age was an independent predictor of OS in the populationbased study using the NCDB on multivariable analysis (P < .01), but its relationship with cancer-specific mortality is unknown.31 Large population-based data have also been used to demonstrate penile cancer survival trends over time. The NCDB study did not show a correlation between the year of diagnosis and OS during the period from 1998 to 2011.31 However, Verhoeven et al35 reported that the 5-year cancer-specific survival rate of patients with penile cancer in the United States has significantly decreased from 72% to 63% based on SEER data, and they also confirmed a significantly increasing relative risk of death with increasing age (relative increase risk of death = 1.15; P < .01). Other groups have also observed an increase in the incidence of regional-stage disease (pN+) over time in US men that also paralleled rising age.36 Furthermore, Arya et al37 reported on more than 9,500 men diagnosed with priCancer Control 413 mary penile cancer in England from 1979 to 2009 and noted that the mortality rates fell by 20% after 1994 (from 0.39 to 0.31 per 100,000 men). The 5-year survival rate they observed also increased from 61.4% to 70.2%, and the 5-year survival rate for men diagnosed between 2006 and 2010 was 77% for men younger than 60 years of age and 53% for men older than 80 years of age.37 The 8% difference in 5-year survival rate (66% vs 74%) between men living in the most affluent vs the most deprived areas during this time was not statistically significant.37 The authors propose that the 21% increase in incidence of penile cancer since the 1970s in England could be explained by changes in sexual habits, greater exposure to sexually transmitted infections, such as HPV infection, and the decreasing rates of childhood and neonatal circumcision.37 They also suggest that the improvement in survival may be due to advances in medical care, including diagnostic, staging, and surgical techniques.37 Conclusions Disparities exist in the incidence, treatment, and outcomes of penile carcinoma. Younger patients are often offered more penile-sparing approaches for primary tumors but more aggressive treatment such as lymphadenectomy for nodal disease. African American men, Hispanics, the uninsured, those who are less educated, and those with lower socioeconomic status appear to have lower rates of survival when compared with their insured, educated, white, non-Hispanic counterparts. Marital status, number of sexual partners, and human papillomavirus status also seem to play a role in prognosis. Although the treatment options and rates of survival from penile squamous cell carcinoma have improved during the past several decades, further understanding of the racial/ethnic, socioeconomic, and age-related differences seen in penile malignancies may help minimize future disparities in cancer care. References 1. American Cancer Society. Cancer Facts and Figures 2016. http:// www.cancer.org/acs/groups/content/@research/documents/document/ acspc-047079.pdf. 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Sichero L, Pierce Campbell CM, Fulp W, et al. High genital prevalence of cutaneous human papillomavirus DNA on male genital skin: the HPV Infection in Men Study. BMC Infect Dis. 2014;14:677. 24. Sharma P, Zargar-Shoshtari K, Spiess PE. Current surgical management of penile cancer. Curr Probl Cancer. 2015;39(3):147-157. 25. Zhu Y, Gu CY, Ye DW. Population-based assessment of the number of lymph nodes removed in the treatment of penile squamous cell carcinoma. Urol Int. 2014;92(2):186-193. 26. Zhu Y, Gu WJ, Wang HK, et al. Surgical treatment of primary disease for penile squamous cell carcinoma: a Surveillance, Epidemiology, and End Results database analysis. Oncol Lett. 2015;10(1):85-92. 27. Rippentrop JM, Joslyn SA, Konety BR. Squamous cell carcinoma of the penis: evaluation of data from the surveillance, epidemiology, and end results program. Cancer. 2004;101(6):1357-1363. 28. Burt LM, Shrieve DC, Tward JD. Stage presentation, care patterns, and treatment outcomes for squamous cell carcinoma of the penis. Int J Radiat Oncol Biol Phys. 2014;88(1):94-100. 29. Gopman JM, Djajadiningrat RS, Baumgarten AS, et al. Predicting postoperative complications of inguinal lymph node dissection for penile cancer in an international multicentre cohort. BJU Int. 2015;116(2):196-201. 30. Tyson MD, Etzioni DA, Wisenbaugh ES, et al. Anatomic site-specific disparities in survival outcomes for penile squamous cell carcinoma. Urology. 2012;79(4):804-808. 31. Sharma P, Ashouri K, Zargar-Shoshtari K, et al. Racial and economic disparities in the treatment of penile squamous cell carcinoma: results from the National Cancer Database. Urol Onc. 2016;34(3):122. 32. Thuret R, Sun M, Budaus L, et al. A population-based analysis of the effect of marital status on overall and cancer-specific mortality in patients with squamous cell carcinoma of the penis. Cancer Causes Control. 2013;24(1):71-79. 33. Thuret R, Sun M, Abdollah F, et al. Competing-risks analysis in patients with T1 squamous cell carcinoma of the penis. BJU Int. 2013;111(4 pt B):E174-E179. 34. Paiva GR, de Oliveira Araújo IB, Athanazio DA, et al. Penile cancer: impact of age at diagnosis on morphology and prognosis. Int Urol Nephrol. 2015;47(2):295-299. 35. Verhoeven RH, Janssen-Heijnen ML, Saum KU, et al. Populationbased survival of penile cancer patients in Europe and the United States of America: no improvement since 1990. Eur J Cancer. 2013;49(6):1414-1421. 36. Barnholtz-Sloan JS, Maldonado JL, Pow-Sang J, et al. Incidence trends in primary malignant penile cancer. Urol Oncol. 2007;25(5):361-367. 37. Arya M, Li R, Pegler K, et al. Long-term trends in incidence, survival and mortality of primary penile cancer in England. Cancer Causes Control. 2013;24(12):2169-2176. October 2016, Vol. 23, No. 4 The underlying biology of carcinogenesis should be addressed in African American men at high risk for prostate cancer. Rose. X-Ray image courtesy of Bryan Whitney. www.x-rayphotography.com. Chemoprevention in African American Men With Prostate Cancer Nagi B. Kumar, PhD, RD, Julio M. Pow-Sang, MD, Philippe E. Spiess, MD, Jong Y. Park, PhD, Ganna Chornokur, PhD, Andrew R. Leone, MD, and Catherine M. Phelan, PhD, MD Background: Recommendations for cancer screening are uncertain for the early detection or prevention of prostate cancer in African American men. Thus, chemoprevention strategies are needed to specifically target African American men. Methods: The evidence was examined on the biological etiology of disparities in African Americans related to prostate cancer. Possible chemopreventive agents and biomarkers critical to prostate cancer in African American men were also studied. Results: High-grade prostatic intraepithelial neoplasia may be more prevalent in African American men, even after controlling for age, prostate-specific antigen (PSA) level, abnormal results on digital rectal examination, and prostate volume. Prostate cancer in African American men can lead to the overexpression of signaling receptors that may mediate increased proliferation, angiogenesis, and decreased apoptosis. Use of chemopreventive agents may be useful for select populations of men. Conclusions: Green tea catechins are able to target multiple pathways to address the underlying biology of prostate carcinogenesis in African American men, so they may be ideal as a chemoprevention agent in these men diagnosed with high-grade prostatic intraepithelial neoplasia. From the Cancer Epidemiology (NBK, JYP, GC, CMP) and Genitourinary Oncology Programs (NBK, JMP-S, PES), H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, and the Departments of Oncologic Sciences (NBK, PES, JYP, GC, CMP), Urology (PES, ARL), Molecular Medicine (JYP), Cell, Molecular and Microbiology (JYP), and Epidemiology and Biostatistics (JYP), University of South Florida, Tampa, Florida. Submitted March 1, 2016; accepted July 6, 2016. Address correspondence to Nagi B. Kumar, PhD, RD, Department of Epidemiology, Moffitt Cancer Center, 12902 Magnolia Drive, MRC-CAN CONT, Tampa, FL 33612. E-mail: [email protected] No significant relationships exist between the authors and the companies/organizations whose products or services may be referenced in this article. The development of this manuscript was supported in part by the National Cancer Institute (grants nos. 1R21CA179659 and R01CA128813). The work was made possible by research funding awarded by the National Institute of Health and the National Cancer Institute (grant no. R01 CA12060-01A1). October 2016, Vol. 23, No. 4 Introduction Despite treatment advances in recent years, prostate cancer remains the leading cause of cancer-related death among men in the United States.1 In 2016, the American Cancer Society estimates that 180,890 new cases of prostate cancer will be diagnosed in the United States, and 26,120 men will die from the disease.1 Racial and geographical differences have been observed, including a 40-fold difference in incidence rates between low-risk (Chinese men) and high-risk populations (African American men).2 In the United States, age-standardized incidence rates for prostate cancer are 272 per 100,000 men for African Americans compared with 164 per 100,000 men for whites.2 Compared with white men, African American men with Cancer Control 415 prostate cancer have more aggressive disease, higher rates of incidence, are diagnosed at a younger age, present with more advanced disease at diagnosis, and have a worse prognosis.3 The mortality rate for African American men with prostate cancer is 3 times higher than white men, although the rate decreased in both groups between 1990 and 2000.2 With disparate rates of prostate cancer as well as aggressive prostate cancer observed in African American men, the logical approach is to focus efforts on prostate cancer screening for early detection and prevention.4,5 However, uncertainties still exist about the overall value of early detection. Although periodic testing for serum concentrations of prostate-specific antigen (PSA) may reduce the mortality of prostate cancer, PSA testing has been linked to increased diagnoses and overtreatment of clinically insignificant, potentially indolent tumors that pose little risk of metastasis or death.5,6 Taking the accumulated evidence into consideration, the US Preventive Services Task Force recommended against PSA-based prostate cancer screening in asymptomatic men.7 However, these recommendations note that, in African American men, firm conclusions cannot be made to balance the risks and benefits of such screening because data do not exist to support a more favorable risk–benefit ratio.7 Two cancer screening trials included a majority of men with European ancestry, thus largely precluding conclusions specifically pertaining to men of African descent.6,8 Hence, no specific evidence-based recommendation regarding prostate cancer screening exists for the high risk population of African American men, underscoring the need for chemoprevention strategies targeting African American men.2,3 Biological Etiology of Disparity The etiology of increased susceptibility of African American men to prostate cancer has not been elucidated, but it is likely multifactorial involving genetic, biological, sociocultural, and lifestyle determinants. The initiation and progression of prostate cancer involves a complex series of events. During progression, genetic changes and loss of cellular control are observed as cell phenotypes change from normal to dysplasia (prostatic intraepithelial neoplasia), severe dysplasia (high-grade prostatic intraepithelial neoplasia [HGPIN]), clinically localized disease, and to metastatic disease.9-12 Observations point to the role of genetic susceptibility factors in human prostate cancer.9-15 Other than older age, African ancestry and family history of prostate cancer are well-established, nonmodifiable risk factors for prostate cancer.9-13 The lifetime risk of prostate cancer increases 1.5- to 4-fold in men with 1 or 2 first-degree relatives with prostate cancer.14 A Scandinavian study of twins estimated that 42% of the observed rate of prostate cancer susceptibility was associ416 Cancer Control ated with inherited genetic risk factors.15 Genetic risk factors are also significant at a younger age, and the attributed risk of inherited susceptibility is thought to be as high as 40% among men diagnosed with prostate cancer at 55 years or younger.13 Although genome-wide association studies (GWASs) and large genetic variation studies have identified more than 100 prostate cancer risk loci, elucidating the biological basis for these associations is challenging.16-18 Identified risk loci include the noncoding variants, such as those located in the 8q24 region, as well as polymorphisms in the gene-coding regions that either alter, or are predicted to alter, protein expression (eg, HNF1B, TERT, RNASEL, KLK3).16,19-22 HNF1B single-nucleotide polymorphisms (rs7501939 and rs4430796) have been identified in GWASs of prostate cancer and are associated with a risk of prostate cancer in African American men.23-25 In addition, the CTBP2 single-nucleotide polymorphism rs4962416 is associated with risk of prostate cancer in white men.23-25 HNF1B encodes a transcription factor protein that forms heterodimers with other members of the HNF1 family and can influence the gene transcription. While it was previously believed that HNF1B expression is specific to the liver, its transcripts have been identified in various tissues, including bone marrow, and the pancreas, urinary tract, gastrointestinal organs, and prostate.26 Mutations in HNF1B cause type 5 maturity-onset diabetes that may be accompanied by urinary tract disorders.27,28 Some men with HNF1B mutations have malformations in the reproductive tract, including epididymal cysts, agenesis of the vas deferens, or infertility due to abnormal spermatozoa.29 Post-GWASs are suggestive of the interaction between genetic variants and environmental risk factors, but our understanding of this is still inadequate.30,31 Rs7501939 at HNF1B has been shown to increase the risk of prostate cancer in African American men who are obese but not in African American men who are not obese or European American men of any body weight.23 Although these are preliminary findings, they suggest that weight-loss interventions may decrease the risk of prostate cancer in African American men who are carriers of the high-risk allele at rs7501939 of HNF1B. Future studies should further examine this observation. CTBP2 encodes a transcriptional co-repressor activated under stress and can mediate the stress-induced migration of tumor cells.32 CTBP2 expression is detected in the prostate and has been linked to decreased PTEN expression and activation of the phosphatidylinositol 3-kinase pathway, which may support or promote the growth of prostate cancer.33 Lindquist et al34 reported a higher prevalence rate of mutations in MUC3A and PRIM2 in African American men with prostate cancer when compared with October 2016, Vol. 23, No. 4 their white counterparts. MUC3 is involved in cell signaling, growth, and survival; MUC3 and PRIM2 are also associated with carcinogenesis.35 The different patterns of somatic mutations observed between racial groups may help provide a basis for understanding the genomic contributions to aggressive tumors and associated disparate outcomes in African American men with prostate cancer. Evidence is also emerging for racial differences in markers of prostate tumor subtypes. For example, gene fusions in TMPRSS2 and ERG are found in prostate tumors.35-43 However, several studies report that the prevalence of TMPRSS2–ERG fusions in the tumors of African American men is lower than that observed in white men.35-43 Thus, future studies must continue to pursue this research because such racial differences in marker expression could reveal mechanisms contributing to race disparities. Differences exist in tumor biology between African American men and white men and may be attributable to race-specific differences in tumor location (ie, anterior vs posterior tumors). African Americans have an increased incidence of prostate cancer (located anterior to the peripheral zone in radical prostatectomy specimens that may potentially have a prognostic significance.44 In a study of 1,245 patients who underwent radical prostatectomy, the overall tumor locations were anterior in 14%, posterior in 58%, or both in 28% of cases.44 The incidence of anterior tumors was higher in African American men compared with white men, and the rates of positive surgical margins in anteriorly and posteriorly located tumors were 60% vs 38% in African American men and 48% vs 27% in white men, respectively.44 In patients with an abnormal level of serum PSA and negative findings on sextant prostate biopsies, biopsy is recommended for the anterior zone of the prostate.45 In a study of 398 men, of whom 70% were African American men, most patients had prostate cancer limited to the peripheral zone or in both the peripheral and anterior to the peripheral zone.46 For 4% of study patients, prostate cancer was limited to the anterior to the peripheral zone — 5% of African Americans vs 2% of those not of African American descent — but this result was not statistically significant.46 Another study showed a biologically important relationship between tumor location and molecular subtype, but racial differences in molecular subtypes did not persist when tumors were analyzed by location.47 The study investigated triple-negative disease and AR signaling. African American men were more likely to be positive for m-SPINK1+ and have triple-negative disease than white men.47 Based on this evidence, the racial differences in location of the prostate cancer do not appear to be significant, nor are they likely to impact the progOctober 2016, Vol. 23, No. 4 nosis and management of prostate cancer in African American men. HGPIN is considered by many to be a premalignant lesion of prostate cancer.48-50 Data from some studies suggest that the prevalence of HGPIN is greater in African American men and that subgroups of African American men with HGPIN are more prone to the development of aggressive, clinically significant cancer.51,52 HGPIN may also be a risk factor for biochemical recurrence following definitive treatment in African American men.51,52 HGPIN is more prevalent in African American men, even after controlling for age, PSA level, abnormal findings on digital rectal examination, and prostate volume.51 Significantly higher prevalence rates of HGPIN have been reported in African American men aged 40 to 49 years compared with white men (46% vs 29%, respectively), suggesting that this early-onset age range may represent the beginning of a racial disparity related to prostate cancer; this is because more African American men with HGPIN go on to develop prostate cancer.52 In concordance with these data, Potts et al53 reported that African American men were more likely to be diagnosed with prostatic intraepithelial neoplasia compared with white men, even after adjusting for PSA levels. In a study to investigate racial differences in tumor burden (cancer volume, cancer percentage, and tumor volume–PSA ratio) in a large cohort of men undergoing radical prostatectomy, African Americans had higher disease burden (estimated tumor volume, percent of cancer involvement, estimated tumor volume–PSA ratio) compared with non–African American men.54 This association was pronounced in low-grade cancer (Gleason score ≤ 6), thus depicting a complex picture of relations between race and tumor burden across the aggressive spectrum of prostate cancer.54 The frequency of HGPIN and the autopsy prevalence of prostate cancer have been reported to be similar in large studies comparing Asian and Western populations, with widely differing incidence and mortality rates, suggesting an environmental influence on the expression of this disease and the possibility of preventing disease progression from HGPIN to prostate cancer through pharmacological means.12,48-50,55,56 Targeting precursor lesions (HGPIN) that may display simpler genomic aberrations relative to early stages of cancer in these high-risk groups may offer more promise to develop and test targeted interventions based on the biological differences reported in prostate carcinogenesis among African American men. Based on this evidence, African American men with biopsy-proven HGPIN are a subset of men who can be considered to be at high risk for prostate cancer and, thus, may be ideal candidates for chemoprevention interventions. Although PSA and its kinetics are used to monitor disease progression, controversy exists regarding the Cancer Control 417 efficacy of PSA level as a screening tool due to its low rate of specificity; in addition, PSA levels are increased in benign prostatic diseases, such as benign prostatic hyperplasia (PSA concentrations can be ≤ 50% higher in some cases).57 African American men continue to have higher PSA levels and Gleason scores than white men, despite a narrowing of the differences in pathological stage.58 One study reported that African American men with prostate cancer and a Gleason score of 6 produce less PSA than white men.59 African American and white men had equal serum PSA and PSA masses despite significantly larger prostates in African American men and all other parameters being the same.60 Another report showed that men with higher levels of testosterone had higher levels of PSA even after taking into account other hormones, age, and race/ethnicity.61 While transcription of the PSA gene is transactivated by the androgen receptor (AR) with bound androgen, it is unclear whether circulating androgens influence circulating PSA levels. Men treated for prostate cancer with androgen-deprivation therapy experience a decline in serum PSA concentration, but this decline may be due to fewer cancer cells remaining to produce PSA and reduced testosterone available to all PSA-producing cells.41 Despite these drawbacks related to specificity, serum PSA as a continuous variable — as well as its doubling time and velocity — has been used in prostate cancer chemoprevention trials and in clinical practice to define risk categories.59,62-67 Other biological differences in benign tissue and prostate tumors have been elucidated in African American and white men alike. Prostate tumors derived from African American men overexpress signaling receptors that may mediate increased proliferation, including EGFR and AR.68,69 On average, AR has a shorter polyglutamine repeat in African American men and, thus, increased AR activity.11 Reports have indicated decreased apoptosis and increased immunostaining for antiapoptotic protein B-cell lymphoma 2 (BCL2), suggesting that increased expression of BCL2 may decrease apoptosis and increase rates of tumor proliferation in African American men.70,71 Metastatic capacity may be higher in prostate tumor cells in African Americans because of the overexpression of several metastasis-related genes (AMFR, CXCR4, CCR7, and MMP9) as well as KI67 and CAV1 in African American men.72-74 Prostate tumors obtained from African American men may have decreased rates of tumor suppression. Decreased TCEAL7 expression has been observed in tumors from African American men compared with tumors from white men.75 Reams et al75 observed that TCEAL7 expression in prostate cancer and in nonmalignant tissue was higher in white men compared with African American men. Chien et al76 demonstrated that TCEAL7 also inhibits the growth of ovarian can418 Cancer Control cer cells, suggesting that TCEAL7 is a tumor-suppressor gene and that varying expression levels of TCEAL7 between white and African American men may explain some of the disparities in the growth patterns observed in prostate cancer–derived tumors cells in these populations. Population studies comparing Japanese and African Americans have observed that short CAG repeats are more frequently associated with higher transactivational function in African Americans, possibly explaining racial differences in the incidence rate of prostate cancer between the 2 populations.11 Taken together, these data suggest that there may be functional biological differences in the prostate tumors of African American men that may predispose them to a biologically more aggressive malignancy. However, these observations have not been validated in clinical trials targeting African American men. Current Approach Chemoprevention refers to the inhibition of preinvasive and invasive cancer and its progression or treatments of identifiable precancers.49,77 Chemoprevention efforts require an understanding of the mechanism of carcinogenesis, including signaling, metabolic, and genetic progression pathways. New technologies in genomics and proteomics have spurred this field of research. Use of this knowledge to develop pharmacological agents, botanicals, and biologics to reverse or halt the process of carcinogenesis is called chemoprevention. Agents for chemoprevention include antipromotion and antiprogression agents that prevent the growth and survival of cells already committed to become malignant.49,77 Finasteride and dutasteride, which block the conversion of testosterone to dihydrotestosterone, have been evaluated for chemoprevention of prostate cancer in large phase 3 chemoprevention trials.78-80 Although these agents significantly reduced the risk of prostate cancer, their use was also associated with an increased rate of high-grade disease, severely limiting their clinical adoption and underscoring the need to identify novel chemoprevention agents for prostate cancer.79 Botanicals influence multiple biochemical and molecular cascades that inhibit mutagenesis, proliferation, induce apoptosis, and suppress the formation and growth of human cancers, thus modulating several hallmarks of carcinogenesis. In addition, these agents appear promising in their potential to impact the field of cancer chemoprevention, because they have a significantly superior safety profile than most available agents.81-88 Several botanicals have been characterized and used for hundreds of years, although existing challenges and limitations have hampered progress in this field.89,90 Multiple botanicals have been identified and appear promising for the chemoprevention of prostate October 2016, Vol. 23, No. 4 cancer.91-93 However, the slow pace of growth might be attributed to the regulatory protection of classical formulations and lack of standardization, quality control, a molecular mechanism-based approach in evaluation, a population-based normal range of biomarkers, laboratory practices, and few translational scientists engaged in conducting well-designed trials. However, several valuable lessons have been learned from previous chemoprevention trials.91,94,95 Critical requirements for moving botanicals from bench to bedside include adopting a systematic, molecular-mechanism based approach and utilizing the same ethical and rigorous methods such as those used to evaluate other pharmacological agents. Chemoprevention trials using combinations of botanicals have demonstrated that synergy between agents can lead to lower doses, improved rates of efficacy, and fewer or less-severe toxicities.96 An assessment of the end points of chemoprevention trials whose results have been used to support approval of an agent for prostate cancer revealed that nearly all have been approved on the basis of intraepithelial neoplasia.97 Intermediate biomarker end points must be identified, validated, and obtained using noninvasive techniques without compromising the safety to men in chemoprevention trials. To reduce patient burden, these markers must be obtained from accessible organs and during the normal course of clinical surveillance. Randomized placebo control trials and the longterm follow-up and monitoring of patients and study participants are critical to meet the requirements of the US Food and Drug Association and to promote the acceptance of new agents into the marketplace.92,93 Green Tea Catechins The Table summarizes the clinical, molecular, and biological characteristics relevant to prostate cancer in African American men and compares them with the effects of green tea catechins used to modulate those characteristics.11,51,52,58,59,68-75,98-116 Laboratory studies have identified epigallocatechin gallate (EGCG) as a potent chemopreventive agent because it affects various key molecular processes in prostate carcinogenesis that help induce apoptosis and inhibit tumor growth and angiogenesis.117-121 Preclinical studies have demonstrated chemopreventive efficacy in prostate cancer, showing that it has significant activity on prostate cancer cells.99,122-129 Phase 1/2 studies have demonstrated the bioavailability and tolerance of green tea catechin at various ranges of doses of EGCG.64,93,98,100,130-136 Although several mechanisms exist by which EGCG may operate in prostate carcinogenesis, EGCG selectively inhibits the proteasome activity in intact human prostate cancer cells and accumulates in IκBα and p27 proteins, thus leading to growth arrest.119-121 High-grade green tea polyphenol extract, which is a mixture of tea catechins with more than 50% of EGCG, inhibits the proteasomal chymotrypsin-like activity with a half maximal inhibitory concentration value of 7 μM.93 The half maximal inhibitory concentration value for trypsin-like activity is higher than 100 μM, Table. — Summary of Relevant Characteristics of Prostate Cancer and the Effects of Green Tea Catechins in African Americans Characteristic of Prostate Cancer Effect of Green Tea Catechins Clinical Increased frequency of HGPIN51,52 Men with HGPIN had significantly reduced disease progression98,101 Higher PSA levels Men with HGPIN had lower PSA levels than the control arm98,101 58 Higher Gleason scores at diagnosis59 Men given short-term daily doses had significant decreases in serum PSA levels100 Molecular Increased Proliferation Decreased Proliferation EGFR overexpression68 In vitro models102-104 In vivo models99,105-107 AR overexpression69 Inhibition of EGFR signaling108 Increased androgen-receptor activity11 Reduced androgen-receptor signaling and activity 99,109-111 Decreased Apoptosis Induced Apoptosis Induction Increased expression of BCL2 70,71 Various mechanisms (eg, reduced BCL2 expression)112-114 Increased Metastatic Capacity Inhibition of Invasion and Metastasis Overexpression of AMFR, CXCR4, CCR7, MMP9, KI67, and CAV1 72-74 Various mechanisms (eg, MMP9, MMP2 suppression)115 Decreased Tumor Suppression Reactivation of Silenced Tumor-Suppressor Genes Downregulation of TCEAL7 75 Restores balanced proliferation116 HGPIN = high-grade prostatic intraepithelial neoplasia, PSA = prostate-specific antigen. October 2016, Vol. 23, No. 4 Cancer Control 419 demonstrating that high-grade green tea polyphenol extract preferentially inhibits the proteasomal chymotrypsin-like activities over other activities.93 Kim et al126 investigated the safety and efficacy of high-grade green tea polyphenol extract in an animal model. Their goal was to reduce the progression of prostate adenocarcinoma in transgenic mice. Mice treated with the green tea extract had significantly fewer tumors and decreased tumoral sizes compared with the animals that did not receive the extract. The high-grade green tea polyphenol extract also significantly inhibited metastasis in the treated mice in a dose-dependent manner. Therefore, the data suggest that high-grade green tea polyphenol extract is an effective chemopreventive agent in preventing the progression of prostate cancer to metastasis in a mouse model.126 These findings provide evidence for the safety and chemopreventive effect of this green tea polyphenol extract for preventing metastatic spread in prostate cancer. Based on the results of previous studies, a placebocontrolled, randomized clinical trial was conducted of the high-grade green tea extract in 97 men with HGPIN, atypical small acinar proliferation, or both conditions.64,92,119-121 No differences were observed in the number of prostate cancer cases. The cumulative rate of prostate cancer plus atypical small acinar proliferation among men with HGPIN but without atypical small acinar proliferation at the start of the study was researched. The data revealed a statistically significant decrease in this composite end point: 3 of 26 (high-grade green tea polyphenol extract gorup) vs 10 of 25 (placebo group).126 A decrease in diagnoses of atypical small acinar proliferation was also seen among those receiving the green tea extract, as was a decrease in serum PSA level, compared with those assigned to placebo.126 Intake of a standardized, decaffeinated green tea catechin mixture every day for 1 year accumulated in plasma and was well tolerated, and researchers saw that its consumption significantly reduced the cumulative rates of prostate cancer and atypical small acinar proliferation among men with HGPIN who did not have atypical small acinar proliferation at baseline.137 Three of the 9 African American men in the study progressed to atypical small acinar proliferation or prostate cancer after 1 year, but no such progression was seen among those assigned to the high-grade green tea polyphenol extract arm.137 This disease progression rate from HGPIN in the placebo arm was higher than US norms and in white men assigned to the placebo arm of this trial (20%).62,64,65,137,138 In men with a baseline diagnosis of atypical small acinar proliferation, the diagnostic rates of cancer at 1 year were similar, regardless of treatment arm assignment or race.137 Overall, a significant increase in plasma EGCG concentration was observed, as was a reduction of serum PSA 420 Cancer Control and disease progression from HGPIN to atypical small acinar proliferation or prostate cancer with green tea catechin treatment. Although these are early observations with small sample sizes, these data are provocative and warrant further evaluation in a well-powered clinical trial targeting African American men with HGPIN, because they suggest that green tea catechins have the potential to decrease the risk of progression to atypical small acinar proliferation and, subsequently, prostate cancer.137 However, the study was limited by its small sample size of African American men, so the researchers were unable to make comparisons among white men with HGPIN in other blood and tissue-based biomarkers. Experimental models to address the fundamental molecular pathways of green tea catechin have yet to be validated in green tea catechin–treated tissue samples from clinical trials.118 In addition to developing and refining the fundamental pathways of green tea catechin, future studies evaluating these molecular pathways should define intermediate biomarkers of prostate carcinogenesis. However, obtaining sufficient tissue from prostate biopsies from precursor lesions in prevention trials continues to present a challenge. Therefore, it will be important to prioritize intermediate biomarkers available for evaluation based on the robustness of evidence and relevance to the agent, the potential molecular mechanism, and the patient cohort and stage of disease targeted in future studies.92,93 Green tea catechins target every major clinical prostate cancer characteristic reported in African American men (see Table).11,51,52,58,59,68-75,98-116 They may do this by acting through the biological mechanisms especially relevant to African American men, including reducing proliferation, inducing apoptosis, and decreasing tumoral metastatic capacity. Thus, it is our opinion that green tea catechins are a promising candidate for the chemoprevention of prostate cancer in African American men. Conclusions Prostate cancer in African American men is a major public health problem with significant morbidity and mortality rates. A variety of laboratory approaches are being applied to unravel the molecular pathogenesis of prostate cancer. African American men with a family history of prostate cancer, diagnosed with high-grade prostatic intraepithelial neoplasia prior to age 50 years, represent an ideal target population for chemoprevention. Green tea catechins have been characterized and evaluated as agents able to target multiple pathways that address the underlying biology of prostate carcinogenesis in African American men. Assessing the efficacy of this intervention might eventually translate into clinical use in high-risk populations. It is our opinion that the greatest challenge to evaluating promOctober 2016, Vol. 23, No. 4 ising agents for chemoprevention is the recruitment and retention of African American men in randomized clinical trials, which will require multiple approaches, actions, and activities for achieving meaningful advances. The process is a complex and progressive one, including the formation of trusting partnerships with target populations and their circles of influence, power sharing, priority setting, capacity building, education and training, the transparent sharing of data and information, the development of goals, and insisting on community involvement in the research. References 1. American Cancer Society. Cancer Facts and Figures 2016. Atlanta, GA: 2016. http://www.cancer.org/acs/groups/content/@research/documents/ document/acspc-047079.pdf. Accessed October 12, 2016. 2. Centers for Disease Control and Prevention. Prostate cancer rates by race and ethnicity. Updated June 16, 2016. http://www.cdc.gov/cancer/ prostate/statistics/race.htm. Accessed October 12, 2016. 3. Makridakis NM, Reichardt JK. Molecular epidemiology of hormonemetabolic loci in prostate cancer. Epidemiol Rev. 2001;23(1):24-29. 4. Chornokur G, Dalton K, Borysova ME, et al. Disparities at presentation, diagnosis, treatment, and survival in African American men, affected by prostate cancer. Prostate. 2011;71(9):985-997. 5. Powell IJ. Epidemiology and pathophysiology of prostate cancer in African-American men. J Urol. 2007;177(2):444-449. 6. Ilic D, O’Connor D, Green S, et al. Screening for prostate cancer: an updated Cochrane systematic review. BJU Int. 2011;107(6):882-891. 7. Moyer VA; US Preventive Services Task Force. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2012;157(2):120-134. 8. Andriole GL, Crawford ED, Grubb RL, 3rd, et al. Mortality results from a randomized prostate-cancer screening trial. 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Presented at: 7th Annual American Association of Cancer Research Science of Cancer Health Disparities in Racial/ Ethnic Minorities and the Medically Underserved; November 9, 2015; San Antonio, TX. 138. Eskew LA, Bare RL, McCullough DL. Systematic 5 region prostate biopsy is superior to sextant method for diagnosing carcinoma of the prostate. J Urol. 1997;157(1):199-202. Cancer Control 423 Challenges remain in the field of cancer care for young adults and adolescents. Yellow Tulips. X-Ray image courtesy of Bryan Whitney. www.x-rayphotography.com. Disparities in Adolescents and Young Adults With Cancer Leidy L. Isenalumhe, MD, Olivia Fridgen, MPH, Lynda K. Beaupin, MD, Gwendolyn P. Quinn, PhD, and Damon R. Reed, MD Background: Cancer care for adolescents and young adults (AYAs) focuses on the care of patients aged 15 to 39 years. Historically, this group has favorable outcomes based on a preponderance of diagnoses such as thyroid cancers and Hodgkin lymphoma. Improvements in outcomes among the AYA population have lagged behind compared with younger and older populations. Methods: We discuss and review recent progress in AYA patient care and highlight remaining disparities that exist, including financial disadvantages, need for fertility care, limited clinical trial availability, and other areas of evolving AYA-focused research. Results: Survival rates have not improved for this age group as they have for children and older adults. Disparities are present in the AYA population and have contributed to this lack of progress. Conclusions: Recognizing disparities in the care of AYAs with cancer has led many medical specialty disciplines to improve the lives of these patients through advocacy, education, and resource development. Research addressing barriers to clinical trial enrollment in this population, quality-of-life issues, and the improvement of survivorship care is also under way. Introduction In 2008, an article published in Cancer Control about adolescents and young adults (AYAs) addressed this emerging, complicated, and multifaceted field.1 The authors concluded that more data were needed on treatment and survivorship in this patient populaFrom the Adolescent and Young Adult Oncology (LLI, OF, GPQ, DRR) and Health Outcomes and Behavior Programs (GPQ, DRR), Sarcoma Department (DRR), H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, Department of Pediatric Oncology (LKB), Roswell Park Cancer Institute, Buffalo, New York, and Morsani College of Medicine (GPQ), University of South Florida, Tampa, Florida. Submitted February 9, 2016; accepted June 2, 2016. Address correspondence to Damon R. Reed, MD, Sarcoma Department, Moffitt Cancer Center, 12902 Magnolia Drive, FOB-1, Tampa, FL 33612. E-mail: [email protected] No significant relationships exist between the authors and the companies/organizations whose products or services may be referenced in this article. 424 Cancer Control tion to improve outcomes and opined that major academic centers should develop the framework for a specialized oncology discipline focusing on AYAs.1 Indeed, published research on AYAs has addressed aspects of their care but has not yet successfully improved upon the entirety of oncology specific to AYAs. Programs devoted to AYAs have developed and specialized their focus to address fertility or psychosocial aspects of care, but no single model has yet to be universally adopted or standardized as the gold standard for the care of AYAs with cancer. Difficulties exist when discussing or acknowledging aspects of AYA care, such as reproductive health and sexuality, which was the theme of the annual conference of the Critical Mass Young Adult Alliance in 2015.2 These topics were presented and discussed within the context of multidisciplinary teams. Disparities are defined by the National Cancer October 2016, Vol. 23, No. 4 Institute as adverse differences in incidence, outcome, or burden of cancer existing among a population group.3 Although chronological age demarcates oncology in AYAs, it is this emerging developmental period of adulthood that brings in other aspects of disparities. In the context of oncology, AYAs are defined as individuals diagnosed with cancer between 15 and 39 years of age.4 Cancer is the primary cause of disease-related death in this population.5 In 2011, an estimated 69,212 AYAs were diagnosed with cancer, equating to 6 times more than children younger than 14 years of age.6 According to a cancer statistics review of Surveillance, Epidemiology, and End Results program data from 1975 to 1997, improvement in 5-year survival rates, as reflected in the average annual percent change in US cancer mortality rates, was significantly lower among individuals 15 to 39 years of age compared with those aged 1 to 14 years.4 AYAs have inferior outcomes compared with children and older adults with the same diagnosis.7-11 Among younger AYAs aged 15 to 24 years, leukemia, lymphoma, central nervous system tumors, sarcomas, and germ cell tumors are the most common malignancies.6 In AYAs 25 to 39 years of age, leukemia and lymphoma are still common, but the incidence rates of breast cancer, melanoma, and colorectal cancer (CRC) are increased (Fig).6 AYAs may experience economic disparities as they enter the workforce, often in jobs without benefits.4 In addition, disparities in health education may exist, because AYAs are inexperienced in navigating the health system or inquiring about clinical trials.4 They also may experience delays in diagnosis, because malignancies are low on the differential diagnosis for ill patients who are young.12 Presentation, Diagnosis, and Access to Health Care Number of Observed Cases Number of Observed Cases Health Insurance and Financial Hardship Cancer diagnosis is typically delayed in AYAs compared with children. The cause is multifactorial and relates to low suspicion of a malignant diagnosis by both patient and caretaker, but also is related to inadequate insurance coverage.4 In the United States, those between the ages of 18 and 24 years and between 25 and 34 years are more likely than any other age group to be uninsured.13,14 Lack of health insurance in AYAs is associated with delays in diagnosis, an increased likelihood of metastatic disease at presentation, and a decreased likelihood of receiving definitive therapy compared with those who are insured.15-18 In a study of more than 39,000 participants aged 20 to 40 years, health insurance coverage was associated with a decreased likelihood of metastatic disease at presentation; those who were uninsured were more likely to be male, nonwhite, and unmarried.15 After adjusting for various factors, health insurance coverage was also significantly associated with lower estimates of all-cause mortality.15 In a study looking at the association between health insurance coverage, socioeconomic status, and the risk of advanced Hodgkin lymphoma in AYAs, pub40,000 12,000 lic insurance coverage for 35,000 10,000 low-income or individuals 30,000 with medical need was as8,000 25,000 sociated with an increased risk of advanced disease 20,000 6,000 on presentation compared 15,000 4,000 with patients with private 10,000 insurance.16 2,000 5,000 Financial hardships are not uncommon in 0 0 Age Age Age Age Age patients with cancer but 15–19 y 20–24 y 25–29 y 30–34 y 35–39 y they may be more burBreast Thyroid Leukemia and lymphoma Germ cell densome among AYAs.19 Melanoma of the skin Leukemia and lymphoma Thyroid CNS Some AYAs may have inColon and rectum CNS Melanoma of the skin Malignant bone tumors Cervix and uterus Soft tissue and Kaposi sarcoma troductory level jobs with Other Soft tissue and Kaposi sarcoma Germ cell Other limited time off and without the ability to take exIncludes testicular cancer. tended leave, have limited Includes breast, cervical, colon, and other less-prevalent cancers. savings, and may have Includes malignant bone tumors and other less-prevalent cancers. college debt.19 Fig. — Common types of cancer affecting adolescents and young adults. CNS = central nervous system. Two-thirds of patients Reproduced with permission from the National Cancer Institute; Surveillance, Epidemiology, and End Results. aged 21 to 40 years reportA snapshot of adolescent and young adult cancer. https://www.cancer.gov/research/progress/snapshots /adolescent-young-adult. Accessed October 5, 2016. ed that their cancer exa b a c a b c October 2016, Vol. 23, No. 4 Cancer Control 425 perience negatively affected their financial situation.19 Financial hardship in relation to the costs of cancer treatment can cause stress, may result in reduced quality of life, and may lead to patients terminating their therapeutic plan.19 The Affordable Care Act has enabled more than 2.5 million young adults aged 19 to 25 years to gain access to health insurance, although the uninsured rate is still highest among those aged 15 to 39 years.14,17 After implementation of the Affordable Care Act Dependent Coverage Expansion, detection rates increased for early-stage cervical cancer among women aged 21 to 25 years secondary to increases in access to health care.20 Diagnosing cervical cancer in its early stage affords the oncologist the possibility of using fertility-sparing treatments; thus, the proportion of young women with cancer able to receive fertility-sparing treatment increased.20 Further analyses are needed to determine whether expanded coverage for health insurance is associated with other favorable changes in AYAs. Treatment The optimal location of care is a complex topic. Expertise for a given cancer diagnosis may lie within either pediatric or medical oncologists. Pathways could provide an optimal range of therapeutic options, identify areas for future clinical research for AYAs, and create disease-specific champions for AYAs passionate about the care of this patient population. Although the treatment protocol may be similar for certain cancers, others may vary with respect to outcomes, cost of care, or intensity of care.21 It is our opinion that a larger pool of expertise may exist at an adult facility for melanoma or neuroendocrine diseases, but patients with sarcoma most likely receive similar care at both the adult and pediatric cancer centers due to shared staffing. Care for a patient with leukemia must involve increasing levels of collaboration to provide personalized care using an evidence-based approach to treatment.22 Patients treated in a National Cancer Institute–designated comprehensive cancer center have superior outcomes compared with those treated at facilities not designated as such, a fact likely due to the preponderance of trials conducted at these centers.18 Barriers impeding access to National Cancer Institute–designated comprehensive cancer centers include lack of health care insurance, public insurance, lower socioeconomic status, and African American or Hispanic race/ethnicity.22 Approximately 28% of patients older than 15 years of age are treated at community centers, not tertiary care centers.23 AYAs are the least likely of all age groups to be treated at comprehensive cancer centers and, therefore, they may lack opportunities for multidisciplinary care, tumor board discussions, subspecialty care (eg, rare tumors), and the opportunity to enroll in clinical trials.22,24 426 Cancer Control Clinical Trial Enrollment The percentage of AYAs enrolled in clinical trials is lower than that seen in younger or older patients.21,25-29 AYAs who are uninsured, older in age, or treated by nonpediatric oncologists are less likely than older patients to be enrolled in a clinical trial.25 Even within institutions that have the same clinical trials, enrollment of AYAs is lower than the enrollment of the pediatric population.28,29 Many obstacles contribute to the low number of AYAs enrolled in clinical trials, one of which is lack of knowledge about clinical trials among AYAs. In 1 study, 62% of AYAs did not know if clinical trials were available for their type of cancer.30 Treatment location is also a factor. A total of 40% of AYAs are treated at academic centers.31 Even when treated at a cancer center, not all clinical trials are available. Some hospitals are not allowed to enroll patients in Children Oncology Group trials if they are not participating institutions.32 In 2012, the Centers for Disease Control and Prevention convened a group of oncologists who were experts in the AYA population to examine barriers to clinical trial enrollment among adolescents. Five issues were identified as the most important barriers33: 1. Low referral rates of adolescents with cancer to pediatric cancer centers 2. Limited availability of clinical trials for certain cancers 3. Physician-related barriers limiting clinical trial accrual 4. Institutional barriers impeding collaboration between pediatric and nonpediatric oncologists on clinical trials 5. Unique psychosocial needs of adolescents with cancer Progress has been made by creating AYA programs at select cancer centers and by increasing the development and availability of clinical trials for AYA patients.34,35 Although the number of programs for AYAs with cancer is increasing in the United States, no formal accreditation, registry, or minimal standard exists by which to measure these targeted programs; thus, the structures available and the services offered vary among programs.36 In an attempt to standardize treatment and services for AYAs with cancer, various organizations have developed treatment guidelines and recommendations for this patient population (Table 1).4,35-40 In 2016, the National Comprehensive Cancer Network published updated treatment guidelines for AYAs with cancer.37 Its recommendations emphasize the need for a comprehensive, multidisciplinary approach to AYA care, including supportive and treatment guidelines that aim to improve treatment tolerance, compliance, and clinical outcomes.37 Although dedicated efforts to design programs October 2016, Vol. 23, No. 4 Table 1. — Select Resources for the Care of AYAs With Cancer Reference Comment Adolescent and Young Adult Oncology Progress Review Group 4 Establish age demarcation of AYA population Summarize epidemiology Dictate disparities and unique issues that affect AYAs Ferrari35 AYAs require patient-focused multidisciplinary approach A need exists for oncologists trained in AYA oncology Importance of establishing a physical space in the institution for AYAs Coccia39 National Comprehensive Cancer Network 37 Identify issues specific to AYAs Explain special considerations related to cancer management in AYAs Provide supportive and treatment guidelines that aim to improve treatment tolerance, compliance, and clinical outcomes Discuss long-term consequences Promote participation in clinical trials Nass 36 Summarize gaps in cancer care confronted by AYAs Describe potential strategies and actions to improve the quality of care for AYAs Focus on quality-of-life issues and late effects Loren40 Discuss fertility preservation with all patients of reproductive ages with cancer and discuss with parents/guardians of children and adolescents A need exists for proper documentation of fertility discussion and options provided to patients Embryo and oocyte cryopreservation now standard practice AYA = adolescent and young adult. aimed at increasing clinical trial enrollment in AYAs have shown some promise, improvements are more likely with sustained, systematic approaches to clinical trial research in the AYA population.41 Efforts to improve trial enrollment are ongoing, some of which use multidisciplinary, collaborative oncology and pediatric specialist teams to study diseases such as leukemia and sarcoma.38 Clinical trial registries, advocacy groups, and efforts to increase collaborations and communication across adult and pediatric cancer centers are likely to continue progress in increasing clinical trial enrollment rates in AYAs (Table 2). Psychosocial Needs and Late Effects The wide age range of AYA care includes patients still under the guardianship of their parents to those in committed relationships and married; thus, the psychosocial needs among this age group widely vary. Quality of life, adjusting to a cancer diagnosis, searching for meaning or understanding after a diagnosis, October 2016, Vol. 23, No. 4 and vocational outcomes can be challenging. AYAs may require psychosocial care throughout the cancer care continuum because, if left unaddressed, such psychosocial issues may lead to poorer outcomes than patients with access to age-appropriate resources. During young adulthood, autonomy and self-reliance are prized and contribute to a person’s sense of accomplishment and maturity.42 AYAs with cancer may have experienced these shortly before medical and financial hardships forced them into the care of their parents, away from the working world or from pursuing their education and possibly isolating them from their peers without cancer.36 This isolation can be reinforced when AYAs see their friends achieving age-specific milestones, such as graduation, career success, marriage, and starting a family, because they may be unable to achieve or experience these same life events while undergoing treatment or recovering in survivorship stages.43 Because of these experiences, the coordination of cancer care while maintaining social connectivity is paramount to the successful treatment of AYAs.42 Some of the services AYAs require while undergoing treatment include financial counseling and insurance assistance, pain management, and mental health and peer support (Table 3). The need for these services is not exclusive to AYAs with cancer; however, the life stage of AYAs exacerbates these associated needs, particularly because many AYAs report that these needs remain unmet.44 AYAs have higher rates of distress at diagnosis than older matched populations, and they maintain high rates of distress during survivorship.45-47 Smith et al48 looked at the unmet needs in AYAs and found that patients who lacked mental health services had the poorest health-related quality-of-life scores. AYAs have identified family support, religious beliefs, and personal encouragement as the strongest sources of support during a cancer diagnosis and subsequent treatment.49 Another study reported that patients who had adequate health care insurance, a good family support system, and were properly informed about preserving their fertility were the most happy with their cancer care.50 In addition, AYAs who were the most capable of coping with their diagnosis maintained involvement in their career, school, or social spheres.47 Relationships can shape the lives of AYAs and may be a helpful source of support throughout the cancer care continuum. Significant others or life partners may also play roles in decision-making, potential discourse, and act as support systems. The key caregiver or health care proxy assisting in medical decisions may vary with each AYA, their state of residence, and may not remain consistent throughout the disease trajectory. Research suggests that the most important opinions about the medical care of AYAs may not come from family members, as a clinical care team may assume; Cancer Control 427 spouses, and siblings, especially if family members make special work arrangeClinical Trial Type of Study Eligibility Study Objective Identifier (Age), y ments and sacrifices to be more available to patients unProspective Feasibility and safety of a pediatric regimen in patients NCT01406756 16–39 phase 2 with ALL treated by a hematologist/oncologist dergoing treatment.56 Standard- or high-dose combination chemotherapy Health care professionRandomized NCT02375204 ≥ 14 and stem-cell transplant in males with relapsed or als have cited end-of-life care phase 3 refractory germ cell tumors as the most difficult need Combination chemotherapy in treating newly NCT01406756 Phase 3 1–31 to meet in the AYA populadiagnosed ALL tion.57-59 Several studies have Randomized Combination chemotherapy in treating nonmetastatic, NCT01231906 ≤ 50 looked at the best time to phase 3 extracranial Ewing sarcoma discuss advanced care planRandomized Combination chemotherapy ± ganitumab in newly NCT02306161 ≤ 50 ning, suggesting that discusphase 2 diagnosed metastatic Ewing sarcoma sions should begin as early NCT02470091 Phase 2 11–49 Use of denosumab for recurrent/refractory osteosarcoma as the initial diagnosis and Use of eribulin mesylate in relapse/refractory NCT02097238 Phase 2 12–49 as late as hospice referral.60-62 osteosarcoma Research also suggests that Preoperative chemoradiotherapy or preoperative Randomized AYAs who make their final NCT02180867 ≥2 radiotherapy ± pazopanib in nonrhabdomyosarcoma phase 2/3 soft-tissue sarcoma wishes known regain more Comparing ipilimumab to high-dose interferon α-2b control of their health care NCT01274338 Phase 3 ≥ 12 in high-risk stage 3/4 melanoma after surgery situation than patients who Targeted therapy directed by genetic testing in do not express their wishNCT02465060 Phase 2 ≥ 18 advanced refractory solid tumors or lymphomas es.63,64 In addition, AYAs who ALL = acute lymphoblastic leukemia, AYA = adolescent and young adult, Ph+ = Philadelphia chromosome positive. had a written advanced care planning document reported higher rates of active coping Table 3. — Select Resources for Adolescents and Adults With Cancer and emotional support than Focus Organization Website those without a written inFertility preservation Oncofertility Consortium www.oncofertility.northwestern.edu structions for advanced care planning.65 One study found Financial assistance SAMFund www.thesamfund.org that advanced care planning Legal assistance Triage Cancer www.triagecancer.org reduced levels of anxiety and Cancer Care www.cancercare.org National support and familial conflict, because resources Critical Mass www.criticalmass.org such wishes were discussed Patient advocacy and in advance and a health care Stupid Cancer www.stupidcancer.org awareness surrogate was identified.63 Physician education Focus Under Forty www.university.asco.org/focus-under-forty Caregivers of AYAs also benefitted from the conversation Program development Teen Cancer America www.teencanceramerica.org about end-of-life planning Program standardization Change it Back www.HCRI.org/programs/change-it-back as they were able, in times of great grief, to realize and carry out the wishes of their instead, AYAs hold opinions of friends and peers in loved one.63 Such events would not likely have haphigher regard.51 Doing so may increase levels of stress pened without guidance for advanced care planning. or isolate patients in such a way that they feel they are Some meaningful progress in AYA care has inmaking decisions on their own.52 volved the formative and focused research to identify Many AYAs are also unsure how or when to share the psychosocial needs of AYAs and the development their cancer diagnosis, impaired fertility, and medical of programs to help address those needs; similarly, debt, among other issues, with a prospective partner.53 AYA-focused organizations strive to provide financial, Self-confidence and vulnerability are important aspects vocational, and insurance assistance to cancer patients, of any relationship formation, but many AYAs struggle survivors, and their friends and families (see Table 3). with negative body issues or low levels of self-esteem, Progress was also made when the American Acadand report that their experience with cancer has negemy of Pediatrics and the Institute of Medicine estabatively affected their developing romantic relationlished recommendations to include AYAs in their own ships.53-55 AYAs may also feel burdensome to parents, end-of-life discussions, stating that such discussions Table 2. — Select Clinical Trials for Adolescents and Young Adults 428 Cancer Control October 2016, Vol. 23, No. 4 did not contradict a hopeful, positive outcome.61 The creation of Five Wishes (Aging With Dignity, Tallahassee, FL) has allowed health care professionals to use a more age-appropriate advance care planning tool to respect the goals and priorities of AYAs at the end of their life.61 This tool has also served as a starting point for feedback from AYAs and to continue to develop the most applicable advance care planning for young adults with cancer and the thoughts they wish to convey to their loved ones. Fertility and Reproductive Health A significant psychosocial concern among AYA patients is loss of fertility. Chemotherapy, radiotherapy, surgery, and cancer itself can cause temporary or permanent damage to the reproductive organs and endocrine or pituitary functioning. The risk of permanent infertility depends on patient age (younger patients typically fare better than older patients), type of cancer and its treatment, and the dose and intensity of the treatment.66,67 In addition, females may experience premature ovarian insufficiency or failure, causing infertility, premature menopause, or both.67 In the midst of a cancer diagnosis, understanding a patient’s risk of infertility and possible options for preserving fertility can be daunting and complex. Decisionmaking about infertility and fertility preservation can be challenging for the AYA patient because multiple barriers exist.67-72 A patient may not have considered his or her desire for biological children in the future, and such decisions may become compounded by the stress of a cancer diagnosis.68 The patient or the oncologist may feel that a delay in treatment to pursue fertility preservation is unwise, and thus the patient may not have time to pursue preservation.69,70 The financial costs associated with fertility preservation are often not covered by health care insurance, thus making fertility preservation out of reach for many AYA patients.67 Ethical, religious, and other matters should be considered and may impede the decision-making of an AYA about fertility preservation. Discussions about fertility and sexual health may be uncomfortable for the AYA patient, particularly if his or her parents are present. Although the parents and loved ones of AYAs with cancer typically want to be helpful and support the patient as much as possible, studies suggest that they may not be appropriate proxy decision-makers about fertility on behalf of AYA patients.71,72 It is also worth noting that AYAs with cancer are as sexually active as their peers without cancer.73-76 Thus, health care professionals should be aware of intimacy concerns and changes due to treatment and have tactful and meaningful conversations with AYAs about reported adverse events and solutions, if possible. Equally important is for the oncologist to refer AYA patients to contraception counseling, because AYAs have been October 2016, Vol. 23, No. 4 shown to take more sexual risk, such as not using adequate contraceptive measures.77,78 Therefore, contraception should be a key discussion point with patients and their medical team, because some patients may assume they are infertile due to their treatment and think they have no need for contraception for pregnancy purposes or they may engage in unprotected sex to verify the fact that their infertility has been impaired.79 It is also worth noting that patients receiving active treatment are more susceptible to sexually transmitted infections because their immune systems are compromised.77,80 Pregnancy while undergoing cancer treatment can pose risks to the fetus as well as the patient, and making difficult decisions to terminate a pregnancy may cause increased stress and turmoil for a young patient already trying to cope with a cancer diagnosis and treatment. Discussions of potential threats to fertility with all patients of childbearing age with newly diagnosed cancer are recommended by several medical organizations, including as the American Society of Clinical Oncology,40 the National Comprehensive Cancer Network,68 and the American Society for Reproductive Medicine.81 In addition to discussion about the potential impact of treatment or cancer type on fertility, the American Society of Clinical Oncology and other resources recommend that AYA patients be referred to a reproductive endocrinologist or infertility specialist to discuss options for fertility preservation as soon as possible after a diagnosis of cancer is received and prior to the start of treatment (see Table 1).4,35-40 The established fertility preservation methods are sperm cryopreservation for postpubertal males and oocyte and embryo cryopreservation for postpubertal females as well as ovarian transposition for patients undergoing pelvic or abdominal radiotherapy.37,40 For prepubertal children, fertility preservation options are experimental and include testicular or ovarian tissue cryopreservation.40 Studies suggest that patients who do not learn about potential threats to their fertility may experience feelings of remorse and regret during the survivorship period.82-84 Although few patients (particularly females) opt to use fertility-preservation methods, most patients report satisfaction and appreciation for learning about this information from their health care professional.85,86 Progress of Cancer Biology Though many common diagnoses afflicting the AYA population overlap with those seen in younger and older patients, new data have emerged showing differences in disease biology by age.8,87,88 Acute lymphoblastic leukemia (ALL) is the most common malignancy and leading cause of cancer-related deaths in AYAs.88 Outcomes of AYAs treated for ALL are worse for those aged 10 years or older.8,88 The Cancer Control 429 treatment varies: In adult-based protocols, transplants are more common, whereas pediatric-based protocols call for intensive therapy, including asparaginase, and do not rely as heavily on transplants.89-92 A difference exists in the frequency of cytogenetic abnormalities that predispose AYAs to worse outcomes, but it may also serve as a target for improved therapy.8,10,93,94 Opportunities for improved outcomes may also exist in Philadelphia chromosome–positive ALL when tyrosine kinase inhibitors are added to treatment (Table 4).7-10,88,93-102 A large prospective trial of 296 patients aged 16 to 39 years demonstrated that treatment with an intensive pediatric regimen showed significant rates of improvement in event-free survival (66%) and overall survival (78%) along with manageable toxicities.89,90 Other trials have shown superior outcomes in AYAs treated in pediatric protocols.89 Such ongoing collaborations with cooperative groups may lead to uniform treatment based on biology, with age being one among many other variables. Sarcoma is a common type of cancer in AYAs.103-107 Overall, these mesenchymal-derived malignancies of the soft tissue and bone represent 8% of new diagnoses in patients aged 15 to 39 years.108 Standard chemotherapies for front-line regimens for osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma have been established through cooperative group studies.103-107 In these studies, pediatric patients typically comprise the majority of the groups. Standard therapies for other soft-tissue sarcomas have been primarily derived from studies of adult populations, in whom these diagnoses are more common.109,110 Oftentimes, no clear consensus exists regarding systemic therapies for metastatic, relapsed, or recurrent disease.108 Some retrospective reviews of single-institution experiences and cooperative group studies explore the presentation, biology, and therapeutic variables and how they generally negatively impact the outcomes of AYA patients compared with younger patients (see Table 4).7-10,88,93-102,111-113 Effort has been made to collaborate through the adultand pediatric-focused cooperative groups and may serve as a model for future trials.38 Breast cancer has an age-related biological difference that dictates outcomes.99,100,114,115 Breast cancer is one of the most frequently diagnosed malignancies among women aged 15 to 39 years and makes up 14% of all cancers diagnosed in AYAs.9 Nearly 7% of all breast cancers are diagnosed in women younger than 40 years of age.8,99 AYAs have a higher incident rate of more aggressive phenotypes, such as triple-negative breast cancer, ERBB2 (formerly known as HER2/neu)-overexpressing cancers, and luminal B cancers.9,99,100,114,115 A low proportion of AYAs present with luminal A disease, which confers a better prognosis.100 In addition, a higher proportion of AYAs present with stage III/IV disease.99 AYA pa430 Cancer Control Table 4. — Select Characteristics and Features of Cancers in AYA Type of Cancer Description Leukemia8,10,93-97 Ph+ ALL t(9,22) BCR-ABL 3% of children 3%–25% of AYAs T-cell leukemia Age 1–9 y: 12.8% Age 10–15 y: 16.9% Age 16–21 y: 24.7% Chromosome 21 (iAMP21) Increase incidence in patients aged > 10 y Hypodiploid MLL at 11q23 TEL-AML1 translocation (ETV6-RUNX1) 50% in children 10% in AYA Sarcoma101,102 Ewing sarcoma More common in AYAs aged ≥ 15 y than children Increasing age associated with poor prognosis Osteosarcoma Poor event-free survival associated with age ≥ 18 y Rhabdomyosarcoma Higher prevalence of alveolar subtype in AYAs, conferring a poorer prognosis Colorectal cancer 10 High incidence of microsatellite instability High incidence of heritable forms of colorectal cancer (adenomatous polyposis, nonpolyposis colon cancer) Breast cancer 99,100 Higher prevalence of BRAC1/BRAC2 mutations Present with stage III/IV disease Higher incidence of aggressive pathology Triple-negative breast cancer Age 15–39 y: 22.8% Age 40–49 y: 14.3% Age ≥ 50 y: 11.7% ERBB2-overexpressing cancer Age 15–39 y: 10.3% Age 40–49 y: 6.9% Age ≥ 50 y: 5.9% Luminal B cancer Age 15–39 y: 17.9% Age 40–49 y: 14.9% Age ≥ 50 y: 10.7% Melanoma88 Risk factors: congenital melanocytic nevi, xeroderma pigmentosa, dysplastic nevus, prior treatment for childhood cancer Comprehensive staging guidelines not established for children and adolescents Metastases to sentinel lymph nodes occur more frequently in children and AYAs than in adults with same disease stage ALL = acute lymphoblastic leukemia, AYA = adolescent and young adult, Ph+ = Philadelphia chromosome positive. October 2016, Vol. 23, No. 4 tients with breast cancer have a high prevalence of BRCA1/BRCA2 mutations.9,99,100,114,115 CRC is another example of the biological and genetic differences seen in AYAs compared with older adults. The AYA population has high incidence rates of microsatellite instability and heritable forms of CRC such as familial adenomatous polyposis and hereditary nonpolyposis colon cancer.10 It may also be true that the disease biology of young patients with CRC but without inherited syndromes may differ from the type of CRC seen in older adults.10 Overall, compared with older patients, AYAs present with more advanced-stage disease at diagnosis and more aggressive tumor features.116 Melanoma can affect individuals at any age, but it is more common in adults than children.87 Its basic disease biology — numerous mutations and a preponderance of BRAF V600E mutations — appears to hold true across all ages.117 Metastases to sentinel lymph nodes occur more frequently in children and AYAs than in adults with the same stage of disease.88 With the approval of ipilimumab, nivolumab, and other inhibitors and combination therapies, we question whether AYAs were adequately represented and enrolled in recent successful trials.118 Based on the biology of melanoma, similar treatment outcomes are expected in the AYA population.118 Remaining Challenges The management of cancer in AYA patients is a continuous process that has experienced progress in recent years. We now understand more about what AYA patients need and are poised to learn even more about possible approaches to improve many aspects of AYA care. However, doing so requires future research that emphasizes the biological differences in certain diseases to develop targeted treatments for this population. Lack of health insurance among this age group is still a major concern because being uninsured can potentially delay diagnosis and access to treatment as well as to the possibility of inhibiting any transition to surveillance and life-long survivorship care. A large study looking at the unmet needs of AYA patients reported that 50% of AYA participants had unmet information needs about cancer recurrence, cancer treatments, and long-term adverse events, and up to 50% of AYA patients had unmet information needs on fertility, nutrition, and financial support.44 Conclusions Adolescent and young adult (AYA) patients face disparities based on age that can lead to a delay in diagnosis, an advanced stage of disease at presentation, suboptimal treatment location, lack of clinical trial availability, and an increased burden of quality survivorship through the loss of fertility or disruption in social, personal, or financial growth and stability. These disOctober 2016, Vol. 23, No. 4 parities in AYAs have inspired individuals and institutions to develop programs designed for AYAs to meet the specific or overall health care needs of this patient population. In addition, some organizations have advocated for AYA cancer care as a specific discipline within oncology; to improve fertility education and access to preservation; to address the root causes of the lack of survival improvement; and to define the essential elements of care for this population. Today we understand more about what AYA patients need, and we are poised to learn even more about approaches to improve many aspects of care for these patients. We are optimistic that motivated patients, health care professionals, advocacy organizations, and institutions will align to develop improved models for the care of AYAs. References 1. Soliman H, Agresta S. Current issues in adolescent and young adult cancer survivorship. Cancer Control. 2008;15(1):55-62. 2. Young Adult Cancer Alliance. Critical Mass Annual Conference. November 4, 2015–November 6, 2015; Chicago, IL. http://criticalmass.org/ the-annual-conference/2015-conference. Accessed October 18, 2016. 3. National Cancer Institute. Cancer health disparities. https://www. cancer.gov/about-nci/organization/crchd/cancer-health-disparities-fact-sheet. Accessed October 5, 2016. 4. Adolescent and Young Adult Oncology Program Review Group. Closing the Gap: Research and Care Imperatives for Adolescents And Young Adults With Cancer. Bethesda, MD: US Department of Health and Human Services; National Institutes of Health; National Cancer Institute; LIVESTRONG Young Adult Alliance; 2006. https://www.cancer.gov/types/ aya/research/ayao-august-2006.pdf. Accessed October 5, 2016. 5. Lewis DR, Seibel NL, Smith AW, et al. Adolescent and Young Adult Cancer Survival. J Natl Cancer Inst Monogr. 2014;2014(49):228-235. 6. National Cancer Institute; Surveillance, Epidemiology, and End Results. A snapshot of adolescent and young adult cancer. https://www.cancer.gov/research/progress/snapshots/adolescent-young-adult. Accessed October 5, 2016. 7. Schafer ES, Hunger SP. Optimal therapy for acute lymphoblastic leukemia in adolescents and young adults. Nat Rev Clin Oncol. 2011;8(7):417-424. 8. Bleyer A, Barr R, Hayes-Lattin B, et al. The distinctive biology of cancer in adolescents and young adults. Nat Rev Cancer. 2008;8(4):288-298. 9. Keegan TH, Press DJ, Tao L, et al. Impact of breast cancer subtypes on 3-year survival among adolescent and young adult women. Breast Cancer Res. 2013;15(5):R95. 10. Tricoli JV, Seibel NL, Blair DG, et al. Unique characteristics of adolescent and young adult acute lymphoblastic leukemia, breast cancer, and colon cancer. J Natl Cancer Inst. 2011;103(8):628-635. 11. Zbuk K, Sidebotham EL, Bleyer A, et al. Colorectal cancer in young adults. Semin Oncol. 2009;36(5):439-450. 12. Martin S, Ulrich C, Munsell M, et al. Delays in cancer diagnosis in underinsured young adults and older adolescents. Oncologist. 2007;12(7):816-824. 13. Grassley CE, ed. Living Without Health Insurance: Hearing Before the Committee on Finance, US Senate. Darby, PA: Diane Publishing; 2001. 14. Smith JC, Medalia C. Health Insurance Coverage in the United States: 2013. Washington, DC: US Department of Commerce; Economics and Statistics Administration; US Census Bureau; 2014. http://www.nber. org/cps/hi/2014redesign/p60-250.pdf. Accessed October 5, 2016. 15. Aizer AA, Falit B, Mendu ML, et al. Cancer-specific outcomes among young adults without health insurance. J Clin Oncol. 2014;32(19):2025-2030. 16. Smith EC, Ziogas A, Anton-Culver H. Association between insurance and socioeconomic status and risk of advanced stage Hodgkin lymphoma in adolescents and young adults: Hodgkin’s lymphoma in adolescents and young adults. Cancer. 2012;118(24):6179-6187. 17. Bleyer A, Ulrich C, Martin S. Young adults, cancer, health insurance, socioeconomic status, and the Patient Protection and Affordable Care Act. Cancer. 2012;118(24):6018-6021. 18.Rosenberg AR, Kroon L, Chen L, et al. Insurance status and risk of cancer mortality among adolescents and young adults. Cancer. 2015;121(8):1279-1286. 19. Bellizzi KM, Smith A, Schmidt S, et al. Positive and negative psychosocial impact of being diagnosed with cancer as an adolescent or young adult. Cancer. 2012;118(20):5155-5162. 20. Robbins AS, Han X, Ward EM, et al. Association between the Affordable Care Act dependent coverage and cervical cancer stage and treatment in young women. JAMA. 2015;314(20):2189-2191. Cancer Control 431 21. Shaw PH, Reed DR, Yeager N, et al. Adolescent and young adult (AYA) oncology in the United States: a specialty in its late adolescence. J Pediatr Hematol Oncol. 2015;37(3):161-169. 22. Wolfson JA, Sun CL, Wyatt LP, et al. Impact of care at comprehensive cancer centers on outcome: results from a population-based study. Cancer. 2015;121(21):3885-3893. 23. Yeager ND, Hoshaw-Woodard S, Ruymann FB, et al. Patterns of care among adolescents with malignancy in Ohio. J Pediatr Hematol Oncol. 2006;28(1):17-22. 24. Wolfson J, Sun CL, Kang T, et al. Impact of treatment site in adolescents and young adults with central nervous system tumors. J Natl Cancer Inst. 2014;106(8):dju166. 25. Parsons HM, Harlan LC, Seibel NL, et al. Clinical trial participation and time to treatment among adolescents and young adults with cancer: does age at diagnosis or insurance make a difference? J Clin Oncol. 2011;29(30):4045-4053. 26. Fern L, Davies S, Eden T, et al. Rates of inclusion of teenagers and young adults in England into National Cancer Research Network clinical trials: report from the National Cancer Research Institute (NCRI) Teenage and Young Adult Clinical Studies Development Group. Br J Cancer. 2008;99(12):1967-1974. 27. McTiernan A. Issues surrounding the participation of adolescents with cancer in clinical trials in the UK. Eur J Cancer Care (Engl). 2003;12(3):233-239. 28. Shaw PH, Ritchey AK. 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Lyon ME, Jacobs S, Briggs L, et al. Family-centered advance care planning for teens with cancer. JAMA Pediatr. 2013;167(5):460. 64. Wicks L, Mitchell A. The adolescent cancer experience: loss of control and benefit finding: Adolescent cancer experience: control and benefit finding. Eur J Cancer Care (Engl). 2010;19(6):778-785. 65. Loberiza FR, Swore-Fletcher BA, Block SD, et al. Coping styles, health status and advance care planning in patients with hematologic malignancies. Leuk Lymphoma. 2011;52(12):2342-2348. 66. Moss JL, Choi AW, Fitzgerald Keeter MK, et al. Male adolescent fertility preservation. Fertil Steril. 2016;105(2):267-273. 67. Levine JM, Kelvin JF, Quinn GP, et al. Infertility in reproductiveage female cancer survivors: infertility in female cancer survivors. Cancer. 2015;121(10):1532-1539. 68. Johnson RH, Kroon L. Optimizing fertility preservation practices for adolescent and young adult cancer patients. J Natl Compr Canc Netw. 2013;11(1):71-77. 69. Quinn GP, Vadaparampil ST, Bell-Ellison BA, et al. Patient-physician communication barriers regarding fertility preservation among newly diagnosed cancer patients. Soc Sci Med. 2008;66(3):784-789. 70. Quinn GP, Vadaparampil ST, Lee JH, et al. Physician referral for fertility preservation in oncology patients: a national study of practice behaviors. J Clin Oncol. 2009;27(35):5952-5957. 71. Crawshaw M. Psychosocial oncofertility issues faced by adolescents and young adults over their lifetime: a review of the research. Hum Fertil. 2013;16(1):59-63. 72. Quinn GP, Vadaparampil ST. Fertility Preservation and adolescent/ young adult cancer patients: physician communication challenges. J Adolesc Health. 2009;44(4):394-400. 73. Vadaparampil ST, Clayton H, Quinn GP, et al. Pediatric oncology nurses’ attitudes related to discussing fertility preservation with pediatric cancer patients and their families. J Pediatr Oncol Nurs. 2007;24(5):255-263. 74. King L, Quinn GP, Vadaparampil ST, et al. Oncology nurses’ perceptions of barriers to discussion of fertility preservation with patients with cancer. Clin J Oncol Nurs. 2008;12(3):467-476. 75. Clayton H, Quinn GP, Lee JH, et al. Trends in clinical practice and nurses’ attitudes about fertility preservation for pediatric patients with cancer. Oncol Nurs Forum. 2008;35(2):249-255. 76. Fallowfield L, Saul J, Gilligan B. Teaching senior nurses how to October 2016, Vol. 23, No. 4 teach communication skills in oncology. Cancer Nurs. 2001;24(3):185-191. 77. Murphy D, Klosky JL, Termuhlen A, et al. The need for reproductive and sexual health discussions with adolescent and young adult cancer patients. Contraception. 2013;88(2):215-220. 78. Maslow BS, Morse CB, Schanne A, et al. Contraceptive use and the role of contraceptive counseling in reproductive-aged women with cancer. Contraception. 2014;90(1):79-85. 79. Benedict C, Shuk E, Ford JS. Fertility issues in adolescent and young adult cancer survivors. J Adolesc Young Adult. 2016;5(1):48-57. 80. Laurence V, Gbolade BA, Morgan SJ, et al. Contraception for teenagers and young adults with cancer. Eur J Cancer. 2004;40(18):2705-2716. 81. Ethics Committee of American Society for Reproductive Medicine. Fertility preservation and reproduction in patients facing gonadotropic therapies: a committee opinion. Fertil Steril. 2013;100(5):1224-1231. 82. Benedict C, Thom B, Kelvin JF. Young adult female cancer survivors’ decision regret about fertility preservation. J Adolesc Young Adult Oncol. 2015;4(4):213-218. 83. Crawshaw M, Sloper P. A Qualitative Study of the Experiences of Teenagers and Young Adults When Faced With Possible or Actual Fertility Impairment Following Cancer Treatment. York, UK: University of York; 2006. http://www.york.ac.uk/inst/spru/pubs/pdf/fertilityExecSumm.pdf. Accessed October 5, 2016. 84. Chapple A, Salinas M, Ziebland S, et al. Fertility issues: the perceptions and experiences of young men recently diagnosed and treated for cancer. J Adolesc Health. 2007;40(1):69-75. 85. Garvelink MM, ter Kuile MM, Bakker RM, et al. Women’s experiences with information provision and deciding about fertility preservation in the Netherlands: “satisfaction in general, but unmet needs.” Health Expect. 2015;18(5):956-968. 86. Letourneau JM, Ebbel EE, Katz PP, et al. Pretreatment fertility counseling and fertility preservation improve quality of life in reproductive age women with cancer. Cancer. 2012;118(6):1710-1717. 87. American Cancer Society. Cancer Facts & Figures 2016. http:// www.cancer.org/acs/groups/content/@research/documents/document/ acspc-047079.pdf. Accessed October 18, 2016. 88. Tricoli JV, Blair DG, Anders CK, et al. Biologic and clinical characteristics of adolescent and young adult cancers: acute lymphoblastic leukemia, colorectal cancer, breast cancer, melanoma, and sarcoma. Cancer. 2016;122(7):1017-1028. 89. 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Mullighan CG, Willman CL. Advances in the biology of acute lymphoblastic leukemia—from genomics to the clinic. J Adolesc Young Adult Oncol. 2011;1(2):77-86. 95. Bleyer WA, Barr RD, eds. Pediatric Oncology: Cancer in Adolescents and Young Adults. New York: Springer; 2007. 96. Roberts KG, Li Y, Payne-Turner D, et al. Targetable kinaseactivating lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med. 2014;371(11):1005-1015. 97. Pui CH, Yang JJ, Hunger SP, et al. Childhood acute lymphoblastic leukemia: progress through collaboration. J Clin Oncol. 2015;33(27):2938-2948. 98. Janeway KA, Barkauskas DA, Krailo MD, et al. Outcome for adolescent and young adult patients with osteosarcoma: a report from the Children’s Oncology Group. Cancer. 2012;118(18):4597-4605. 99. Keegan TH, DeRouen MC, Press DJ, et al. Occurrence of breast cancer subtypes in adolescent and young adult women. Breast Cancer Res. 2012;14(2):R55. 100. Assi HA, Khoury KE, Dbouk H, et al. Epidemiology and prognosis of breast cancer in young women. J Thorac Dis. 2013;5(suppl 1):S2-S8. 101. Janeway KA, Pappo A. Treatment guidelines for gastrointestinal stromal tumors in children and young adults. J Pediatr Hematol Oncol. 2012;34:S69-S72. 102. Bisogno G, Compostella A, Ferrari A, et al. Rhabdomyosarcoma in adolescents: a report from the AIEOP Soft Tissue Sarcoma Committee. Cancer. 2012;118(3):821-827. 103. Marina N, Bielack S, Whelan J, et al. International collaboration is feasible in trials for rare conditions: the EURAMOS experience. In: Jaffe N, Bruland OS, Bielack S, eds. Pediatric and Adolescent Osteosarcoma. Boston: Springer US; 2010. 104.Gorlick R, Janeway K, Lessnick S, et al. Children’s Oncology October 2016, Vol. 23, No. 4 Group’s 2013 blueprint for research: bone tumors.. Pediatr Blood Cancer. 2013;60(6):1009-1015. 105. Womer RB, West DC, Krailo MD, et al. Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children’s Oncology Group. J Clin Oncol. 2012;30(33):4148-4154. 106.Malempati S, Hawkins DS. Rhabdomyosarcoma: review of the Children’s Oncology Group (COG) Soft-Tissue Sarcoma Committee experience and rationale for current COG studies. Pediatr Blood Cancer. 2012;59(1):5-10. 107. Weiss A, Gill J, Goldberg J, et al. Advances in therapy for pediatric sarcomas. Curr Oncol Rep. 2014;16:395. 108. Amankwah EK, Conley AP, Reed DR. Epidemiology and therapies for metastatic sarcoma. Clin Epidemiol. 2013;5:147-162. 109. Judson I, Verweij J, Gelderblom H, et al. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial. Lancet Oncol. 2014;15(4):415-423. 110. van der Graaf WT, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebocontrolled phase 3 trial. Lancet. 19;379(9829):1879-1886. 111. Streby KA, Ruymann FB, Whiteside S, et al. Rhabdomyosarcoma in adolescent and young adults: a 25-year review at Nationwide Children’s Hospital. J Adolesc Young Adult Oncol. 2012;1(4):164-167. 112. Collins M, Wilhelm M, Conyers R, et al. Benefits and adverse events in younger versus older patients receiving neoadjuvant chemotherapy for osteosarcoma: findings from a meta-analysis. J Clin Oncol. 2013;31(18):2303-2312. 113. Haddox CL, Han G, Anijar L, et al. Osteosarcoma in pediatric patients and young adults: a single institution retrospective review of presentation, therapy, and outcome. Sarcoma. 2014;2014: 402509. 114. Parise CA, Bauer KR, Caggiano V. Variation in breast cancer subtypes with age and race/ethnicity. Crit Rev Oncol Hematol. 2010;76(1):44-52. 115. Gewefel H, Salhia B. Breast cancer in adolescent and young adult women. Clin Breast Cancer. 2014;14(6):390-395. 116. Teng A, Lee DY, Cai J, Patel SS, et al. Patterns and outcomes of colorectal cancer in adolescents and young adults. J Surg Res. 2016;205(1):19-27. 117. Lu C, Zhang J, Nagahawatte P. The genomic landscape of childhood and adolescent melanoma. J Invest Dermatol. 2015;135(3):816-823. 118. Sreeraman Kumar R, Messina JL, Sondak VK, et al. Treating melanoma in adolescents and young adults: challenges and solutions. Clin Oncol Adolesc Young Adults. 2015;5:75-86. Cancer Control 433 Tobacco-related health disparities exist at each point of the cancer care continuum. Iris. X-Ray image courtesy of Bryan Whitney. www.x-rayphotography.com. Tobacco-Related Health Disparities Across the Cancer Care Continuum Vani Nath Simmons, PhD, Bárbara Piñeiro, PhD, Monica Webb Hooper, PhD, Jhanelle E. Gray, MD, and Thomas H. Brandon, PhD Background: Use of tobacco is the leading preventable cause of death in the United States. Racial/ethnic minorities and individuals of low socioeconomic status disproportionately experience tobacco-related disease and illness. Unique challenges and circumstances exist at each point in the cancer care continuum that may contribute to the greater cancer burden experienced by these groups. Methods: We reviewed tobacco-related disparities from cancer prevention to cancer survivorship. We also describe research that seeks to reduce tobacco-related disparities. Results: Racial/ethnic minorities and low-income individuals experience unique social and environmental contextual challenges such as greater environmental cues to smoke and greater levels of perceived stress and social discrimination. Clinical practice guidelines support the effectiveness of pharmacotherapy and behavioral counseling for racial and ethnic minorities, yet smoking cessation rates are lower in this group when compared with non-Hispanic whites. Superior efficacy for culturally adapted interventions has not yet been established. Conclusions: To reduce health disparities in this population, a comprehensive strategy is needed with efforts directed at each point along the cancer care continuum. Strategies are needed to reduce the impact of contextual factors such as targeted tobacco marketing and social discrimination on smoking initiation and maintenance. Future efforts should focus on increasing the use of evidence-based cessation treatment methods and studying its effectiveness in these populations. Attention must also be focused on improving treatment outcomes by reducing smoking in diverse racial and ethnic patient populations. From the Health Outcomes and Behavior Program (VNS, THB) and Department of Medical Oncology (JEG), H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, Department of Clinical Psychology and Psychobiology (BP), University of Santiago de Compostela, Santiago de Compostela, Spain, and the Department of Psychology (MWH), Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida. Submitted April 13, 2016; accepted July 28, 2016. Address correspondence to Vani N. Simmons, PhD, Health Outcomes and Behavior Program, Moffitt Cancer Center, 4115 East Fowler Avenue, Tampa, FL 33617. E-mail: [email protected] Dr Brandon receives grants and research support from Pfizer and is a consultant for Voxiva and the Australian General Solicitor. The other authors report no significant relationships with the companies/organizations whose products or services may be referenced in this article. 434 Cancer Control Introduction In the United States, tobacco smoking represents the leading preventable cause of death.1,2 Nearly one-third of all cancer-related deaths are attributable to tobacco use.1-3 The health burden of tobacco use is not equally distributed: Racial and ethnic minorities who smoke and have lower levels of education, income, and occupational status disproportionately experience tobacco-related disease burden and illness.4 Examples of tobacco-related disparities include exposure to tobacco smoke, current patterns of use and cessation, subsequent health consequences among specific population October 2016, Vol. 23, No. 4 groups, capacity and infrastructure, and access to resources.4 Attention to tobacco-related health disparities has been growing, and the number of priority populations has extended beyond racial and ethnic minorities to include individuals of low socioeconomic status as well as sexual minorities (lesbian, gay, bisexual, and transgender).5 In addition, those in the tobacco-related health disparities field have moved beyond descriptive studies and have begun to develop and test interventions to help reduce smoking among these vulnerable populations.6 Although tobacco use contributes to the presence and exacerbation of health disparities with respect to health outcomes such as stroke, diabetes, and coronary heart disease, this paper specifically focuses on the association between tobacco use and cancer.7 Unique challenges and circumstances also exist at different points along the cancer care continuum that contribute to the larger cancer burden experienced by ethnic/racial minorities and underserved populations (Fig).3,4,8-27 Cancer Prevention dition to the potential health outcomes of increased exposure to second-hand smoke, less-restrictive policies may serve to maintain smoking behavior. Compared with workplaces that do not have smoking restrictions, workplaces that prohibit smoking result in fewer cigarettes smoked, greater cessation attempts, and more quitting successes among employees.30 Research also suggests that lack of self-imposed smoking restrictions in the home contributes to greater maintenance of smoking behavior, whereas the adoption of smoke-free restrictions results in greater cessation ability.31 Individuals who smoke, have a lower socioeconomic status, and are African American are less likely than non-Hispanic whites to impose smoking bans in the home and automobile; thus, environmental exposure in these settings is an additional barrier to consider.10-13 Disproportionate exposure to tobacco smoke is also a public health issue among residents of multiunit housing properties who may be exposed to second-hand smoke due to shared air between units and poor ventiliation.32 Residents of subsidized housing also experience high levels of stress, which can impact smoking behavior.33 Evidence suggests that cigarette smoking is associated with increased risks of developing oropharyngeal, laryngeal, esophageal, tracheal, bronchial, lung, stomTargeted Marketing ach, liver, pancreatic, kidney, ureteral, cervical, bladAnother key factor that influences the initiation and der, and colorectal cancers as well as acute myeloid maintenance of tobacco smoking among low-income leukemia.1,2 Thus, decreasing rates of tobacco initiation, as well as increasing smoking cessation rates, are imKey Factors Influencing Disparities at Each Point portant steps for cancer prevention. To further our understanding of toCancer Prevention Cancer Diagnosis Cancer Survivorship bacco initiation and maintenance among racial/ethnic minorities and individuals of lower socioeconomic Environmental Multiple negative status, it is important to consider enAfrican Americans influences contribute effects of continued have highest lung vironmental and social contextual into smoking, exposure smoking on cancer cancer incidence fluences.9 to second-hand outcomes 3,22 compared to all smoke9-13 Environmental Influences Tobacco-control policies, such as smoking restrictions, can be effective at reducing tobacco initiation, use, and related health care costs.2 Despite progress on reducing the amount of exposure to second-hand smoke via smoke-free restrictions in public places, disparities in workplace policies can create or exacerbate tobacco-related disparities in racial/ethnic minority and underserved populations.28 For example, those who smoke and are employed in blue-collar or service occupations are more likely to work in environments that permit smoking.29 In adOctober 2016, Vol. 23, No. 4 Targeted tobacco marketing creates vulnerability14 Perceived stress/ discrimination leads to more smoking15,16 Validated smoking cessation options lacking for minorities20 other racial and ethnic groups21 Racial and ethnic minorities more likely to be diagnosed at more advanced-stage disease23 Potential unequal implementation of cancer screening guidelines8,17-19 Low representation of racially/ethnically diverse patients with cancer in cessation trials26,27 Lack of education, training, and infrastructure for providers to implement smoking cessation into clinical care 4,24,25 Fig. — Tobacco-related health disparities exist across the cancer care continuum. Cancer Control 435 and racial/ethnic minority populations is targeted tobacco marketing.2 The tobacco industry uses targeted marketing and promotions to reach ethnic/racial minorities, sexual minorities, and low-income communities.2,14 Examples of these industry efforts include a greater presence of tobacco billboards in specific neighborhoods and the targeted marketing of menthol cigarettes.14 In a systematic review, the presence and quantity of tobacco marketing at tobacco retailers were examined by neighborhood characteristics such as race, ethnicity, and socioeconomic status.14 The results suggested that lower-income neighborhoods are exposed to more tobacco marketing, and the amount of marketing of menthol products is higher in both urban neighborhoods and communities with larger numbers of African American residents.14 Among neighborhoods with a greater proportion of Hispanic residents, no observed increase in tobacco marketing was seen (possibly due to cultural reasons).2,14 Perceived Stress and Social Discrimination Racial/ethnic minorities and low-income individuals report higher levels of perceived stress, which is defined by the degree to which individuals perceive circumstances in their life as stressful.15,34 Elevated levels of stress may can be attributed to several factors such as lower wages, more daily hassles, and stressful life events.15,35 Social discrimination is also a commonly perceived stressor among African Americans and Latinos.34 Perceived levels of stress and social discrimination have been associated with cancer burden and tobacco smoking.2 The prevalence of tobacco smoking is higher among individuals who perceive greater rates of discrimination.16 For example, compared with nonminority individuals, lesbian, gay, bisexual, and transgender individuals are more likely to experience stressors such as discrimination and stigma and have a higher smoking prevalence rate (between 24% and 45%).36 In addition, an inverse relationship has been observed between perceived levels of stress and rates of smoking cessation.37 A primary mechanism through which stress may influence smoking behavior is via negative-affect management.34 Although tobacco smoking may not actually reduce stress (except for nicotine withdrawal-related stress), if those who smoke believe that smoking reduces stress, then that belief will motivate smoking — ie, smoking is often used as a coping strategy for dealing with stress, and, as stress increases, so does smoking.38 The relationship between negative affect and smoking has been well documented.39,40 The greater perceived level of stress among racial/ethnic minorities and lowincome populations, as well as the robust relationship between stress and smoking, remains an important factor to assess and consider in the development of targeted interventions for underserved persons who smoke. 436 Cancer Control Secondary Prevention To work toward eliminating tobacco-related cancer disparities, we must add to our understanding of social and environmental factors that influence tobacco use among underserved populations so that primary prevention strategies to prevent smoking initiation may be implemented. Equally important are secondary prevention strategies that seek to develop effective smoking cessation interventions to help those who have started smoking. Several evidence-based treatments exist for treating tobacco dependence. Clinical practice guidelines from the US Public Health Service summarize these treatments and describe a brief intervention model called the 5 As8,41: ask about tobacco use, advise to quit smoking, assess interest in quitting smoking, assist in quitting smoking via counseling and pharmacotherapy, and arrange follow-up. These recommendations apply to a broad population of persons who smoke and include those from all racial and ethnic groups, individuals with low socioeconomic status, those with limited formal education, those who are hospitalized, and those who identify as lesbian, gay, bisexual, or transgender.41 Despite the applicability of these guidelines for diverse populations, the unequal implementation of these guidelines has been documented.8,17-19 Among those who smoke, Hispanics and those with low socioeconomic status are less likely to receive advice and assistance from their health care professional about smoking cessation compared with non-Hispanic whites and those with higher socioeconomic status, respectively.17-19 Access to evidence-based smoking cessation methods is also lacking for individuals with limited or no English proficiency.42 The absence of readily available, Spanish-language, evidencebased materials has been cited as a key barrier to the ability of primary care physicians to assist with smoking cessation.43 Targeted Smoking Cessation The US Public Health Service guidelines for evidence-based smoking cessation interventions apply to all racial and ethnic minorities.8 However, important differences exist between racial/ethnic minorities and whites that warrant research on the effectiveness of smoking cessation interventions.44 The smoking prevalence rate for non-Hispanic whites (18.2%) is comparable with that seen in African Americans (17.5%) but is lower for Hispanics (11.2%).45 However, smoking prevalence varies by cultural subgroup; for example, the smoking prevalence among individuals of Puerto Rican and Cuban descent exceeds 30%.46 Moreover, racial and ethnic minorities are disproportionately represented in lower-income categories, where smoking prevalence is highest.45 Several notable differences in smoking behavior patterns also exist among different groups. Although smoking prevalences among African October 2016, Vol. 23, No. 4 Americans and non-Hispanic whites are comparable, African Americans start smoking at a later age, are more likely to smoke menthol cigarettes, and smoke fewer cigarettes per day on average.3,47,48 Despite lower daily rates of smoking among Hispanics and African Americans compared with non-Hispanic whites, racial and ethnic minorities who smoke have greater difficulty quitting smoking.49 Cultural factors and acculturation must be taken into account, because those who are more acculturated are more likely to smoke and have lower odds of sustaining cessation.46 Limited interventional research has also been conducted with American Indians and Alaska Natives, who have the highest rates of tobacco use — including both ceremonial and commercial tobacco use.5,45 Benowitz et al50,51 also reports that differences may exist in the genetics and physiology (eg, how fast nicotine is metabolized) among racial and ethnic groups that warrant the evaluation of specific smoking cessation interventions among these groups, rather than assuming equivalent rates of efficacy across groups. This concept is relevant given that most clinical trials for smoking cessation medications include few minorities who smoke.50 Narrative and meta-analytic reviews of smoking cessation interventions have been conducted for racial and ethnic minorities who smoke.44,52-54 One comprehensive and narrative review included 64 studies involving African Americans, Latinos, American Indians, Asians, and Pacific Islanders who smoked.44 Pharmacotherapy, behavioral interventions, and community interventions for smoking cessation were examined. The authors concluded that existing data support the use of pharmacotherapy treatments for smoking cessation among African Americans, Latinos, and Hispanics who smoke.44 Specifically, nicotine patches, nicotine nasal sprays, and bupropion were effective in African Americans who smoke, whereas the nicotine patch alone was effective for Hispanics who smoke.44 Nicotine gum has not demonstrated efficacy in 3 studies with African Americans who smoke, and trials have not been conducted with nicotine lozenges, inhalers, or combination nicotine-replacement therapy.44 Regardless of the outcomes of efficacy trials, real-world effectiveness and use of pharmacotherapy must be considered. Qualitative research conducted by Fu et al55 with minorities who smoke (African Americans, American Indians, and Southeast Asians) revealed that knowledge is lacking about how pharmacotherapy works as well as the skepticism regarding the effectiveness of smoking cessation. These beliefs may explain the low utilization of pharmacotherapy among racial and ethnic minorities who smoke.56 Further research on the beliefs and barriers of racial and ethnic differences regarding pharmacotherapy may aid in the development of strategies to increase use of cessation methods. October 2016, Vol. 23, No. 4 Tested modalities for behavioral interventions have included both group and individual counseling.46,54 In a randomized trial, Webb et al57 found that African Americans who smoked and received group-based cognitive behavioral therapy to help them quit smoking had higher cessation rates than African Americans who smoked and were involved in a general health education group that controlled for contact and intensity. In addition to support for group therapy, researchers concluded that individual counseling (in-person and on the telephone) was effective for aiding smoking cessation among racial and ethnic minorities.44 Some research has focused on the development of culturally adapted smoking cessation interventions that take into account unique cultural characteristics.44 However, little research has been conducted to evaluate the effectiveness of culturally adapted or culturally specific interventions compared with generic interventions. Select studies conducted with African Americans who smoke have been mixed.20,58-62 One study found evidence of a greater level of interest and attention for culturally specific materials, yet readiness to quit and cessation attempts were greater for the standard materials.58 By contrast, a study conducted with African Americans who smoke found greater rates of smoking abstinence at a 12-month follow-up period among participants who received culturally tailored materials than those who received standard materials.59 Other studies have also demonstrated the benefits of culturally tailored interventions for Hispanics who smoke.60,61 Overall, researchers have reported that study participants are generally accepting of interventional materials that include information about cultural adaptation, yet additional research is needed to determine whether such cultural tailoring is superior to standard materials to improve smoking cessation rates among minorities.20,58,62 Cancer Diagnosis Higher rates of cancer morbidity and mortality are evident among racial/ethnic minorities and those with low socioeconomic status.21 Several pathways exist in which the relationship between tobacco and cancer health disparities can present. A higher risk of tobaccorelated cancers among persons who smoke and have low incomes could, in part, be a function of higher smoking prevalence rates. Although the overall prevalence of smoking has declined to 16.8%, low-income individuals who smoke (ie, household income below the poverty level) have a smoking prevalence rate of 30.4%.63 Other pathways are less clear. Referred to as the “smoker’s paradox,” African Americans smoke fewer cigarettes per day and are less likely to smoke daily, yet they have higher rates of lung, esophageal, and oral cancers than non-Hispanic whites who smoke.64 Cancer Control 437 Disparities in Lung Cancer Lung cancer is the leading cause of cancer-related deaths in the United States, and 80% of these deaths are attributable to cigarette smoking.2 African Americans have the highest lung cancer incidence and mortality rates compared with all other racial and ethnic groups.3,21 Risk factors for poor cancer outcomes have been attributed to several factors such as treatment access and lower socioeconomic status, as well as smoking-related factors.22 The disproportionate burden in lung cancer risk among African Americans cannot be explained by a greater number of cigarettes smoked.64 However, a distinguishing smoking behavior among African Americans who smoke, which may aid in explaining disparate disease outcomes, is that African Americans are more likely to smoke menthol cigarettes than whites.3 As part of the 2009 Family Smoking Prevention and Tobacco Control Act, the Tobacco Products Scientific Advisory Committee of the US Food and Drug Administration was tasked with submitting a report on the impact of menthol.65 Findings from that report suggest that little evidence exists to demonstrate that menthol contributes to greater disease risk; however, menthol cigarettes may have more addictive qualities than nonmenthol cigarettes, which could contribute to low rates of smoking cessation.3,65 Menthol also has cooling and anesthetic effects that reduce the harshness of cigarette smoke.65 Use of menthol cigarettes is also associated with increased initiation and progression to cigarette smoking and difficulty quitting smoking.65 Based on these findings, the Tobacco Products Scientific Advisory Committee concluded that no longer selling menthol cigarettes would be of a public health benefit.65 However, more research is needed to further examine the potential role that menthol plays in the unequal disease burden experienced by African Americans.3 Specifically, as noted by Alexander et al,64 research is needed on examining additional pathways such as the role of taste sensitivity and the effects of menthol on cellular mechanisms and subsequent disease processes. Role of Beliefs About Lung Cancer Research suggests that beliefs about lung cancer may differ by race/ethnicity. Compared with whites, African Americans have lower perceived notions of risk for lung cancer and are more likely to doubt the relationship between lung cancer and behavior.66,67 African Americans also have demonstrated greater skepticism regarding surgical treatment for lung cancer.68,69 Moreover, the belief that exposure to air during surgery can cause the tumor to spread and fatalistic beliefs (eg, “If I have lung cancer, I believe it was meant to be”) may serve as barriers to accepting surgical intervention among racial and ethnic minorities.68,69 These 438 Cancer Control findings underscore the need to understand perceptions of lung cancer by race/ethnicity to identify potential barriers to smoking cessation and lung cancer treatment. Challenges in Screening Based on evidence from the National Lung Cancer Screening Trial, low-dose computed tomography for lung cancer screening provides an opportunity to reduce the rate of lung cancer mortality.70 A concern raised by Holford et al71 is that the 30 pack-years’ eligibility criteria required by the US Preventive Services Task Force and Centers for Medicare & Medicaid Services may result in fewer screenings for African American men who smoke and have fewer pack years. African Americans have also been found to be more reluctant to get screened for lung cancer due to fear of the disease.66 Thus, it is possible that unequal implementation of newer screening modalities and heightened fears of disease may broaden cancer disparities. Head and Neck Cancers Tobacco use is a major risk factor for the development of head and neck cancers: 75% of all head and neck cancers are attributable to tobacco and alcohol use.72 Molina et al23 examined survival rates of head and neck cancers based on race/ethnicity and socioeconomic status. Their findings suggested that, compared with non-Hispanic whites, African Americans were diagnosed with head and neck cancers at a younger age and at more advanced-disease stages.23 In addition, the average survival time for African American patients was significantly lower than whites (21 vs 40 months).23 Poor survival outcomes in African Americans were observed despite the lack of difference in the frequency of smoking. Living in an area of high poverty was found to be an independent predictor of worse outcomes.73 Poor cancer outcomes among patients from impoverished communities has also been attributed to lack of access to health care, decreased likelihood of insurance coverage, and advanced disease at presentation.73 Among Hispanics and Latinos, incidence and mortality rates of head and neck cancers are lower than both African Americans and non-Hispanic whites.74 Cancer Survivorship Once an individual who smokes has been diagnosed with cancer, he or she may mistakenly believe that it is too late to quit smoking; however, a growing body of research suggests that patients with cancer who continue to smoke are at risk for several adverse health outcomes.1 The 2014 report of the US Surgeon General concluded that sufficient evidence has accumulated to infer a causal relationship between individuals with cancer who smoke cigarettes and cancer October 2016, Vol. 23, No. 4 survivors for both all-cause mortality and cancer-specific mortality.1 Evidence also suggests that continued smoking results in an increased risk for second primary cancers known to be caused by cigarette smoking, and, although this evidence is insufficient to infer a causal relationship, an association does exist between cigarette smoking and risk of cancer recurrence, poor response to treatment, and increased rates of cancer treatment-related toxicity.1 Because racial and ethnic minorities are more likely to be diagnosed with late-stage tobacco-related cancers, it is possible that they could be particularly vulnerable to the adverse effects of continued smoking. Park et al22 reported that smoking cessation represents a modifiable risk factor that could result in better treatment outcomes in African Americans with lung cancer by improving rates of treatment efficacy and quality of life. Given the strong associations between continued smoking and cancer outcomes, organizations such as the American Society of Clinical Oncology and American Association for Cancer Research have called for smoking cessation assistance to be provided to cancer survivors.75 The National Comprehensive Cancer Network also established practice guidelines for smoking cessation that call for all patients with cancer to receive evidence-based smoking cessation interventions.76 Implementation of the 5As model for a brief cessation intervention has been suboptimal in the oncology setting.8,24,25,77 Although the “ask” and “advise” steps are often implemented, the remaining 3 steps are not routinely completed.8,24 A review of members of the American Society of Clinical Oncology reported that 44% of its members surveyed said they discuss medication options for smoking cessation, and 39% said they provided smoking cessation treatment.24 These findings coincide with patient reports of low levels of cessation assistance provided by oncology specialists.77 Because racial and ethnic minorities who smoke are generally less likely to receive assistance from their physicians in quitting smoking, it is plausible that this assistance may also not occur in the oncology setting.18,19 Perceptions of inadequate training in tobacco cessation interventions and low rates of self-efficacy in helping patients to quit have been cited barriers to cessation support by health care professionals.24 These findings suggest a need for improved education and training of health care professionals to better convey the rationale for smoking cessation and to develop strategies to implement smoking cessation into clinical care. In the absence of health care professional training, and taking into consideration the constraint of time, an alternative ask–advise–refer model may be more feasible to implement.25 This model involves asking about tobacco use, advising the patient to quit, and then referring the patient to existing, evidence-based resources (eg, national tobacco quit line [800-QUIT-NOW]). October 2016, Vol. 23, No. 4 Despite the importance of quitting smoking for individuals with cancer, few clinical trials of smoking cessation have been conducted in this population. In a systematic review and meta-analysis, 10 randomized controlled trials and 3 prospective cohort studies were evaluated.26 Studies included a range of nonpharmacological (eg, counseling, self-help) and pharmacological (eg, nicotine-replacement therapy) interventions.26 Overall, findings indicated that tobacco cessation interventions in the oncology setting were not significantly different from usual care, suggesting the need for additional research to enhance smoking cessation among patients with cancer.26 Although a single smoking cessation trial demonstrated feasibility of recruiting African American patients, most smoking cessation trials conducted in the oncology setting have had low representation of racially and ethnically diverse patients.26,27 To our knowledge, cessation interventions are not available and have not been tested in Spanish-speaking patients. Thus, as new interventions are developed and tested in the oncology setting, the inclusion of racial and ethnic minorities is imperative to extend the generalizability of findings and reduce tobacco-related cancer disparities. Conclusions Racial and ethnic minorities experience shared social and environmental contextual factors that impact the initiation and maintenance of smoking, and the potential for tobacco-related health disparities exist at each point of the oncology care continuum. Thus, a comprehensive strategy for reducing health disparities must call for future research efforts at each of these points. Health disparities exist in the incidence and mortality of the 2 most strongly associated tobacco-related cancers, namely lung and head and neck cancers.2,3,21,23,72-74 Future research is needed to elucidate the causes of these disparities. As new cancer screening tools become available, attention must be paid to prevent the widening of health disparities due to unequal implementation. Overall rates of smoking cessation tend to be lower among racial and ethnic minorities.46,49 Culturally adapted interventions are more acceptable44,46; however, research has not yet supported their effectiveness when compared with standard materials.55,61 Future research efforts should be directed at increasing the use of treatment and greater rates of efficacy in these vulnerable populations. Individuals with cancer must also be provided with cessation assistance and interventions aimed at helping them quit smoking to improve cancer outcomes.75,76 Additional education and training are needed for oncologists so they can begin to understand the impact of continued smoking for patients as well as to increase their comfort level for providing smoking cessation treatment to their patients who need it.25 Due to the disproportionate disease burden experienced by Cancer Control 439 African Americans and other underserved populations who smoke, future trials on smoking cessation interventions must include diverse racial and ethnic patient populations and those cessation tools should be validated for use in all vulnerable patient populations.3,26,27 References 1. US Department of Health and Human Services. The Health Consequences of Smoking: 50 Years Of Progress. A Report of the Surgeon General. 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Race and lung cancer surgery--a qualitative analysis of relevant beliefs and management preferences. Oncol Nurs Forum. 2010;37(6):740-748. 69.Jonnalagadda S, Bergamo C, Lin JJ, et al. Beliefs and attitudes about lung cancer screening among smokers. Lung Cancer. 2012;77(3):526-531. 70. Aberle DR, Adams AM, Berg CD, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365(5):395-409. 71. Holford TR, Levy DT, Meza R. Comparison of smoking history patterns among African American and white cohorts in the United States born 1890 to 1990. Nicotine Tob Res. 2016;18(suppl 1):S16-S29. 72. Blot WJ, McLaughlin JK, Winn DM, et al. Smoking and drinking in relation to oral and pharyngeal cancer. Cancer Res. 1988;48(11):3282-3287. 73. Conway DI, Petticrew M, Marlborough, et al. Socioeconomic inequalities and oral cancer risk: a systematic review and meta-analysis of case-control studies. Int J Cancer. 2008;122(12):2811-2819. 74. Fagan P, Moolchan ET, Lawrence D, et al. Identifying health disparities across the tobacco continuum. Addiction. 2007;102(suppl 2):5-29. 75. Toll BA, Brandon TH, Gritz ER, et al. Assessing tobacco use by cancer patients and facilitating cessation: an American Association for Cancer Research policy statement. Clin Cancer Res. 2013;19(8):1941-1948. 76. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Smoking Cessation. v.2.2015. https://www.nccn.org/ professionals/physician_gls/pdf/smoking.pdf. Accessed August 4, 2016. 77. Simmons VN, Litvin EB, Unrod M, et al. Oncology healthcare providers’ implementation of the 5A’s model of brief intervention for smoking cessation: patients’ perceptions. Patient Educ Couns. 2012;86(3):414-419. October 2016, Vol. 23, No. 4 Cancer Control 441 Case Series Human Metapneumovirus Infection in Immunocompromised Patients Sharmeen Samuel, MD, Sowmya Nanjappa, MBBS, MD, Christopher D. Cooper, MD, and John N. Greene, MD Summary: Human metapneumovirus (HMPV) is a pathogen associated with respiratory tract infection and is related to avian pneumovirus. Typically, children, the elderly, and those who are immunocompromised are the most susceptible to HMPV infection; however, the virus can infect persons of all ages. In otherwise healthy individuals, HMPV infection is generally self-limiting, but immunocompromised individuals can develop fatal complications. We present a case series of 3 severely immunocompromised patients who were infected with HMPV and describe their clinical course. All 3 patients had acute myeloid leukemia, histories of neutropenic fever, and prolonged hospitalization stays. This case series highlights the severe sequelae observed in individuals infected with HMPV, particularly among those who are immunocompromised. Introduction In 2001, van den Hoogen et al1 identified human metapneumovirus (HMPV) in children with respiratory tract infection, because they were able to obtain a genomic sequence of the pathogen via randomly primed polymerase chain reaction (PCR). The virus was found to be related to avian pneumovirus, a member of the Metapneumovirus genus.2 HMPV is an emerging pathogen associated with both upper and lower respiratory tract infections in all age groups, but it is more common in children (age < 5 years), in the elderly (age > 60 years), and in those with compromised immune systems.3,4 Although its formal discovery occurred 15 years ago, HMPV may have been responsible for respiratory tract infections for at least 60 years. 1 Case Reports This series presents the cases of 3 immunocompromised patients treated at the H. Lee Moffitt Cancer Center & Research Institute (Tampa, FL) who were infected with HMPV. A summary of the case series is found in the Table. Case 1 A Hispanic woman 47 years of age with acute myeloid leukemia (AML) had a clinical course complicated by central nervous system malignancy, bacterial enteritis, and diffuse alveolar and left-sided retinal hemorrhages. She was taking cladribine, cytarabine, and growthFrom the Departments of Internal Medicine (SS, SN) and Infectious Diseases (JNG), H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, the Department of Infectious Diseases (CDC), Florida Hospital, Altamonte Springs, Florida. Submitted February 17, 2016; accepted May 31, 2016. Address correspondence to John N. Greene, MD, Department of Infectious Diseases, Moffitt Cancer Center, 12902 Magnolia Drive, FOB-3 BMT PROG, Tampa, FL 33612. E-mail: [email protected] No significant relationships exist between the authors and the companies/organizations whose products or services may be referenced in this article. 442 Cancer Control factor therapy for AML and received multiple doses of intrathecal methotrexate. Three months later she was readmitted to the hospital for blast crisis and reinduction chemotherapy. During that admission, she developed bacteremia with vancomycin-resistant enterococcus and Streptococcus mitis. She was subsequently treated with daptomycin, liposomal amphotericin B, cefepime, and acyclovir. One month later she developed intermittent hemoptysis and mild dyspnea on ambulation that progressed to hypoxia (oxygen saturation = 90% on room air). She also experienced confusion, fever (temperature = 105.5 °F), bilateral scattered rhonchi, and crackles on auscultation. Noncontrast computed tomography (CT) of the thorax was obtained and revealed new focal consolidative infiltrates, including increased peripheral, dense consolidation of the right middle, left upper, and left lower lobes, widespread ill-defined nodules, and ground-glass infiltrates due to alveolar hemorrhage (Fig). Bronchoalveolar fluid cultures obtained by bronchoscopy were negative for bacteria and fungi. However, HMPV was detected by PCR from nasopharynx swab sampling. Findings on PCR testing of other viral agents (adenovirus, influenza, parainfluenza, and rhinoviruses) were negative. The patient was treated with oral ribavirin (RBV) 600 mg 3 times a day. After 14 days of therapy, her condition clinically improved and oxygen therapy was discontinued. Repeat CT showed improved multifocal pneumonia compared with the findings on the initial imaging study. Case 2 An African American man 61 years of age with hepatitis B virus infection and non-Hodgkin lymphoma presented with fever and chills. Laboratory work-up studies were ordered and the results revealed pancytopenia. Findings on bone marrow biopsy were conclusive of AML. He was treated with cladribine, cytarabine, and October 2016, Vol. 23, No. 4 Table. — Summary of the Case Series Case No. Underlying Malignancy Etiology of Immunocompromised State Clinical Signs and Symptoms Treatment Outcome 1 AML CNS Chemotherapy Dyspnea Fever Hemoptysis Oral RBV 600 mg TID Survived 2 AML NHL Chemotherapy Cough Dyspnea Fever Oral RBV 600 mg TID Died 3 AML Chemotherapy Cough Dyspnea Fever Oral RBV 600 mg TID Died AML = acute myeloid leukemia, CNS = central nervous system, NHL = non-Hodgkin lymphoma, RBV = ribavirin, TID = 3 times a day. growth factors and eventually achieved remission. Several months later, bone marrow biopsy was repeated, the results of which showed that the AML had relapsed; thus, cycle 1 of azacitidine therapy was initiated. The treatment course was complicated by pneumonia (presumed to be fungal in origin based on findings seen on CT of his chest). The patient was given daily liposomal amphotericin B to treat pneumonia. On his hospital readmission for the second cycle of azacitidine, the patient developed submandibular cellulitis, transaminitis, and became infected with type 1 herpes simplex virus and respiratory syncytial virus. He was treated with intravenous meropenem every day for 6 weeks, weekly liposomal amphotericin B, acyclovir, and lamivudine. However, his clinical course was complicated by neutropenic fever and worsening dyspnea. Blood cultures grew Enterococcus faecium and multi–drug-resistant S maltophilia. Samples on bronchoscopy were positive for S maltophilia and Candida glabrata. He was treated with intravenous daptomycin and minocycline. Blood cultures were repeated and the results were negative after 6 days. However, the patient again developed fever (temperature = 102.5 °F), dry cough, and hypoxia (oxygen saturation = 92% on room air). Respiratory viral panel was repeated and HMPV was detected in his nasopharynx swab specimen. He was treated with oral RBV 600 mg 3 times a day. The patient died 4 days after the start of therapy. Case 3 A Hispanic man 54 years of age with relapsed AML was admitted to the hospital for induction chemotherapy and was treated with cladribine, cytarabine, and growth-factor therapy. One week later while on neutropenic prophylaxis (ciprofloxacin, voriconazole, and acyclovir), the patient developed cough, mild dyspnea (oxygen saturation = 94% on room air), and fever (temperature = 103.0 °F). Although findings on CT of the chest revealed bilateral patchy and nodular opacities consistent with an infectious process, sputum and bronOctober 2016, Vol. 23, No. 4 Fig. — Computed tomography of the chest from the patient in case 1. Findings show focal consolidative infiltrates and dense peripheral consolidation in the left upper and lower lobes. choalveolar fluid cultures were negative for bacteria and fungi. However, findings on respiratory viral panel from nasopharynx sampling were positive for HMPV. The patient was treated with oral RBV 600 mg 3 times a day. Repeat CT of his chest showed extensive bilateral ground-glass nodules consistent with bronchiolitis obliterans organizing pneumonia. His clinical presentation initially improved after oral RBV therapy, but he presented again with high-grade fever, tachycardia, and hypotension. He was started on meropenem, tobramycin, voriconazole, and acyclovir. Blood cultures were obtained and grew Escherichia coli. Despite aggressive treatment with antibiotics, the patient died the following day from septic shock. Discussion HMPV is an enveloped virus with a nonsegmented, negative-sense RNA genome.1 Genetic analysis has elucidated 2 subgroups of the virus that often circulate together in a population.5 Although the virus is related to avian pneumovirus, HMPV does not cause illness in birds.4,6 Study results have shown that the inoculaCancer Control 443 tion of HMPV in other nonhuman primates can lead to significant viral replication restricted to the respiratory tract with the subsequent development of upper respiratory tract symptoms.7 HMPV is commonly associated with respiratory tract infection, causing flulike symptoms, bronchiolitis, and pneumonia. HMPV infection may also be associated with exacerbations of asthma.8 The data available are limited on the association of HMPV with infections of other organ systems beyond the respiratory tract. In a case report concerning a previously healthy child 14 months of age who died of encephalitis, HMPV RNA was detected in both brain and lung tissue, although HMPV antigens went undetected in these tissues via immunostaining.9 Several studies have demonstrated the presence of HMPV and absence of other pathogenic organisms among patients with respiratory disease.8,10 Williams et al11 examined the nasal-wash specimens from children with lower respiratory tract infections during a 25-year period. A viral cause other than HMPV was identified in 41% of health care visits among 2,009 otherwise healthy infants and children presenting with acute symptoms.11 No viral or bacterial cause was identified in 59% of visits; of the available specimens for which no cause was previously identified, 20% tested positive for HMPV.11 This finding extrapolates to 12% of lower respiratory tract infections in their patient population. Thus, Williams et al11 concluded that HMPV infection is an important cause of respiratory tract illness, particularly during the first few years of life. In general, transmission of HMPV is through direct or close contact via large-particle aerosols, droplets, and fomites.12 Many nosocomial infections have been reported in children and adults.13 Case 2 most likely represents a nosocomial infection, because the patient in this case was hospitalized for a prolonged duration prior to developing symptoms. HMPV infection also causes a variable array of clinical symptoms, including self-limiting cough, low-grade fever, rhinorrhea, severe respiratory failure, and death.14 The incubation period has not yet been defined but is thought to be 5 to 6 days in most cases.15 Little is known about the pathogenesis of HMPV, but an integrin alpha v beta 1 receptor has been identified that facilitates infection of the epithelial cells of the respiratory tract.16 The most common reasons for hospitalization in children are bronchiolitis and pneumonia. Although HMPV has been associated with upper respiratory tract infections (rhinopharyngitis, laryngitis, croup), severe lower respiratory tract infection has been reported.8 The infection can occur in adults of all ages, although elderly persons with histories of long hospitalization stays and cardiopulmonary disease are at greater risk for becoming infected.5 The possible role of HMPV in the exacerbation of chronic obstructive pulmonary disease in adults is controversial.17 444 Cancer Control Respiratory tract infections are a significant source of morbidity and mortality in immunocompromised patients, and this is especially true for individuals with hematological malignancies and in those receiving hematopoietic stem cell transplantation (HSCT).18 Prospective and retrospective studies of patients receiving HSCT have provided data on the incidence of upper and lower respiratory tract infections caused by HMPV infection and the associated mortality rates.19,20 In these studies, cohorts of symptomatic and asymptomatic patients with HSCT were followed for 4 years, and the virus was identified through PCR testing of nasopharyngeal specimens.19,20 The incidence rates of HMPV infections in patients receiving HSCT ranged from 3% to 7% in those with any respiratory disease, whereas the rate increased to between 27% and 41% among patients with lower respiratory disease.19,20 The rate of deaths associated with lower respiratory tract infection was between 33% and 40%, and the rate of deaths related to overall infections (upper and lower respiratory tracts) was between 0% and 14%.19 In the retrospective study, bronchoalveolar lavage specimens were obtained for the work-up of pulmonary infiltrates from 163 patients after receiving HSCT; of these, 3% were positive for HMPV and 20% of patients died due to respiratory failure.20 These results highlight the potential severity of HMPV-related pneumonia in recipients of HSCT. Because many such patients have concurrent bacterial and fungal infections, describing the exact clinical features of HMPV infection can be difficult. HMPV infection has important associations with respiratory tract illness in patients with hematological malignancies and in those who have received lung transplants.21,22 A retrospective evaluation of 55 children (age range, 5 months–19 years) with laboratory-confirmed HMPV infection highlighted a number of associations. HMPV infection was associated with underlying hematological malignancy (44%), HSCT (15%), solid tumors (16%), and solid organ transplants (15%).21 Another report showed that 25% of study patients with hematological disease who tested positive for HMPV infection also had pneumonia.22 A review by Kamboj et al23 of 1,899 study patients with cancer showed that nearly 3% were positive for HMPV; more children were positive than adults. To diagnose HMPV infection, reverse transcriptase (RT)-PCR is the most sensitive and commonly used method available; it detects the virus in nasal and bronchial secretions and is easy to perform.24 Other less-commonly used methods for detecting the virus include direct fluorescent antibody test, serology, and viral culture. The incidence of HMPV infection increases during the winter and spring.25 Patients in cases 1 and 2 in our series were infected with HMPV in June 2015, and the patient in case 3 was infected in May 2014. Prior infection with HMPV does not protect against reinfection, October 2016, Vol. 23, No. 4 which can occur throughout life.4 A live recombinant vaccine for HMPV is still in preclinical trials.26 However, we must learn more about its pathogenesis, genetics, and serological properties to achieve a safe and effective vaccine against HMPV. Treatment for HMPV infection is mainly supportive, and no data exist on any antiviral agent shown to have significant activity against the virus. No guidelines are available for treatment, but some centers use RBV and intravenous immunoglobulin; however, the usefulness of RBV in HMPV infection is controversial.27 Some animal models have shown that RBV reduces viral replication in HMPV-infected mice,28 and use of RBV to successfully treat the infection in humans has been previously described.29 Other study data show that RBV does not reduce mortality in immunocompromised patients and is not effective against the virus.30 Although case 1 in our series is an example of successful treatment against HMPV using oral RBV, this finding does not establish a beneficial effect of RBV against HMPV infection. Conclusions Discovered 15 years ago, human metapneumovirus (HMPV) can cause respiratory tract infections.1 Although data have been published on the prevalence of the virus in high-risk groups (eg, children < 5 years of age, persons > 60 years of age with comorbidities [eg, cardiopulmonary diseases], immunocompromised individuals), important information on the immunological properties and pathogenesis of the virus is still unknown.5 This case series presents the clinical courses of 3 severely immunocompromised patients infected with HMPV and describes the impact of the virus on their disease course. Infection with HMPV can add to the severity of an underlying malignancy, especially in immunocompromised patients, and can be a contributing factor toward the death of such patients. Therefore, it is important to prevent this viral infection in immunocompromised individuals. Measures to control such infection, including avoiding contact with large-particle aerosols and droplets, practicing proper hand hygiene, and, when possible, limiting the visitation of persons who are ill, can all help to prevent the spread of HMPV. A need exists for recommendations to guide treatment for HMPV infection in high-risk patient groups, such as the severely immunocompromised patients presented in this case series. Development of an HMPV vaccine is a reasonable goal for the prevention of this pathogen. Acknowledgment: We gratefully acknowledge the help of Peter P. Karpawich, MD, from the Detroit Medical Center in Michigan for reviewing this case series. References 1. van den Hoogen BG, de Jong JC, Groen J, et al. A newly discovered human pneumovirus isolated from young children with respiratory October 2016, Vol. 23, No. 4 tract disease. Nat Med. 2001;7(6):719-724. 2. Fauquet CM, Mayo MA, Maniloff J, et al, eds; Virology Division International Union of Microbiological Societies. Virus Taxonomy: Classification and Nomenclature of Viruses. Eighth Report of the International Committee on Taxonomy of Viruses. Oxford, UK: Elsevier Academic Press; 2005. 3. Kahn JS. Epidemiology of human metapneumovirus. Clin Microbiol Rev. 2006;19(3):546-557. 4. Falsey AR, Walsh EE. Viral pneumonia in older adults. Clin Infect Dis. 2006;42(4): 518-524. 5. Boivin G, Mackay I, SlootsTP, et al. Global genetic diversity of human metapneumovirus fusion gene. Emerg Infect Dis. 2004;10(6):1154-1157. 6. Njenga MK, Lwamba HM, Seal BS. Metapneumovirus in birds and humans. Virus Res. 2003;91(2):163-169. 7. Boivin G, DeSerres G, Côté S, et al. Human metapneumovirus infections in hospitalized children. Emerg Infect Dis. 2003;9(6):634-640. 8. Mullins JA, Erdman, DD, Weinberg GA, et al. Human metapneumovirus infection among children hospitalized with acute respiratory illness. Emerg Infect Dis. 2004;10(4):700-705. 9. Schildgen O, Glatzel T, Geikowski T, et al. Human metapneumovirus RNA in encephalitis patient. Emerg Infect Dis. 2005;11(3):467-470. 10. Williams JV, Wang CK, Yang CF et al. The role of hMPV in upper respiratory tract infections in children: a 20 year experience. J Infect Dis. 2006;193(3):387-395. 11. Williams JV, Harris PA, Tollefson SJ, et al. Human metapneumovirus and lower respiratory tract disease in otherwise healthy infants and children. N Engl J Med. 2004;350(5):443-450. 12. Williams JV. Human metapneumovirus: an important cause of respiratory disease in children and adults. Curr Infect Dis Rep. 2005;7(3):204-210. 13. van Dijk NM, Linssen, CF, Bussink M, et al. Critical illness after horizontal nosocomial transmission of human metapneumovirus in the haemotology ward. Neth J Crit Care. 2012;16(1):22-25. http://njcc.nl/sites/default/ files/NJCC%2001%20casereport-vDijk.pdf. Accessed August 24, 2016. 14. Xepapadaki P, Psarras S, Bossios A, et al. Human metapneumovirus as a causative agent of acute bronchiolitis in infants. J Clin Virol. 2004;30(3):267-270. 15. Centers for Disease Control and Prevention. Outbreaks of human metapneumovirus in two skilled nursing facilities-West Virginia and Idaho, 2011-2012. MMWR Morb Mortal Wkly Rep. 2013;62(46):909-913. 16. Cseke G, Maginnis MS, Cox RG, et al. Integrin alphabeta1 promotes infection by human metapneumovirus. Proc Natl Acad Sci USA. 20093;106(5):1566-1571. 17. Hamelin ME, Côté S, Laforge J, et al. Human metapneumovirus infection in adults with community acquired pneumonia and exacerbation of chronic obstructive pulmonary disease. Clin Infect Dis. 2005;41(4):498-502. 18. Renaud C, Campbell AP. Changing epidemiology of respiratory viral infections in hematopoietic cell transplant recipients and solid organ transplant recipients. Curr Opin Infect Dis. 2011;24(4):333-343. 19. Milano F, Campbell AP, Guthrie KA, et al. Human rhinovirus and coronavirus detection among allogeneic hematopoietic stem cell transplantation recipients. Blood. 2010;115(10):2088-2094. 20. Englund JA, Boeckh M, Kuypers J, et al. Brief communication: fatal human metapneumovirus infection in stem cell transplant recipients. Ann Intern Med. 2006;144(5): 344-349. 21. Chu HY, Renaud C, Ficken E, et al. Respiratory tract infections due to human metapneumovirus in immunocompromised children. J Pediatric Infect Dis Soc. 2014;3(4):286-293. 22. Godet C, Le Goff J, Beby-Defaux A, et al. Human metapneumovirus pneumonia in patients with hematological malignancies. J Clin Virol. 2014;61(4):593-596. 23. Kamboj M, Gerbin M, Huang CK, et al. Clinical characterization of human metapneumovirus infection among patients with cancer. J Infect. 2008;57(6):464-471. 24. Côté S, Abed Y, Boivin G. Comparative evaluation of real-time PCR assays for detection of human metapneumovirus. J Clin Microbiol. 2003;41(8):3631-3635. 25. Caracciolo S, Minni C, Colombrita D, et al. Human metapneumovirus infection in young children hospitalized with acute respiratory tract disease: virologic and clinical features. Pediatr Infect Dis J. 2008;27(5):406-412. 26. Buchholz UJ, Nagashima K, Murphy BR, et al. Live vaccines for human metapneumovirus designed by reverse genetics. Expert Rev Vaccines. 2006;5(5):695-706. 27. Hirsch HH, Martino R, Ward KN, et al. Fourth European Conference on Infections in Leukaemia (ECIL-4): guidelines for diagnosis and treatment of human respiratory syncytial virus, parainfluenza virus, metapneumovirus, rhinovirus, and coronavirus. Clin Infect Dis. 2013;56(2):258-266. 28. Hamelin ME, Prince GA, Boivin G. Effect of ribavirin and glucocorticoid treatment in a mouse model of human metapneumovirus infection. Antimicrob Agents Chemother. 2006;50(2):774-777. 29. Kitanovski L, Kopriva S, Pokorn M, et al. Treatment of severe human metapneumovirus pneumonia in an immunocompromised child with oral ribavirin and IVIG. J Pediatr Hematol Oncol. 2013;35(7):e311-e313. 30. Debur MC, Vidal LR, Stroparo E, et al. Human metapneumovirus infection in hematopoietic stem cell transplant recipients. Transpl Infect Dis. 2010;12(2):173-179. Cancer Control 445 Special Report Systematic Review and Case Series Report of Acinar Cell Carcinoma of the Pancreas Evan S. Glazer, MD, PhD, Kevin G. Neill, MD, Jessica M. Frakes, MD, Domenico Coppola, MD, Pamela J. Hodul, MD, Sara E. Hoffe, MD, Jose M. Pimiento, MD, Gregory M. Springett, MD, PhD, and Mokenge P. Malafa, MD, PhD Background: Acinar cell carcinoma of the pancreas is a rare malignancy representing less than 1% of all pancreatic malignancies. Methods: We report on a case series of 21 patients with acinar cell carcinoma of the pancreas treated at a high-volume quaternary center. A systematic review of the medical literature was performed that described typical therapeutic management approaches for acinar cell carcinoma of the pancreas and reported on disease control and survival rates. Data for the case series were obtained from a prospective database. Results: In our systematic review of 6 articles, study patients had a median age of 61 years, 66% were male, 52% had stage I/II disease, and 55% of lesions were located in the pancreatic head. The rates of median survival were approximately 47 months after resection with adjuvant therapy, 38 months for nonmetastatic, locally unresectable disease, and 17 months for metastatic disease treated with chemotherapy. Combination fluoropyrimidine-based chemotherapy regimens had better rates of disease control than other therapies. Our case series included 21 study patients, 14 of whom required resection and 7 who had metastatic disease. The rates of median survival were 40.2 ± 31.9 months in those who underwent surgery and were treated with adjuvant therapy and 13.8 ± 11.3 months for patients with metastatic disease. Conclusions: Multidisciplinary treatment for acinar cell carcinoma of the pancreas should be considered due to the rarity of the disease and its lack of high-level therapeutic data. Progress in the molecular analysis of this tumor may improve outcomes through the use of personalized therapy based on underlying tumor mutations. Introduction Acinar cell carcinoma of the pancreas is a rare exocrine malignancy representing less than 1% of all pancreatic neoplasms.1 The exocrine pancreas is primarily composed of ductal cells and acinar cells. Acinar cells are enzyme-secreting cells that release amylase, lipases, and proteases. Debate exists regarding whether acinar cell carcinoma of the pancreas is unique from pancreatic ductal adenocarcinoma2,3; however, acinar cell carcinoma of the pancreas responds to treatment differently than pancreatic ductal adenocarcinoma and its rates of overall survival are not similar4 — data suggesFrom the Departments of Gastrointestinal Oncology (ESG, PJH, JMP, MPM), Pathology (KGN, DC, GMS), and Radiation Oncology (JMF, SEH), H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida. Submitted February 18, 2016; accepted May 31, 2016. Address correspondence to Mokenge P. Malafa, MD, PhD, Department of Gastrointestinal Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, FOB-2 GI PROG, Tampa, FL 33612. E-mail: [email protected] Dr Glazer is now affiliated with the Division of Surgical Oncology in the Department of Surgery at the University of Tennessee Health Sciences Center, Memphis, Tennessee. No significant relationships exist between the authors and the companies/organizations whose products or services may be referenced in this article. 446 Cancer Control tive that it is a distinct entity. The rarity of acinar cell carcinoma of the pancreas, lack of high-quality evidence, and its diagnostic difficulty have all limited consensus among authors regarding the most appropriate management of this disease.5-7 Although patients who have undergone resection for acinar cell carcinoma of the pancreas may appear to have higher survival rates than patients with pancreatic ductal adenocarcinoma3,4 — whose median survival rate is between 4 and 5 years1 — the limited and selection-biased data make assertions difficult. Nonsurgical treatment options for patients with acinar cell carcinoma of the pancreas include chemotherapy and radiotherapy. Use of various chemotherapeutic agents, including capecitabine monotherapy and folinic acid/fluorouracil/oxaliplatin (FOLFOX), have been reported in the literature.8,9 Whether radiotherapy improves survival rates in patients with acinar cell carcinoma of the pancreas remains unclear.10-12 Case reports of the use of radiotherapy to treat acinar cell carcinoma of the pancreas have noted an association with extended rates of survival.8,13 The patterns of genetic alterations and specific driver mutations in patients with acinar cell carcinoma of the pancreas are not well described in the literature. Studies have demonstrated lower rates of October 2016, Vol. 23, No. 4 EGFR and KRAS mutations in acinar cell carcinoma of the pancreas than in pancreatic ductal adenocarcinoma.14 Some have suggested that pancreatic ductal adenocarcinoma may develop from acinar cells that undermutate p53 without evidence of developing acinar cell carcinoma of the pancreas.15 In addition, nearly one-half of acinar cell carcinoma of the pancreas tumors have alterations in APC.16 Unlike pancreatic ductal adenocarcinoma, KRAS mutation is infrequently a driving force in acinar cell carcinoma of the pancreas; however, chromosomal imbalances are common in acinar cell carcinoma of the pancreas.14 Whole-exome sequencing has revealed that mutations in BRCA2 and the FAT family are common in patients with acinar cell carcinoma of the pancreas, but these mutations are not yet readily targetable.17 p53 expression has been demonstrated as both a positive and negative prognostic indicator in acinar cell carcinoma of the pancreas.18 More than 70% of tumors of the acinar cell carcinoma of the pancreatic type demonstrated a decrease or complete loss of DCC expression on immunohistochemistry.14 Bergmann et al14 also suggested that DCC variation is an early genetic change in acinar cell carcinoma of the pancreas, whereas others have suggested that it is a late change in pancreatic ductal adenocarcinoma.19 Purpose The purpose of this systematic review is to delineate the most appropriate treatment and expected outcomes in patients diagnosed with acinar cell carcinoma of the pancreas. Our article focuses on adult patients because genetic mutations in childhood tumors suggest alternative etiologies. Methods Literature and Systematic Review We searched the medical literature for studies describing typical therapeutic management approaches for acinar cell carcinoma of the pancreas and reported on disease control and survival rates. Studies were excluded during the initial search if they investigated fewer than 4 patients, focused on mixed carcinoma, were not written in English, did not include clinical data, were review articles, or were a technical manuscript on a surgical procedure alone. Case reports with fewer than 4 patients were also excluded due to lack of ability (too few patients to develop a systematic approach given the rarity of the malignancy). For studies that included previously published data, the most complete and most recent data were used for our systematic analysis. When studies listed patient-level data for multiple histologies, only data concerning acinar cell carcinoma of the pancreas were used. Rates of disease control were calculated using complete response in combination with partial response and stable disease (based on the definition used in each study). No studOctober 2016, Vol. 23, No. 4 ies were identified as having high-level evidence. A total of 132 manuscripts were identified during the search, and 10 studies were included based on our inclusion/exclusion criteria.20 Six studies were then identified and selected for summary analysis of response rates to chemotherapy and radiotherapy as well as to estimate the average median overall survival rate.3,21-25 Four studies contained incomplete data or nonstandard treatment approaches and were excluded from the summary data analyses but were included in the systematic review. Case Series We reviewed our records for patients with acinar cell carcinoma of the pancreas treated between 2004 and 2014 at the H. Lee Moffitt Cancer Center & Research Institute (Tampa, FL). Demographical, clinical, and pathological data were obtained from a retrospective database. Charts were reviewed to confirm data. The Institutional Review Board at our institution approved this research. Statistical Analyses For the systematic review, summary clinical data from each study were averaged in a weighted fashion to determine the overall value for each characteristic (demographic, treatment, or survival data). STATA statistical software was utilized for analysis (StataCorp, College Station, Texas). For the case series, data analyses were also performed with STATA (StataCorp), using χ2, KaplanMeier, and multivariate linear-regression techniques. Statistical significance was set to α being equal to .05. Uncertainties are standard deviations of the mean unless otherwise specified. Results A total of 68 patients identified from the systematic review had a median age of 61 years, and 66% were men (Table 1). These results are similar to other nonsystemTable 1. — Characteristics of Patients With Acinar Cell Carcinoma of the Pancreas in Select Studies Study Butturini25 No. of Median Study Age, y Patients 9 Male, % Stage Pancreatic I/II, Head, % % 53 67 57 67 39 60 77 46 44 Lowery 24 40 65 73 55 55 Matos 3 17 60 Unknown 59 76 Holen 21 4 63 75 25 62 Seth23 14 57 33 86 64 Current series 21 64 76 33 66 Seki 22 Cancer Control 447 atic analyses in which the male-to-female patient ratio is at least 2:1.3,18,21-26 In our systematic review, 52% of patients with acinar cell carcinoma of the pancreas had resectable disease (stage I/II; see Table 1).3,21-25 Nonspecific symptoms, such as nausea, abdominal pain, and weight loss, were observed in most patients.18 We also found that 55% of patients with acinar cell carcinoma of the pancreas had tumors located in the pancreatic head. The data derived from the systematic review also demonstrated that most of the lesions described were generally well circumscribed without significant peritumoral stroma.3,25 Diagnosis The diagnosis of acinar cell carcinoma of the pancreas is confirmed by biopsy, such as fine needle aspiration, or resection of the pancreatic tumor — with the latter being more reliable than the other methods.27 The highly cellular nodules of monotonous tumor cells have little to no stroma and lack a desmoplastic response (Fig 1). Therefore, tumor cells may be difficult to identify with fine needle aspiration alone but reliably seen on a resected specimen.1 Tumor cells are arranged in solid sheets with spaces between the acinar structures and small lumens.18 Cytologically, these cells exhibit basal polarization. Fig 1 also demonstrates that nuclei can range from moderate to marked atypia and contain a single, prominent nucleolus. In the apical region, the cells contain moderate to abundant eosinophilic cytoplasm rich in zymogen granules. Other groups have utilized immunohistochemistry to confirm the diagnosis, and researchers have demonstrated that an antibody against a portion of the B-cell chronic lymphocytic leukemia/lymphoma 10 protein has utility in diagnosing acinar cell carcinoma of the pancreas.18 In addition, immunohistochemistry staining for trypsin and chymotrypsin in A the acinar pattern and, typically, lack of staining for neuroendocrine neoplasm markers (neural cell adhesion molecule, chromogranin, synaptophysin) can confirm the diagnosis of acinar cell carcinoma of the pancreas.14 Radiotherapy Our systematic review revealed a modest response rate to radiotherapy in patients with localized acinar cell carcinoma of the pancreas. In several studies, a “major response” rate was seen in 25% to 35% of these patients. 21,23 However, if stable disease was included in the definition of response (ie, disease control rate), significantly higher response rates were seen in highly selected studies when radiotherapy was added (Table 2).3,21-25 Radiotherapy is often used to “down-stage” or convert a tumor from being borderline resectable to resectable, and, in general, is provided with both conventional fractionation and hypofractionated stereotactic body radiotherapy (SBRT).25 Lack of progression following neoadjuvant radiotherapy can help select patients who may benefit from resection. Chemotherapy Significant heterogeneity was seen in the systematic review regarding specific chemotherapeutic protocols; however, most study patients received combination gemcitabine- or fluoropyrimidine-based chemotherapy protocols. 23,25 Indeed, Holen et al 21 and Lowery et al24 concurred on the favored use of combination fluoropyrimidine-based therapies and radiotherapy in patients with acinar cell carcinoma of the pancreas. However, data regarding disease control rate (complete response + partial response + stable disease) are mixed (see Table 2).3,21-25,28 Combination fluoropyrimidine-based chemotherapies were shown to be associated with higher rates of B Fig 1A–B. — (A) Acinar cell carcinoma of the pancreas in a man aged 83 y and (B) pancreatic ductal adenocarcinoma in a woman aged 65 y. Hematoxylin and eosin stain, ×20. 448 Cancer Control October 2016, Vol. 23, No. 4 disease control (Table 3).3,21-25 Therefore, FOLFOX or folinic acid/fluorouracil/irinotecan (FOLFIRI) is usually administered to patients with high performance status, whereas patients with a lower performance status usually receive gemcitabine/protein-bound paclitaxel.3,8,9,21-25 Table 2. — Disease Control Rates of Chemotherapy and Radiotherapy in Select Series of Acinar Cell Carcinoma of the Pancreas Study Type of Treatment No. of Patients Disease Control Rate,a % Butturini25 Gemcitabine-based chemotherapy 7 29 Holen21 Fluoropyrimidine-based chemotherapy 22 41 RT alone 1 100 Fluoropyrimidine-based chemotherapy RT 4 100 Lowery 24 Gemcitabine-based chemotherapy 20 35 Matos3 Mixed chemotherapy 4 50 Mixed chemotherapy RT 2 100 Gemcitabine-based chemotherapy 1 0 Fluoropyrimidine-/gemcitabinebased chemotherapy 3 33 Seth23 Mixed chemotherapy RT 4 100 Current series Gemcitabine-based chemotherapy 6 50 Fluoropyrimidine-based chemotherapy 6 67 Mixed chemotherapy RT 5 100 Seki22 Table 4. — Systematic Review Summary of Survival Differences Between Select Patients With Resectable and Nonresectable Acinar Cell Carcinoma of the Pancreas Disease Status Metastatic Primary Treatment Median Rate of Overall Survival, mos Chemotherapy 17 Unresectable Chemotherapy and radiotherapy 38 Resectable Resection and adjuvant therapy 47 Patient Characteristic No. of Patients (%) Sex Male 16 (76) Female 5 (24) II Table 3. — Summary of Select Disease Control Rates For the Nonsurgical Therapy of Acinar Cell Carcinoma of the Pancreas No. of Patients Disease Control Rate,a % Any chemotherapy 79 55 Any radiotherapy 16 100 Gemcitabine-based chemotherapy 34 28 Fluoropyrimidine-based chemotherapy 35 60 a Complete response + partial response + stable disease. Data from references 3 and 21 to 25. Table 5. — Select Patient Characteristics From Current Patient Series American Joint Committee on Cancer Stage Study patients not receiving chemotherapy are not included. response + partial response + stable disease. RT = radiotherapy. October 2016, Vol. 23, No. 4 Treatment at Our Institution We identified 21 patients in a case series; 7 patients had metastatic disease based on imaging at the time of initial presentation (Table 5). Most patients were Data from references 3 and 21 to 25. a Complete Treatment Surgery Overall, surgical resection remains the mainstay of therapy for nonmetastatic disease, although adjuvant therapy is common. Most patients with acinar cell carcinoma of the pancreas undergo negative margin resection.3,21 From our systematic review, we found that patients who underwent resection had an overall median survival rate of approximately 47 months (Table 4).3,21-25 The contribution of adjuvant chemotherapy and radiotherapy has not been well investigated in the literature. Resection and adjuvant chemotherapy were associated with the longest rate of median overall survival (see Table 4).3,21-25 7 (33) III 5 (24) IV 9 (43) Site Head 8 (38) Neck/body 7 (33) Tail 6 (29) Surgical Intervention Whipple 6 (29) Distal pancreatectomy 3 (14) Total pancreatectomy 2 (10) Unresectable 3 (14) No surgery 7 (33) Mean age ± standard deviation: 63.5 ± 14 y. Cancer Control 449 100 No surgery Surgery P < .001 75 50 25 0 0 20 Survival Probability, % No surgery Surgery 7 14 0 8 80 0 3 0 1 0 0 100 75 No RT RT P = .008 50 25 0 0 20 40 No RT RT 16 5 4 4 1 2 C 80 0 1 0 0 Discussion No chemo Chemo P = .09 100 75 50 25 0 0 20 40 60 80 0 1 0 0 Months No. at Risk No chemo Chemo 60 Months No. at Risk Survival Probability, % 60 Months No. at Risk B 40 4 17 1 7 1 2 Fig 2A–C. — (A) Kaplan-Meier survival estimates based on surgery, (B) RT, and (C) chemotherapy. Patients with acinar cell carcinoma of the pancreas had significantly improved rates of survival following surgery (P < .001) and RT (P = .008) but not chemotherapy (P = .09). RT = radiotherapy. men. The average age was 63.5 ± 14.1 years, and 38% of lesions were located in the pancreatic head. No patients had stage I disease. The median follow-up period was 1.2 years (range, 1 month to 6.5 years), and 62% of study patients were initially diagnosed elsewhere. Of the 21 patients, 14 were candidates for curative resection. Of those, 11 underwent R0 or R1 resections and 3 patients received R2 resection. At last follow-up, 43% of patients were alive; rates of actual 1- and 5-year survival were 67% and 5%, respectively. All patients who received radiotherapy lived for at 450 Cancer Control least 13 months after diagnosis. Of the patients who underwent surgery, 1 patient also received neoadjuvant chemotherapy and 1 patient also received neoadjuvant radiotherapy. Eight patients received adjuvant chemotherapy, and 4 patients received adjuvant radiotherapy. More surgical patients received chemotherapy than nonsurgical patients (93% vs 57%; P < .05), with 82% of those receiving a gemcitabine-based chemotherapy protocol. Five patients (24%) received radiotherapy, and all were surgical patients: 1 in a neoadjuvant and 4 in adjuvant settings. Utilizing Kaplan-Meier analysis, we found rates of survival to be statistically associated with stage of disease (P = .005), surgery (Fig 2A; log-rank P < .001), and radiotherapy (Fig 2B; log-rank P = .008), but not chemotherapy (Fig 2C; log-rank P = .09). Patients who underwent resection followed by adjuvant radiotherapy had the longest survival (Fig 3). On multivariate Cox regression analysis, higher disease stage was associated with a shorter rate of survival (hazard ratio [HR] 6.70, P =.003) and adjuvant radiotherapy was associated with longer survival (HR 0.05, P = .03), but neither R0 margin nor adjuvant chemotherapy was statistically associated with improved rates of survival (0.70 and 0.30, respectively; P = .2 for both). Few large trials have studied acinar cell carcinoma of the pancreas because it is such a rare tumor. We were only able to identify 6 studies that fully met the criteria for our systematic review. Our institutional experience with 21 patients is the second largest case series in the literature. Because acinar cell carcinoma of the pancreas is treated similarly to pancreatic ductal adenocarcinoma, it is interesting to compare the outcomes. Analysis of Surveillance, Epidemiology, and End Results data Survival Probability, % Survival Probability, % A 100 75 No RT RT P = .018 50 25 0 0 20 60 80 0 1 0 0 Months No. at Risk No RT RT 40 9 5 4 4 1 2 Fig 3. — Kaplan-Meier survival estimates among patients undergoing surgery and receiving RT. Surgical candidates with acinar cell carcinoma of the pancreas had significant improvement in their rates of survival probability when treated with RT. RT = radiotherapy. October 2016, Vol. 23, No. 4 demonstrated higher rates of survival in acinar cell carcinoma of the pancreas compared with pancreatic ductal adenocarcinoma for both resected and unresected cases,1 and analysis of the National Cancer Database demonstrated 5-year survival rates for patients with resected acinar cell carcinoma of the pancreas of 52%, 40%, 23%, and 17% for stages I, II, III, and IV, respectively.29 Positive nodal disease was not associated with decreased rates of survival in patients with acinar cell carcinoma of the pancreas, but patients with high-grade acinar cell carcinoma of the pancreas had a 2-fold worse rate of 5-year survival (P = .003).29 Regarding margin status, negative microscopic margins were associated with 2-year median survival rates compared with 1-year median survival rates for patients with R1-/R2-positive margins (P < .02).29 Debate exists as to whether pancreatic ductal adenocarcinoma is a radiosensitive tumor, but acinar cell carcinoma of the pancreas does appear to be radiosensitive based on the multivariate analysis and Kaplan-Meier survival curves presented here along with other published data.30 Given the findings here and in the literature, it appears that, although acinar cell carcinoma of the pancreas and pancreatic ductal adenocarcinoma are similar exocrine pancreatic malignancies, they are distinct entities.29,30 This systematic review and case series illuminate 3 important findings. As expected, patients able to tolerate surgery live significantly longer than patients with unresectable disease.3,21-25 Patients who undergo radiotherapy in combination with surgery also live significantly longer than those not receiving radiotherapy.3,21-25 The biological mechanism of this result is unknown, but we hypothesize it is because acinar cell carcinoma of the pancreas is a radiosensitive tumor. This survival advantage of radiotherapy was seen despite 11 of 14 patients in our case series receiving surgery (R0/R1 resections), further suggesting that radiotherapy is valuable regardless of margin status. We did not find an association between use of chemotherapy and survival rate. This may be due to the low number of patients in the nonchemotherapy group, but lack of high-level evidence remains problematic given the overall poor prognosis of acinar cell carcinoma of the pancreas. The cell of origin for acinar cell carcinoma of the pancreas is presumed to be the acinar cell, whereas the cell of origin for pancreatic adenocarcinoma is the duct epithelium.31-33 However, controversy is ongoing regarding this assumption because it is based on the phenotype of pancreatic ducts in normal tissue, pancreatic intraepithelial neoplastic lesions, and carcinoma.31 For example, injury to benign cells in the setting of malignancy (ie, enzyme-mediated cell destruction due to malignant local duct obstruction) may create a setting in which malignancy may appear to originate in a duct cell when in fact it actually originated in an aciOctober 2016, Vol. 23, No. 4 nar cell.33 An alternative pathway for carcinogenesis is described by KRAS-mediated acinar-ductal metaplasia and the subsequent development of pancreatic ductal adenocarcinoma.31,34 In this setting, KRAS is hypothesized as being the driving force for the development of pancreatic ductal adenocarcinoma, as most commonly seen in the humans, whereas non–KRAS-mutated exocrine pancreatic carcinomas develop into acinar cell carcinoma of the pancreas.35-37 Assuming this is true, then KRAS wild-type status would be a critical finding in distinguishing acinar cell carcinoma of the pancreas from pancreatic ductal adenocarcinoma. Mutation of DCC may also serve as an early genetic change in acinar cell carcinoma of the pancreas; by contrast, it is a late change in pancreatic ductal adenocarcinoma. Furthermore, the rate of disease control was higher in patients with acinar cell carcinoma of the pancreas than in those with pancreatic ductal adenocarcinoma. This finding suggests that acinar cell carcinoma of the pancreas and pancreatic ductal adenocarcinoma are 2 distinct malignancies arising from similar cells but with important and early points of divergence (KRAS vs DCC). Other groups have demonstrated that acinar cell cystadenoma, a benign and rarely premalignant pancreatic lesion, may have genetic alteration patterns more similar to pancreatic ductal adenocarcinoma than to acinar cell carcinoma of the pancreas, suggesting that some genetic overlap may be present.38 At our institution, we favor the initial use of FOLFOX followed by FOLFIRI as second-line treatment for patients with acinar cell carcinoma of the pancreas and moderate to high performance status (Eastern Cooperative Oncology Group [ECOG] 0–1) either in the adjuvant setting or as systemic therapy (Fig 4). Use of folinic acid/fluorouracil/irinotecan/oxaliplatin (FOLFIRINOX) as first-line therapy for metastatic acinar cell carcinoma of the pancreas has been described in the literature, but whether the benefits of such an aggressive regimen outweighs the risks is unclear.39 Because rates of disease control are higher with the use of combination, fluoropyrimidine-based chemotherapies, we also consider FOLFIRINOX in relatively young, very highly active individuals with ECOG performance status 0 (but rarely seen in our clinical practice). Among patients with moderate ECOG performance status 1 to 2, gemcitabine combined with protein-bound paclitaxel is our preferred chemotherapy regimen, with single-agent gemcitabine used for patients with poor performance status not wishing to enter hospice or palliative care. In the neoadjuvant setting, our clinical approach for pancreatic cancer typically involves treating patients with SBRT who have borderline resectable or locally advanced disease. Therapy involves 5 days of fiducial marker–based radiotherapy applied to gross disease (median dose of 30 Gy and simultaneously Cancer Control 451 50 Gy to the area of vessel involvement/abutment) to help facilitate a negative margin resection.40,41 In patients with acinar cell carcinoma of the pancreas, this general treatment approach could be considered given the high R0 resection rates and minimal rates of late toxicity.30,42 Based on data from the National Cancer Database, R0 resection has been shown to improve rates of overall survival on multivariate analysis, so neoadjuvant radiotherapy should be considered when a likelihood exists of positive margins.29 Because patients with locally advanced tumors are unlikely to be candidates for resection, care must be taken to avoid late radiation-associatDiagnosis Made on Biopsy (eg, FNA) ed toxicities to the surrounding gastrointestinal organs. As such, intensity-modulated radiotheraComplete Staging py can be considered instead of Local/regional: SBRT for locally advanced acinar • Endoscopic ultrasonography to evaluate superior mesenteric vein/artery and portal vein cell carcinoma of the pancreas. • CT protocol for the pancreas (cut 3 mm, arterial/portal/venous phase) Distant: • CT of the thorax with contrast and PET-CT Performance status Resectable Pancreaticoduodenectomy or distal pancreatectomy Borderline Resectable Neoadjuvant chemotherapy + SBRT + resectiona Adjuvant Chemotherapy FOLFOX Adjuvant Radiotherapy Positive margins SBRT-naïve Locally Advanced Systemic chemotherapy FOLFOX RT Metastatic Systemic chemotherapy FOLFOX Progression Second-Line Therapy FOLFIRI Third-Line Therapy Gemcitabine/protein-bound paclitaxel Palliative Care Fig 4. — Algorithm for the treatment of acinar cell carcinoma of the pancreas. This treatment plan is based on expert opinion and focuses on the importance of negative-margin resection coupled with RT. CT = computed tomography, FNA = fine needle aspiration, FOLFIRI = folinic acid/fluorouracil/irinotecan, FOLFOX = folinic acid/fluorouracil/oxaliplatin, PET = positron emission tomography, RT = radiotherapy, SBRT = stereotactic body radiotherapy. aIf no progression on repeat staging. 452 Cancer Control Limitations Due to the rarity of this malignancy, we did not identify any prospective studies or large casecontrol studies to help guide clinical management. Likewise, oncologists are more familiar with the treatment protocols for pancreatic ductal adenocarcinoma, because this disease is more common, and, as such, these regimens are often utilized for acinar cell carcinoma of the pancreas despite the fact that evidence is lacking. The retrospective nature of this review also limits our interpretation of the results. Fundamentally, this limitation is also due to the rarity of the malignancy, thus limiting the initiation of prospective trials. Another important limitation relates to tumor response rates in retrospective studies. Oftentimes, the time to progression is based on when a patient is scheduled for his or her next imaging, not a predefined time point, as seen in a prospective study. As such, unless a patient is symptomatic, the time to progression may be partially related to an institutional bias. This is a difficult to quantify but important limitation. Future Research Three critical inquiries must be explored to improve rates of survival among individuals with acinar cell carcinoma of the pancreas. Specific mechanisms (ie, gene mutaOctober 2016, Vol. 23, No. 4 tions) that lead to acinar cell carcinoma of the pancreas must be better elucidated to (theoretically) incorporate small molecule inhibitors into therapy. As demonstrated by the overall higher survival rates seen in acinar cell carcinoma of the pancreas (see Table 4), acinar cell carcinoma of the pancreas may likely be molecularly driven in a distinct way from pancreatic ductal adenocarcinoma.3,21-25 The radiosensitivity of acinar cell carcinoma of the pancreas must also be investigated and modulated to optimize therapy. Our data suggest that acinar cell carcinoma of the pancreas is a radiosensitive tumor. Similar to many other malignancies, active chemotherapeutics also need identification. Whether current chemotherapy options add any improved likelihood of long-term survival remains unclear based on published data. Conclusions Acinar cell carcinoma of the pancreas is a rare pancreatic malignancy with a prognosis slightly better than ductal adenocarcinoma. At Moffitt Cancer Center, our standard approach is surgical resection followed by adjuvant fluorouracil-based chemotherapy, radiotherapy, or both (see Fig 4). The utility of chemotherapy is uncertain; however, when it is used, a fluorouracil-based regimen is often proposed because of its higher rates of disease control when compared with gemcitabine or other chemotherapeutic agents. (However, this treatment plan is based on expert opinion and individualized for patient performance status.) Negative microscopic margins are the most important prognostic factor, because survival for patients with positive microscopic margins is generally as poor as those seen with positive gross margins. Multidisciplinary management of pancreatic acinar cell carcinoma should be considered due to the lack of high-level data in treating this patient population. In addition, referral to a quaternary center is appropriate given the rarity of this malignancy. Despite the rarity of this disease, further investigation is needed to personalize care to improve long-term survival in these patients. 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Aggressive approach to acinar cell carcinoma of the pancreas: a single-institution experience and a literature review. Langenbecks Arch Surg. 2011;396(3):363-369. 26. Lack EE, Cassady JR, Levey R, et al. Tumors of the exocrine pancreas in children and adolescents. A clinical and pathologic study of eight cases. Am J Surg Pathol. 1983;7(4):319-327. 27. Kim HJ, Kim YK, Jang KT, et al. Intraductal growing acinar cell carcinoma of the pancreas. Abdominal Imaging. 2013;38(5):1115-1119. 28. Sudo K, Ishihara T, Hirata N, et al. Randomized controlled study of gemcitabine plus S-1 combination chemotherapy versus gemcitabine for unresectable pancreatic cancer. Cancer Chemother Pharmacol. 2014;73(2):389-396. 29. Schmidt CM, Matos JM, Bentrem DJ, et al. Acinar cell carcinoma of the pancreas in the United States: prognostic factors and comparison to ductal adenocarcinoma. J Gastrointest Surg. 2008;12(12):2078-2086. 30. Moningi S, Dholakia AS, Raman SP, et al. The role of stereotactic body radiation therapy for pancreatic cancer: a single-institution experience. Ann Surg Oncol. 2015;22(7):2352-2358. 31. Shi C, Hong SM, Lim P, et al. KRAS2 mutations in human pancreatic acinar-ductal metaplastic lesions are limited to those with PanIN: implications for the human pancreatic cancer cell of origin. Mol Cancer Res. 2009;7(2):230-236. 32. Morohoshi T, Held G, Kloppel G. Exocrine pancreatic tumours and their histological classification. A study based on 167 autopsy and 97 surgiCancer Control 453 cal cases. Histopathology. 1983;7(5):645-661. 33. Bockman DE. Cells of origin of pancreatic cancer: experimental animal tumors related to human pancreas. Cancer. 1981;47(6 suppl):1528-1534. 34. Aichler M, Seiler C, Tost M, et al. Origin of pancreatic ductal adenocarcinoma from atypical flat lesions: a comparative study in transgenic mice and human tissues. J Pathol. 2012;226(5):723-734. 35. Morris JP IV, Wang SC, Hebrok M. KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma. Nat Rev Cancer. 2010;10(10):683-695. 36. Shi G, DiRenzo D, Qu C, et al. Maintenance of acinar cell organization is critical to preventing Kras-induced acinar-ductal metaplasia. Oncogene. 2013;32(15):1950-1958. 37. Wood LD, Klimstra DS. Pathology and genetics of pancreatic neoplasms with acinar differentiation. Semin Diagn Pathol. 2014;31(6):491-497. 38. Jones M, Zheng Z, Wang J, et al. Impact of next-generation sequencing on the clinical diagnosis of pancreatic cysts. Gastrointest Endosc. 2016;83(1):140-148. 39. Schempf U, Sipos B, Konig C, et al. FOLFIRINOX as first-line treatment for unresectable acinar cell carcinoma of the pancreas: a case report. Zeitschrift Gastroenterol. 2014;52(2):200-203. 40. Mellon EA, Hoffe SE, Springett GM, et al. Long-term outcomes of induction chemotherapy and neoadjuvant stereotactic body radiotherapy for borderline resectable and locally advanced pancreatic adenocarcinoma. Acta Oncol. 2015;54(7):979-985. 41. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Pancreatic Adenocarcinoma. v I.2016. https:// www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. Accessed August 9, 2016. 42. Herman JM, Chang DT, Goodman KA, et al. Phase 2 multi-institutional trial evaluating gemcitabine and stereotactic body radiotherapy for patients with locally advanced unresectable pancreatic adenocarcinoma. Cancer. 2015;121(7):1128-1137. 454 Cancer Control October 2016, Vol. 23, No. 4 Special Report A Single-Institution Study of Demographics and Outcomes of Adult Patients With Multiple Cancers Thanh P. Ho, MD, Nathan R. Foster, MS, and Aminah Jatoi, MD Background: Few studies have described the demographics and outcomes in patients with multiple cancers. Methods: We reviewed the health records of patients with at least 3 invasive solid-tumor malignancies (lung, colorectal, pancreatic, prostate, breast, or ovarian) diagnosed between 1995 and 2014 at our institution. Results: A total of 163 patients were identified. The median age at first cancer diagnosis was 61 years. Sixteen (10%) had a family history of cancer, and 7 (4%) had a cancer-predisposing syndrome. Most had early-stage malignancies and underwent a series of surgical resections. The median survival from the first cancer diagnosis was 14 years (95% confidence interval: 12–16). Forty-three percent developed 4 or more cancers. In univariate analyses, older age, male sex, smoking history, concurrent cancer, and stage IV disease were associated with worse survival; by contrast, breast cancer as the first cancer diagnosis yielded better survival. In multivariate analyses, older age, smoking history, and stage IV disease were associated with worse survival. Conclusions: A small group of patients with no ostensible risk factors develop multiple early-stage cancers, receive curative therapy (often surgery), and live for years. These patients merit further study to ascertain the broader prevalence rates of individuals with multiple invasive cancers and to better understand factors that contribute to cancer risk. Introduction Adult patients with cancer are living longer.1 Zeng et al2 reported on patients with cancer aged 50 to 64 years at the time of their diagnosis between 2005 and 2009 and observed that, when compared with similar patients diagnosed during an earlier time interval, the hazard ratios (HRs) for patients with colorectal, breast, liver, and prostate cancers were 0.57 (95% confidence interval [CI]: 0.55–0.60), 0.48 (95% CI: 0.45–0.51), 0.61 (95% CI: 0.57–0.69), and 0.32 (95% CI: 0.30–0.36), respectively. These findings suggest that patients with cancer are living longer and that cancer can, at times, be viewed as a long-term disease.2 Few studies have focused in general terms on patients who live for many years following a first diagnosis of cancer and then continue to be diagnosed with multiple cancers over time.3,4 Previous studies have described multiple cancers in adult patients with predisposing syndromes, showing, for example, that individuals with Lynch syndrome or BRCA1/BRCA2 mutations have a more favorable prognosis after cancer diagnoses.5,6 Others have described patients with therapy-related malignancies who have worse progFrom the Departments of Medicine (TPH), Health Sciences Research (NRF), and Oncology (AJ), Mayo Clinic, Rochester, Minnesota. Submitted March 10, 2016; accepted May 3, 2016. Address correspondence to Aminah Jatoi, MD, Department of Oncology, Mayor Clinic, 200 First Street SW, Rochester, Minnesota 55905. E-mail: [email protected] No significant relationships exist between the authors and the companies/organizations whose products or services may be referenced in this article. October 2016, Vol. 23, No. 4 noses compared with their counterparts who develop de novo cancers.7,8 However, to our knowledge, these studies and others have not explored the presence of multiple cancers in the absence of predisposing syndromes or therapy-related secondary cancers. Purpose This study explored demographics and outcomes in patients who developed multiple cancers. Some patients contend with multiple malignancies throughout their lives, thus displaying a poorly characterized predisposition to cancer and a need for ongoing cancer surveillance. Reporting on the characteristics and outcomes of patients with multiple cancers might help oncologists better counsel patients about prognoses and realistic treatment goals in the setting of multiple malignancies. Methods Overview This single-institution study focused on patients with cancer seen at the Mayo Clinic (Rochester, MN) from 1995 to 2014, encompassing a 20-year interval that saw national improvements in cancer outcomes.2 The Mayo Clinic Tumor Registry, which relied in part on International Classification of Diseases codes, pathology reports, and other clinical sources to input data, was searched for patients who met study criteria. Eligible patients had to be diagnosed between 1995 and 2014 with at least 3 invasive malignancies of at least 1 of the following types: lung, colorectal, panCancer Control 455 creatic, prostate, breast, or ovarian. These malignancies were chosen because they are among the most common and lethal in the United States and have 5-year relative survival rates of 16%, 59%, 7%, 95%, 85%, and 41%.9 Inclusion criteria were determined a priori. No major changes occurred in the Mayo Clinic Tumor Registry or in institutional infrastructure within the interval above; hence, data retrieval uniformly occurred over time. The Institutional Review Board at the Mayo Clinic approved this study. Medical Record Review Each patient’s health records were reviewed and abstracted for date of birth, sex, date of each cancer diagnosis, stage of each cancer, smoking history, family history of cancer (cancer in ≥ 2 first-degree relatives), documentation of genetic predisposition to cancer, cancer treatment, vital status, and date of death or last follow-up visit. Because definitions of predisposing syndromes to cancer have evolved over time to include clinical criteria and, in some instances, molecular criteria, the methodology congruent with a real-time contemporary standard was used in this study. If a date was not clearly documented, then a mid-month or midyear date was used. If the health record lacked clear documentation of an item, then an unknown category was used. Data Analyses Results are reported with means and percentages; all analyses are considered exploratory. Because patients were heavily selected based on 6 targeted cancer types, this study was not designed to report on the prevalence rates of patients with multiple cancers. Kaplan-Meier curves were constructed to assess survival, and data were censored as appropriate. Cox proportional hazard models were used to explore whether certain clinical variables were associated with survival. Variables were chosen based on their clinical relevance to cancer outcomes and based on a desire for parsimony to ensure stability of statistical models; in this context, age at cancer diagnosis, sex, smoking history, concurrent cancer diagnosis, stage IV disease (any malignancy), and cancer type at first diagnosis were chosen. HRs and 95% CIs were reported. A 2-tailed P value of less than .05 was considered statistically significant. All analyses were performed with JMP Statistical Software (SAS Institute, Carey, NC). Results Baseline Demographics Nine patients were excluded because of lack of clarity as to whether 1 or more of their cancers represented a new malignancy, a metastatic site, or recurrence of a previous cancer. The remaining 163 patients are the focus of this report. 456 Cancer Control The median age of the study participants was 61 years (range, 24–87). Sixteen (10%) had cancer in at least 2 first-degree relatives, and 7 (4%) had a known syndrome that predisposed them to cancer. Other patient demographics appear in Table 1. Cancer Characteristics Cancer of the breast, colorectum, and lung were the 3 most common cancer types in the study group (Table 2). Seventy patients (43%) had more than 3 cancers. In 10 patients, the first cancer diagnosis did not fall within the 1995 to 2014 time interval, but these patients were eligible for the study because they developed 3 invasive cancers during this interval. The median interval from the first ever to the second cancer diagnosis was 2.6 years (range, 0–45), and the median interval from the first ever to the third cancer diagnosis was 6.2 years (range, 0–58; Fig 1). Most patients had relatively early-stage malignancies, and the majority also underwent surgical treatment for all 3 cancers. Fewer than one-half of these specific cancers were treated with chemotherapy or radiotherapy. Table 1. — Characteristics of Study Patients (N = 163) Characteristic Study Patients, n (%) Median age at first cancer diagnosis, y (range) 61 (24–87) Sex Male Female 75 (46) 88 (54) Cancer in ≥ 2 first-degree relatives Yes No 16 (10) 144 (88) Genetic syndrome Yes No Unknown 7 (4) 12 (7) 144 (88) Smoking history Yes No 118 (74) 42 (26) Concurrent cancer Yes, 1 Yes, 2 No 13 (8) 17 (10) 133 (82) ≥ 4 cancers a Yes No 70 (43) 93 (57) Percentages may not sum to 100% because of rounding or missing data. aOther cancers included multiple cases of colorectal cancer, multiple cases of lung cancer, multiple cases of breast cancer, 6 cases of lymphoma, 5 cases of bladder cancer, 4 cases of melanoma, 4 cases of prostate cancer, 3 cases of head and neck cancers, 2 cases of small bowel cancer, 2 cases of ureteral cancer, 2 cases of ovarian cancer, and 1 each of chronic myelogenous and lymphocytic leukemias, and tubal, esophageal, pancreatic, testicular, and cervical cancers. October 2016, Vol. 23, No. 4 Table 2. — Cancer Diagnoses Among Study Patients (N = 163) Diagnosis Study Patients, n (%) Diagnosis First Cancer Cancer Type Breast Colorectal Lung Ovarian Pancreas Prostate Other Study Patients, n (%) Diagnosis Second Cancer 43 (26) 40 (25) 38 (23) 3 (2) 1 (1) 26 (16) 12 (7) Cancer Type Breast Colorectal Lung Ovarian Pancreas Prostate Other Stage I II III IV 72 (47) 43 (28) 31 (20) 7 (5) Surgery Yes No Study Patients, n (%) Third Cancer 39 (24) 52 (32) 55 (34) 0 1 (1) 13 (8) 3 (2) Cancer Type Breast Colorectal Lung Ovarian Pancreas Prostate Other 28 (17) 44 (27) 78 (48) 1 (1) 3 (2) 6 (4) 3 (2) Stage I II III IV 87 (55) 40 (25) 26 (16) 6 (4) Stage I II III IV 80 (55) 30 (21) 19 (13) 17 (12) 147 (90) 15 (9) Surgery Yes No 145 (90) 17 (10) Surgery Yes No 126 (78) 36 (22) Systemic Therapy Yes No 69 (43) 93 (57) Systemic Therapy Yes No 64 (40) 97 (60) Systemic Therapy Yes No 62 (39) 99 (61) Radiotherapy Yes No 53 (33) 107 (66) Radiotherapy Yes No 34 (21) 126 (78) Radiotherapy Yes No 42 (26) 117 (73) A B 50 60 50 40 40 Years Years 30 20 30 20 10 10 0 0 No. of Patients No. of Patients Fig 1A–B. — Time interval between cancer diagnoses. These bar graphs show time on the vertical axis and each bar is representative of the number of patients. (A) The interval from the first to the second cancer diagnosis was 2.6 years (range, 0–45 years). (B) The median interval from the first to the third cancer was 6.2 years (range, 0–58 years). October 2016, Vol. 23, No. 4 Cancer Control 457 Patients Alive, % Cancer Outcomes of cancer, and 2 had a documented genetic predispoA total of 92 patients (56%) had died. The median folsition to cancer. The median age at first cancer dilow-up of patients still living was 11.4 years (range, agnosis was 64 years (range, 33–80). Thirty-one pa0.3–58.0). In 62 (67%) of the deceased patients, the tients (74%) were diagnosed with stage I disease. The cause of death was cancer; in 6 (7%), a nonmalignant remaining stage distribution included 5 with stage II, cause was determined; and, in 24 (26%), the cause was 5 with stage III, 1 with stage IV, and 1 whose stage unknown. The overall median survival for the entire was unknown. A total of 41 patients (95%) were treatgroup was 14 years from the time of first cancer diaged with surgery for the first cancer, 26 (60%) were nosis (95% CI: 12–16; Fig 2). treated with chemotherapy for the first cancer, and In univariate analyses, older age, male sex, a 25 (58%) were treated with radiotherapy for the first smoking history, a concurrent cancer diagnosis, and stage 100 IV disease among any of the 3 malignancies yielded a statistically significant asso80 ciation with worse survival (Table 3). Breast cancer as the first diagnosis of cancer was 60 associated with improved survival. However, in multivariate analyses, older age, smoking history, and any diagnosis 40 of stage IV disease yielded a statistically significant association with worse survival 20 (see Table 3). Among the 43 patients who had breast cancer as 0 their first cancer, all were 0 2 4 6 8 10 12 14 16 18 20 22 24 women. A total of 29 (69%) Years From First Cancer Diagnosis had a smoking history (med ian of 35 pack-years), Fig 2. — The overall median survival was 14 years. The 95% confidence intervals of 12 and 16 years are 5 (12%) had a family history shown as the parallel dotted lines. Table 3. — Results of the Cox Proportional Hazards Models Univariate Analyses (N = 163, n = 92 deaths) Variable HR (95% CI) P Valueb Multivariate Analyses (n = 136, n = 72 deaths)a P Valueb HR (95% CI) Age (1-y increase) 1.06 (1.04–1.09) < .0001 1.09 (1.06–1.13) < .0001 Sex (male vs female) 1.99 (1.31–3.04) .0010 0.92 (0.47–1.82) .8020 1.79 (1.07–3.19) .0240 2.53 (1.36–5.04) .0020 1.98 (1.13–3.28) .0190 1.54 (0.76–2.90) .2180 .0240 2.02 (1.09–3.65) Smoking history (yes vs no) c Concurrent cancers (yes vs no) Stage IV (vs not stage IV)d First diagnosis of cancer Breast Colorectal Lung Other (ref) 1.84 (1.09–3.02) .0040 0.48 (0.25–0.87) 1.43 (0.83–2.43) 1.06 (0.60–1.83) — .0250 .4300 0.75 (0.31–1.84) 0.96 (0.46–1.95) 1.42 (0.69–2.87) — aThe multivariate model included 72 deaths as a result of missing data. Separate models that included select variables above yielded similar findings, thus demonstrating the stability of the model. bLikelihood-ratio P value. c Missing 3 observations and 2 events (n = 160, n = 90 events). d Missing 24 observations and 18 events (n = 139, n = 74 events). CI = confidence interval, HR = hazard ratio. 458 Cancer Control October 2016, Vol. 23, No. 4 cancer. Second cancers within this group included breast cancer in 25 (58%), colorectal cancer in 9 (21%), and lung cancer in 9 (21%). Third cancers included breast cancer in 16 (37%), colorectal cancer in 6 (14%), lung cancer in 18 (42%), ovarian cancer in 1 (2%), pancreatic cancer in 1 (2%), and another type of cancer in 1 (2%). Twenty-eight patients remain alive at the time of this report; the rate of overall median survival was 16 years. Among the 15 deceased patients, the cause of death was related to cancer in 9 cases. Discussion This study focused on patients diagnosed with 3 or more common, invasive, and sometimes lethal malignancies. It was not intended to report on the prevalence rates of patients with multiple cancers because our eligibility criteria were deliberatively selective; however, the scenario of multiple cancers appears to be rare, particularly when considering the number of cancer diagnoses every year at our institution — 868 patients were diagnosed with breast cancer in 2014 at the Mayo Clinic alone (unpublished data) — and when acknowledging that cancer remains a major cause of death around the world.10 We have identified a small cohort of patients who illustrate this clinical scenario. This study contributes to a small but growing body of literature that reports on the development of multiple cancers in a group of patients who have not been specifically selected based on a genetic or otherwise known predisposition for having a higher risk of cancer.4,11 Despite the presumed rarity of this clinical scenario, this study provides important insights. These patients often develop an early-stage malignancy, undergo surgical resection, and then live for many years prior to developing a subsequent malignancy that can be treated in a similar fashion. The median survival for the study group exceeded 10 years, underscoring the fact that this subgroup is treated and then re-treated for a new cancer over time. Thus, a history of more than 1 early-stage cancer should not negatively impact the management of subsequent early-stage cancers. In addition, although comparisons across data sets are perilous and, although our sample size is too small to allow for formal adjusted comparisons across data sets, when we examined patients who were first diagnosed with breast cancer and then developed multiple malignances thereafter, we did not observe major differences in survival based on benchmark data.9 For example, the latter shows that 88% of patients with breast cancer reached the 5-year mark,9 whereas a survival curve from patients with breast cancer in our study shows that more than 90% did the same (data not shown). Risk factors for early death remain relevant to patients with multiple cancers. Older age, smoking, and stage IV disease are all associated with poor survival in patients with multiple cancers. These prognostic facOctober 2016, Vol. 23, No. 4 tors remain important regardless of whether a patient has been diagnosed with 1 cancer type or several. More than 40% of the patients in our study were diagnosed with 4 or more cancers. Although old age is a risk factor for cancer, the patients in the current study were not elderly when diagnosed with their first malignancy (median age, 61 years). Moreover, a small percentage had a known syndrome that predisposed them to cancer or a compelling reason to suspect that their history of recurrent cancers was the result of prior cancer therapy, although our understanding of genetic predisposition to cancer has grown over the years. However, many of these patients were treated surgically — a therapy not generally known to spawn secondary cancers. Thus, perhaps other, undiscovered factors are at play to explain the development of multiple cancers. This potential for uncharacterized risk factors for cancer — including genetic factors — requires further investigation. Limitations The retrospective design of our study is a limitation and led to missing data in some instances, as is the case in any retrospective study. However, by using a retrospective design, we were able to assess 20 years of data within a short time frame. Another limitation is our small sample size, which is the result of our single-institution study design. However, our single-institution focus enabled us to acquire detailed information on the dates, cancer stage, cancer therapy, and, in some cases, causes of death. The single-institution nature of our study may have also allowed for a greater degree of homogeneity among data elements, thereby enabling us to identify conclusions more readily. Conclusions Patients diagnosed with multiple cancers may continue to live for years. To our knowledge, little insight exists in the literature on the attitudes of health care professionals toward patients with a history of multiple malignancies, and repeated cancer diagnoses followed by a cumulative history of cancer treatment could conceivably lead to a biased approach to repeat cancer therapy over time. The findings from this study underscore the need to continue to try to apply curative therapy to patients with a history of multiple cancers, regardless of whether these cancers are primary, secondary, or tertiary. These findings also suggest the need to further investigate the prevalence and risk factors for the development of multiple cancers. References 1. American Cancer Society. Cancer Facts and Figures 2016. http://w w w.cancer.org/acs/groups/content /@research/documents/ document/acspc-047079.pdf. Accessed September 2, 2016. 2. Zeng C, Wen W, Morgans AK, et al. Disparities by race, age, and sex in the improvement of survival for major cancers: results from the NaCancer Control 459 tional Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program in the United States, 1990 to 2010. JAMA Oncol. 2015;1(1):88-96. 3. Utada M, Ohno Y, Hori M, et al. Incidence of multiple primary cancers and interval between first and second primary cancers. Cancer Sci. 2014;105(7): 890-896. 4. Xu LL, Gu KS. Clinical retrospective analysis of cases with multiple primary malignant neoplasms. Genet Mol Res. 2014;13(4):9271-9284. 5. Van den Broek AJ, Schmidt MK, van ’t Veer LJ, et al. Worse breast cancer prognosis of BRCA1/BRCA2 mutation carriers: what’s the evidence? A systematic review with meta-analysis. PLoS One. 2015;10(3):e0120189. 6. Gryfe R, Kim H, Hsieh ET, et al. Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer. N Engl J Med. 2000;342(2):69-77. 7. Travis LB. The epidemiology of second primary cancers. Cancer Epidemiol Biomark Prev. 2006;15(11):2020-2026. 8. Travis LB, Fosså SD, Schonfeld SJ, et al. Second cancers among 40,576 testicular cancer patients: focus on long-term survivors. J Natl Cancer Inst. 2005;97(18):1354-1365. 9. US Cancer Statistics Working Group. United States Cancer Statistics: 1999–2013 Incidence and Mortality Web-Based Report. Atlanta, GA: US Department of Health and Human Services; Centers for Disease Control and Prevention; National Cancer Institute; 2016. https://nccd.cdc.gov/uscs /Survival/Relative_Survival_Tables.pdf. Accessed September 2, 2016. 10. World Health Organization. The top 10 causes of death. http://www. who.int/mediacentre/factsheets/fs310/en/index2.html. Accessed September 13, 2016. 11. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7-30. 460 Cancer Control October 2016, Vol. 23, No. 4 Ten Best Readings Relating to Health Disparities in Oncology Sharma P, Ashouri K, Zargar-Shoshtari K, et al. Racial and economic disparities in the treatment of penile squamous cell carcinoma: results from the National Cancer Database. Urol Oncol. 2016;34(3):122.e9-15. Researchers evaluated overall survival (OS) differences in economics and sociodemographics and economic differences among 5,412 study patients with penile squamous cell carcinoma. Survival did not change over the study period, but the authors found that black patients had worse median OS and presented with a more advanced stage of disease. Those who had median incomes of at least $63,000 and carried private insurance had better median OS and presented with a lower stage of disease. Thus, the researchers determined that racial and economic differences exist in the OS rates of patients with penile squamous cell carcinoma. Langford AT, Resnicow K, Dimond EP, et al. Racial/ ethnic differences in clinical trial enrollment, refusal rates, ineligibility, and reasons for decline among patients at sites in the National Cancer Institute’s Community Cancer Centers Program. Cancer. 2014;120(6):877-884. Racial and ethnic differences were studied among patients who had enrolled in, refused to enroll, were ineligible to enroll, or wanted to participate in a clinical trial enrollment. Age 65 years or older, male sex, and non-Hispanic black race were significantly associated with more medical or physical conditions. Those who were aged 65 years or older were significantly more likely to have low clinical trial enrollment; by contrast, being male was significantly associated with low refusal rates. The authors concluded that better management of physical or medical conditions before and during treatment might increase the pool of patients eligible to enroll in clinical trials. Spratt DE, Chan T, Waldron L, et al. Racial/ethnic disparities in genomic sequencing. JAMA Oncol. 2016;2(8):1070-1074. A retrospective review of individual patient data was conducted to determine the racial distribution among samples sequenced within The Cancer Genome Atlas (TCGA) and the number of samples still needed to detect select mutational frequencies in racial minorities. Of the 5,729 samples analyzed, 77% were white, 12% were black, 3% were Asian, 3% were Hispanic, and less than 0.5% were Native Americans. These percentages, thus, over-represent whites comOctober 2016, Vol. 23, No. 4 pared with the US population and under-represent Asians and Hispanics. All tumor types from whites contained enough samples to detect a 10% mutational frequency; however, group-specific mutations with a 10% frequency were detectable for black patients with breast cancer alone. It is probable but not well understood that ethnic diversity may be related to the pathogenesis of cancer and may have an impact on the generalizability of these study findings. Dutil J, Golubeva VA, Pacheco-Torres AL, et al. The spectrum of BRCA1 and BRCA2 alleles in Latin America and the Caribbean: a clinical perspective. Breast Cancer Res Treat. 2015;154(3):441-453. A review of the medical literature reporting on the prevalence and/or spectrum of BRCA1 and BRCA2 variants was conducted. A total of 4,835 individuals from Latin America, the Caribbean, and Hispanics from the United States were included, of which 167 unique pathogenic variants were reported. In unselected breast cancer cases, the prevalence ranged from 1.2% to 27.1%. Some countries presented with few recurrent pathogenic variants, whereas others were characterized by diverse, nonrecurrent variants. The proportion of BRCA pathogenic variants shared between US Hispanics and Latin American populations was estimated to be 10.4%. Within Latin America and the Caribbean, 8.2% of the BRCA variants were present in more than 1 country. Countries with a high prevalence of BRCA pathogenic variants may benefit from more aggressive testing strategies, and testing of recurrent variant panels might present a cost-effective solution for improving genetic testing in some countries. Weitzel JN, Clague J, Martir-Negron A, et al. Prevalence and type of BRCA mutations in Hispanics undergoing genetic cancer risk assessment in the southwestern United States: a report from the Clinical Cancer Genetics Community Research Network. J Clin Oncol. 2013;31(2):210-216. Researchers sought to determine the prevalence and type of BRCA1 and BRCA2 mutations among Hispanics in the southwestern United States and their potential impact on genetic cancer risk assessment. Deleterious BRCA mutations were detected in 25% of 746 samples. A total of 11% of 189 samples were large rearrangement mutations, of which 62% were BRCA1 exon 9 to exon 12 deletions. Nine recurrent mutations accounted for 53% of the total. Among these, BRCA1 exon 9 to exon 12 deletions appear be a Mexican Cancer Control 461 founder mutation representing up to 12% of all BRCA1 mutations in select cohorts. The authors conclude that the high frequency of large rearrangement mutations warrants screening in every case. Meyskens FL Jr, Mukhtar H, Rock CL, et al. Cancer prevention: obstacles, challenges and the road ahead. J Natl Cancer Inst. 2015;108(2):pii:djv309. The genetic heterogeneity and complexity of advanced cancers support rationale for interrupting the carcinogenic process early and target prevention to reduce the burden of cancer; however, the focus of cancer prevention should be on persons at high risk and on primary localized disease, for which screening and detection should also play a role. The timing and doses of chemopreventive interventions also affect response. The intervention may be ineffective if the target population is very high risk or presents with preneoplastic lesions and irreversible cellular changes. The field must begin to focus on targeted organ-site prevention approaches in patients at high risk. The authors also suggest that comparative effectiveness research designs and the value of information obtained from large-scale prevention studies are necessary so that preventive interventions become a routine part of cancer management. Carlson RW, Scavone JL, Koh WJ, et al. NCCN framework for resource stratification: a framework for providing and improving global quality oncology care. J Natl Compr Canc Netw. 2016;14(8):961-969. This article describes the rationale for resourcestratified guidelines and the methodology for developing the National Comprehensive Cancer Network (NCCN) Framework. Disparities in available resources for cancer care are enormous, which is one reason why the NCCN developed a framework for stratifying its clinical practice for cancer. NCCN also hopes to help health care systems with varying levels of available resources provide optimal care for patients with cancer. The framework is modified from a method developed by the Breast Health Global Initiative. The NCCN Framework for Resource Stratification identifies 4 resource environments and presents the recommendations in a graphic format that maintains the context of the NCCN guidelines. DeSantis CE, Siegel RL, Sauer AG, et al. Cancer statistics for African Americans, 2016: progress and opportunities in reducing racial disparities. CA Cancer J Clin. 2016;66(4):290-308. Approximately 189,910 new cases of cancer and 69,410 cancer-related deaths will occur among blacks in 2016. Although blacks continue to have higher rates of cancer-related mortality than whites, the disparity has narrowed for all cancers combined in men and 462 Cancer Control women and for lung and prostate cancers in men. The racial gap in death rates has widened for breast cancer in women and remained stable for colorectal cancer in men. In men, incidence rates from 2003 to 2012 decreased for all cancers combined as well as for the top 3 cancer sites. In women, overall rates during the corresponding time period remained unchanged, reflecting increasing trends in breast cancer combined with decreasing trends in lung and colorectal cancer rates. The 5-year relative survival rate is lower for blacks than whites for most cancers at each stage of diagnosis. The extent to which these disparities reflect unequal access to health care vs other factors remains an active area of research. Ward E, Jemal A, Cokkinides V, et al. Cancer disparities by race/ethnicity and socioeconomic status. CA Cancer J Clin. 2004;54(2):78-93. The authors sought to identify disparities in cancer incidence, mortality, and survival rates in relation to race and ethnicity. For all cancer sites combined, residents of poorer counties had 13% higher death rates from cancer in men and 3% higher rates in women when compared with individuals living in more affluent counties. Among both sexes, the 5-year survival rate for all cancers combined was 10% lower among persons who live in poorer rather than more affluent census tracts. When the census tract poverty rate was accounted for, African American, American Indian, Alaskan Native, and Asian/Pacific Islander men and African American, American Indian, and Alaskan Native women had lower 5-year survival rates than non-Hispanic whites. Detailed analyses of select cancers showed large variations in rate of cancer survival by race and ethnicity. Quinn GP, Sanchez JA, Sutton SK, et al. Cancer and lesbian, gay, bisexual, transgender/transsexual, and queer/questioning (LGBTQ) populations. CA Cancer J Clin. 2015;65(5):384-400. The authors review the literature on 7 cancer sites that may disproportionately affect lesbian, gay, bisexual, transgender/trans-sexual, and queer/questioning populations. For each cancer site, descriptive statistics, primary prevention, secondary prevention and preclinical disease, tertiary prevention and late-stage disease, and clinical implications are discussed. The authors also provide an overview of psychosocial factors related to cancer survivorship as well as strategies for improving access to care. October 2016, Vol. 23, No. 4 Peer Reviewers, 2016 Peer review is the indispensable and critical element in the evaluation of all manuscripts being considered for publication in our journal. The oncology professionals who took part in our peer review process this past year are listed below, and we thank them for their invaluable efforts on behalf of Cancer Control. — The Editor External Reviewers Abate, Getahun, MD, PhD Saint Louis University Alberg, Anthony J., PhD, MPH Medical University of South Carolina Alcaraz, Kassandra, PhD, MPH American Cancer Society Ahmad, Nazeel, MD James A. Haley Veterans Administration Medical Center Allott, Emma H., PhD University of North Carolina at Chapel Hill Alrabaa, Sally, MBBS University of South Florida Apata, Jummai, MBBS, MPH Morgan State University Bao, Renyue, MD University of Houston Biermann, Martin, MD University of Bergen, Norway Bowen, Deborah J., PhD University of Washington Briere, Elizabeth C., MD, MPH Centers for Disease Control and Prevention Brierley, James, D., MB Princess Margaret Cancer Centre Bull, Joan M.C., MD University of Texas Health Science Center at Houston Chevez-Barrios, Patricia, MD Houston Methodist Chowdary, Sajeel, MD Boca Raton Regional Hospital Climent, Consuelo, MD University of Puerto Rico Colon-Otero, Gerardo, MD Mayo Clinic Dagan, Roi, MD University of Florida DeGregorio, Richard, MD Surgical Pathology Laboratories October 2016, Vol. 23, No. 4 Deneve, Jeremiah L., MD University of Tennessee Health Science Center Dickson, Paxton, MD University of Tennessee Health Sciences Center Drucker, Mitchell D., MD University of South Florida Eisbruch, Avraham, MD University of Michigan Friedman, Scott, MD Mount Sinai Hospital Glas, Martin, MD Robert Janker Clinic University of Bonn Medical Center Glezerman, Ilya G., MD Memorial Sloan Kettering Cancer Center Goovaerts, Pierre, PhD BioMedware Hara, Wendy, MD Stanford University Harbour, J. William, MD Bascom Palmer Eye Institute Hassanein, Ashraf, MD, PhD Florida Dermatologic Surgery & Aesthetics Institute Florida Pathology Hernandez, Brenda Y., PhD, MPH University of Hawaii Jatoi, Aminah, MD Mayo Clinic Jones, Lovell A., PhD Prairie View A&M University College of Nursing Lichtman, Stuart, MD Memorial Sloan Kettering Luque, John, MD Medical University of South Carolina Mahtani, Reshma L., MD University of Miami Health System Maluccio, Mary A., MD, MPH Indiana University School of Medicine Margo, Curtis, MD University of South Florida Margolies, Laurie, MD Mount Sinai School of Medicine Montero, Jose, MD University of South Florida Moore, Charles E., MD Emory University School of Medicine Muro-Cacho, Carlos, MD James A. Haley Veterans Hospital Nevidjon, Brenda, MSN, RN Oncology Nursing Society Nguyen, Jennifer, PhD, MPH University of Florida Oehler, Richard, MD James A. Haley Veterans Administration Hospital Pentz, Rebecca D., PhD Emory School of Medicine Phuphanich, Surasak, MD Cedars-Sinai Medical Center Razis, Evangelia, MD, PhD Hygeia Hospital Rigakos George, MD, MSc Hygeia Hospital Kamen, Charles, PhD University of Rochester Medical Center Rowe, Christopher, MD University of Newcastle Kanji, Jamil, MD University of Alberta Rusch, Valerie W., MD Memorial Sloan Kettering Cancer Center Lavand’homme, Patricia, MD, PhD Université Catholique de Louvain LeRuhn, Emilie, MD University Hospital and Oscar Lambret Center Saeed, Maythem, MD University of California at San Francisco Sheikhattari, Payam, MD, MPH Morgan State University Cancer Control 463 Peer Reviewers, 2016 Simmons, Melissa A., MD Northwestern University Sioutos, Panayiotis, MD Hygeia Hospital Sniffin, Jason, DO Florida Hospital Orlando Infectious Disease Consultants Tang, Haidong, PhD University of Texas Southwestern Medical Center Thompson, Haley, PhD Barbara Ann Karmanos Cancer Institute Wayne State University Tyson, Mark D., MD Mayo Clinic Vander Poorten, Vincent, MD Leuven Cancer Institute Wayman, Laura L., MD Vanderbilt University Yom, Sue S., MD, PhD University of California at San Francisco Zhang, Paul J., MD University of Pennsylvania Internal Reviewers (H. Lee Moffitt Cancer Center & Research Institute) Ahmad, Nazeel, MD Arrington, John, MD Balducci, Lodovico, MD Caracciolo, Jamie, MD Caudell, Jimmy J., MD, PhD Chon, Hye Sook, MD Clark, Terry J., MScA Coppola, Domenico, MD Dessureault, Sophie, MD Dhillon, Jasreman, MD Dossett, Lesly, MD Green, B. Lee, PhD Greene, John N., MD Gwede, Clement K., PhD Harrison, Louis B., MD Hudson, Janella, PhD Kumar, Nagi B., PhD Laber, Damian A., MD Lancet, Jeffrey, MD Makanji, Rikesh, MD Mullinax, John E., MD Nanjappa, Sowmya, MD Niell, Bethany, MD, PhD Otto, Kristen, MD Pasikhova, Yanina, PharmD Pow-Sang, Julio M., MD Quinn, Gwendolyn P., PhD So, Wonhee, PharmD Sutton, Steve K., PhD Trotti, Andy, MD Wang, Xia, MD Zager, Jonathan S., MD 464 Cancer Control October 2016, Vol. 23, No. 4 Index for 2016, Volume 23 Vol. 23, No. 1: Regional Therapeutics 3 Art, Science, and Personalized Cancer Care Through Regional Therapeutics 61Special Report: Genetic Investigation of Uterine Carcinosarcoma: Case Report and Cohort Analysis Timothy N. Hembree, DO, PhD, Jamie K. Teer, PhD, Ardeshir Hakam, MD, and Alberto A. Chiappori, MD Kristen Otto, MD, and Jonathan S. Zager, MD 6 Stereotactic Body Radiotherapy for Recurrent Unresectable Head and Neck Cancers Tobin Strom, MD, Christian Wishka, and Jimmy J. Caudell, MD, PhD 12 Developments in Intralesional Therapy for Metastatic Melanoma 67Special Report: Advances in the Endoscopic Diagnosis of Barrett Esophagus Ashley H. Davis-Yadley, MD, Kevin G. Neill, MD, Mokenge P. Malafa, MD, and Luis R. Peña, MD 78Special Report: Association of microRNA 21 With Biological Features and Prognosis of Neuroblastoma Yaodong Zhou, MD, and Bo Sheng, MD Sarah Sloot, MD, Omar M. Rashid, MD, JD, Amod A. Sarnaik, MD, and Jonathan S. Zager, MD 21Stereotactic Body Radiotherapy in the Management of Oligometastatic Disease Kamran A. Ahmed, MD, and Javier F. Torres-Roca, MD Vol. 23, No. 2: Ocular Oncology 90Are Ocular and Ocular Adnexal Cancers Overdiagnosed? Historical Perspectives on Diagnosis 30Local Ablation for Solid Tumor Liver Metastases: Techniques and Treatment Efficacy Curtis E. Margo, MD 93Assessing Prognosis in Uveal Melanoma Joyce Wong, MD, and Amanda Cooper, MD Zélia M. Corrêa, MD, PhD 36Hyperthermic Intraperitoneal Chemotherapy and Cytoreductive Surgery in the Management of Peritoneal Carcinomatosis Rahul Rajeev, MBBS, and Kiran K. Turaga, MD 47Disparities Report: Racial Disparity in Time Between First Diagnosis and Initial Treatment of Prostate Cancer Ballington L. Kinlock, PhD, Roland J. Thorpe Jr, PhD, Daniel L. Howard, PhD, Janice V. Bowie, PhD, Louie E. Ross, PhD, David O. Fakunle, and Thomas A. LaVeist, PhD 52Disparities Report: Exploring the Perceptions of Anal Cancer Screening and Behaviors Among Gay and Bisexual Men Infected With HIV Alexis M. Koskan, PhD, Natalie LeBlanc, MPH, and Isabella Rosa-Cunha, MD 99Therapeutic Options for Retinoblastoma Pia R. Mendoza, MD, and Hans E. Grossniklaus, MD 110 Primary Vitreoretinal Lymphoma: Management of Isolated Ocular Disease Matthew T. Witmer, MD 117 Management of Primary Acquired Melanosis, Nevus, and Conjunctival Melanoma Andrew Kao, MD, Armin Afshar, MD, Michele Bloomer, MD, and Bertil Damato, MD, PhD 126Sebaceous Carcinoma of the Eyelid Carlos Prieto-Granada, MD, and Paul Rodriguez-Waitkus, MD, PhD 133Role of Vismodegib in the Management of Advanced Periocular Basal Cell Carcinoma Kyle F. Cox, MD, and Curtis E. Margo, MD 59Case Report: Hyperuricemia in 2 Patients Receiving Palbociclib for Breast Cancer David J. Bromberg, MD, Mauricio Valenzuela, MD, Sowmya Nanjappa, MD, and Smitha Pabbathi, MD 140Extranodal Marginal Zone B-cell Lymphoma of the Ocular Adnexa October 2016, Vol. 23, No. 4 Jean Guffey Johnson, MD, Lauren A. Terpak, MS, Curtis E. Margo, MD, and Reza Setoodeh, MD Cancer Control 465 Index for 2016, Volume 23 150Ophthalmic Complications Related to Chemotherapy in Medically Complex Patients 213Clinical Benefits of Proton Beam Therapy for Tumors of the Skull Base Lynn E. Harman, MD 157Disparities Report: Disparities Among Minority Women With Breast Cancer Living in Impoverished Areas of California Sundus Haji-Jama, Kevin M. Gorey, PhD, Isaac N. Luginaah, PhD, Guangyong Zou, PhD, Caroline Hamm, MD, and Eric J. Holowaty, MD 163Infectious Disease Report: Bordetella pertussis Infection in Patients With Cancer Abraham Yacoub, MD, Sowmya Nanjappa, MD, Tyler Janz, and John N. Greene, MD 167Pharmacy Report: Megestrol Acetate-Induced Adrenal Insufficiency Sowmya Nanjappa, MD, Christy Thai, PharmD, Sweta Shah, MD, and Matthew Snyder, PharmD 170 Pathology Report: Presacral Noncommuni- cating Enteric Duplication Cyst Shabnam Seydafkan, MD, David Shibata, MD, Julian Sanchez, MD, Nam D. Tran, MD, Marino Leon, MD, and Domenico Coppola, MD 175 Symposium Report: Second Annual Moffitt Anatomic Pathology Symposium Vol. 23, No. 3: Head and Neck Cancers 192Maximizing Cures and Preserving Function in Head and Neck Cancers Louis B. Harrison, MD, and Jimmy J. Caudell, MD, PhD 197Management of Oropharyngeal Cancer in the HPV Era Arash O. Naghavi, MD, Tobin J. Strom, MD, Kamran A. Ahmed, MD, Michelle I. Echevarria, MD, Yazan A. Abuodeh, MD, Puja S. Venkat, MD, Jessica M. Frakes, MD, Louis B. Harrison, MD, Andy M. Trotti, MD, and Jimmy J. Caudell, MD, PhD 208Definitive Radiotherapy for Squamous Cell Carcinoma of the Glottic Larynx William M. Mendenhall, MD, Roi Dagan, MD, Curtis M. Bryant, MD, Robert J. Amdur, MD, and Anthony A. Mancuso, MD 466 Cancer Control Kamran A. Ahmed, MD, Stephanie K. Demetriou, Mark McDonald, MD, and Peter A.S. Johnstone, MD 220Management of BCC and SCC of the Head and Neck Tobin J. Strom, MD, Jimmy J. Caudell, MD, PhD, and Louis B. Harrison, MD 228Treatment of Head and Neck Paragangliomas Kenneth Hu, MD, and Mark S. Persky, MD 242Multidisciplinary Management of Salivary Gland Cancers Matthew J. Mifsud, MD, Jon N. Burton, MD, Andy M. Trotti, MD, and Tapan A. Padhya, MD 249Pathology Report: Practical Issues for Retroperitoneal Sarcoma Vicky Pham, MS, Evita Henderson-Jackson, MD, Matthew P. Doepker, MD, Jamie T. Caracciolo, MD, Ricardo J. Gonzalez, MD, Mihaela Druta, MD, Yi Ding, MD, and Marilyn M. Bui, MD, PhD 265Infectious Diseases Report: Primary Gangrenous Cutaneous Mold Infections in a Patient With Cancer and Neutropenia Abraham Yacoub, MD, Kiran K. Soni, Lysenia Mojica, MD, Jane Mai, MD, Jamie Morano, MD, C. Wayne Cruse, MD, Ramon L. Sandin, MD, Sowmya Nanjappa, MBBS, MD, Chandrashekar Bohra, MBBS, Ganesh Gajanan, MBBS, and John N. Greene, MD 272Case Series: Diffuse Alveolar Hemorrhage in Acute Myeloid Leukemia Sowmya Nanjappa, MBBS, MD, Daniel K. Jeong, MD, Manjunath Muddaraju, MD, Katherine Jeong, MD, Eboné D. Hill, MD, and John N. Greene, MD 278Case Series: Marijuana Smoking in Patients With Leukemia Sara Khwaja, MD, Abraham Yacoub, MD, Asima Cheema, MD, Nancy Rihana, MD, Robin Russo, MD, Ana Paula Velez, MD, Sowmya Nanjappa, MBBS, MD, Ramon L. Sandin, MD, Chandrashekar Bohra, MBBS, Ganesh Gajanan, MBBS, and John N. Greene, MD October 2016, Vol. 23, No. 4 Index for 2016, Volume 23 284 Special Report: Platelet-to-Lymphocyte Ratio and Use of NSAIDs During the Perioperative Period as Prognostic Indicators in Patients With NSCLC Undergoing Surgery Brenda M. Lee, MD, Andrea Rodríguez, MD, Gabriel Mena, MD, Vijaya Gottumukkala, MB, MD, Reza J. Mehran, MD, David C. Rice, MB, Lei Feng, MS, Jun Yu, MS, and Juan P. Cata, MD 295Special Report: Resection of the First Rib With Preservation of the T1 Nerve Root in Pancoast Tumors of the Lung Andreas K. Filis, MD, Lary A. Robinson, MD, and Frank D. Vrionis, MD, PhD 302Special Report: Feasibility, Preliminary Efficacy, and Lessons Learned From a Garden-Based Lifestyle Intervention for Cancer Survivors Colleen K. Spees, PhD, RDN, Emily B. Hill, Elizabeth M. Grainger, PhD, RDN, Jackie L. Buell, PhD, RDN, Susan E. White, PhD, Matthew D. Kleinhenz, PhD, and Steven K. Clinton, MD, PhD 311 Special Report: Hypofractionated Stereotactic Radiotherapy for Auditory Canal or Middle Ear Cancer Taro Murai, MD, Shin-Etsu Kamata, MD, Kengo Sato, MD, Kouki Miura, MD, Mitsuhiro Inoue, Naoki Yokota, MD, Seiji Ohta, MD, Michio Iwabuchi, MD, Hiromitsu Iwata, MD, and Yuta Shibamoto, MD Vol. 23, No. 4 Supplement: Lung Cancer 2 Best Practices in Treatment Selection for Patients With Advanced NSCLC 2 Mark A. Socinski, MD, and Nathan Pennell, MD, PhD Vol. 23, No. 4: Health Disparities in Oncology 327Barriers to Clinical Trial Enrollment in Racial and Ethnic Minority Patients With Cancer Lauren M. Hamel, PhD, Louis A. Penner, PhD, Terrance L. Albrecht, PhD, Elisabeth Heath, MD, Clement K. Gwede, PhD, RN, and Susan Eggly, PhD 338Racial and Ethnic Differences in the Epidemiology and Genomics of Lung Cancer 347Black Heterogeneity in Cancer Mortality: US-Blacks, Haitians, and Jamaicans Paulo S. Pinheiro, MD, PhD, Karen E. Callahan, MPH, Camille Ragin, PhD, MPH, Robert W. Hage, MD, PhD, DLO, MBA, Tara Hylton, MPH, and Erin N. Kobetz, PhD, MPH 359Genomic Disparities in Breast Cancer Among Latinas Filipa Lynce, MD, Kristi D. Graves, PhD, Lina Jandorf, MA, Charité Ricker, MS, Eida Castro, PsyD, Laura Moreno, Bianca Augusto, Laura Fejerman, PhD, and Susan T. Vadaparampil, PhD 373Clinical Considerations of Risk, Incidence, and Outcomes of Breast Cancer in Sexual Minorities Anne E. Mattingly, MD, John V. Kiluk, MD, and M. Catherine Lee, MD 383Construction and Validation of a Multi Institutional Tissue Microarray of Invasive Ductal Carcinoma From Racially and Ethnically Diverse Populations Edward Seijo, MS, Diana Lima, MPH, Egiebade Iriabho, MS, Jonas Almeida, PhD, Jesus Monico, MPH, MS, Margarita Echeverri, PhD, Sylvia Gutierrez, MD, Idhaliz Flores, PhD, Ji-Hyun Lee, PhD, Kate Fisher, MA, William E. Grizzle, MD, PhD, Gabriel L. Sica, MD, PhD, Charles Butler, Chindo Hicks, PhD, Cathy D. Meade, PhD, RN, Stephen Olufemi Sodeke, PhD, Krzysztof Moroz, MD, Domenico Coppola, MD, and Teresita Muñoz-Antonia, PhD 390Determinants of Treatment Delays Among Underserved Hispanics With Lung and Head and Neck Cancers Evelinn A. Borrayo, PhD, Katie L. Scott, PhD, Ava R. Drennen, PhD, Tiare MacDonald, PhD, and Jennifer Nguyen, MS 401Geographical Factors Associated With Health Disparities in Prostate Cancer Scott M. Gilbert, MD, Julio M. Pow-Sang, MD, and Hong Xiao, PhD 409Disparities in Penile Cancer October 2016, Vol. 23, No. 4 Matthew B. Schabath, PhD, W. Douglas Cress, PhD, and Teresita Muñoz-Antonia, PhD Pranav Sharma, MD, Kamran Zargar-Shoshtari, MD, Curtis A. Pettaway, MD, Matthew B. Schabath, PhD, Anna R. Giuliano, PhD, and Philippe E. Spiess, MD Cancer Control 467 Index for 2016, Volume 23 415 Chemoprevention in African American Men With Prostate Cancer Nagi B. Kumar, PhD, RD, Julio M. Pow-Sang, MD, Philippe E. Spiess, MD, Jong Y. Park, PhD, Ganna Chornokur, PhD, Andrew R. Leone, MD, and Catherine M. Phelan, PhD, MD 424Disparities in Adolescents and Young Adults With Cancer Leidy L. Isenalumhe, MD, Olivia Fridgen, MPH, Lynda K. Beaupin, MD, Gwendolyn P. Quinn, PhD, and Damon R. Reed, MD 434Tobacco-Related Health Disparities Across the Cancer Care Continuum Vani Nath Simmons, PhD, Bárbara Piñeiro, PhD, Monica Webb Hooper, PhD, Jhanelle E. Gray, MD, and Thomas H. Brandon, PhD 442 Case Series: Human Metapneumovirus Infection in Immunocompromised Patients Sharmeen Samuel, MD, Sowmya Nanjappa, MBBS, MD, Christopher D. Cooper, MD, and John N. Greene, MD 446Special Report: Systematic Review and Case Series Report of Acinar Cell Carcinoma of the Pancreas Evan S. Glazer, MD, PhD, Kevin G. Neill, MD, Jessica M. Frakes, MD, Domenico Coppola, MD, Pamela J. Hodul, MD, Sara E. Hoffe, MD, Jose M. Pimiento, MD, Gregory M. Springett, MD, PhD, and Mokenge P. Malafa, MD, PhD 455Special Report: A Single-Institution Study of Demographics and Outcomes of Adult Patients With Multiple Cancers Thanh P. Ho, MD, Nathan R. Foster, MS, and Aminah Jatoi, MD 468 Cancer Control October 2016, Vol. 23, No. 4 Current Perspectives in Oncology Nursing Save the Date! | Call for Abstracts February 16–17, 2017 Moffitt Cancer Center, Tampa, FL 16th Annual Nursing Conference Special Event The 22nd Annual Rhinehart Reception & Lecture | February 15, 2017 Moffitt Cancer Center Vincent A. Stabile Research Building 12902 Magnolia Drive, Tampa, FL 33612 ( For additional conference information please contact Gina Woodward at 813-745-1741 or [email protected] (
