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Oncology Advances Summer 2015 Page 2 PD-1 Inhibitor Trials Target Gastrointestinal Cancers, Span Many Cancer Types in Combination Studies Immunotherapy trials at Dana-Farber/Brigham and Women’s Cancer Center using PD-1 inhibitors have expanded to include studies for several gastrointestinal cancers and combination studies spanning a wide range of cancers. Page 4 New Study Finds Many Patients Choose Mastectomy, Despite Eligibility for Breast Conserving Therapy At the American Surgical Association’s 135th Annual Meeting, Mehra Golshan, MD, a breast surgeon at Brigham and Women’s Hospital and Medical Director of International Oncology Programs at Dana-Farber/Brigham and Women’s Cancer Center, presented findings of a multicenter study evaluating the impact of neoadjuvant chemotherapy in Stage II-III triple negative breast cancer on eligibility for breast conserving surgery and breast conservation rates. Page 5 New Clinic Studies Innovative Approaches to Prevent the Progression of Blood Cancer in Patients with Precursor Conditions The new Blood Cancer Prevention of Progression Clinic is designed to enhance the understanding of the progression and clonal evolution of blood cancers in order to provide targeted approaches to prevent the development of blood cancers in patients with precursor conditions. Page 6 Thyroid Cancer Center Focuses on Targeted Therapy, Tailored Approaches to Evaluation and Treatment The multidisciplinary team in the new Thyroid Cancer Center is employing novel approaches to the evaluation, diagnosis, treatment, and management of all forms of thyroid cancer, as well as nodular disease. Page 7 Now Available: Next Day Access for New Patients in Boston 2 | Oncology Advances PD-1 Inhibitor Trials Target Gastrointestinal Cancers, Span Many Cancer Types in Combination Studies Immunotherapy trials at Dana-Farber/Brigham and Women’s Cancer Center using PD-1 inhibitors have expanded to include studies for several gastrointestinal cancers and combination studies spanning a wide range of cancers. of gastric cancers. An earlier phase study of PD-1 inhibition across a range of cancers also showed specific benefit in patients with gastric cancer. The Center for Immuno-Oncology at Dana-Farber/Brigham and Women’s Cancer Center, led by Director F. Stephen Hodi, Jr., MD, and Clinical Director Patrick A. Ott, MD, PhD, offers more than 20 early phase immunotherapy trials using a variety of approaches. Dr. Hodi and Dr. Ott also collaborate with disease center leaders at Dana-Farber/Brigham and Women’s Cancer Center to initiate immunotherapy trials in cancers where immunotherapy has not traditionally been used. A New Approach for Gastrointestinal Cancers The Gastrointestinal Cancer Center at Dana-Farber/Brigham and Women’s Cancer Center is currently enrolling patients in a phase II trial of the PD-1 inhibitor pembrolizumab for patients with metastatic gastric or gastroesophageal junction adenocarcinoma who have progressed on at least two prior chemotherapy regimens, including trastuzumab. Charles Fuchs, MD, MPH, Director of the Gastrointestinal Cancer Center, is the site Principal Investigator of this study, which is based on previous demonstration of efficacy in earlier studies of PD-1 inhibition in gastric cancer. For more information regarding this trial, please contact Christopher Graham, RN, at (617) 632-5960. The Center is expected to open numerous additional trials using pembrolizumab in the fall of 2015, including first line and second line therapy for patients with gastrointestinal cancers. Another study will combine pembrolizumab with ramucirumab, a monoclonal antibody VEGFR-2 antagonist that was approved after demonstrating a survival benefit in advanced gastric cancer in a separate study led by Dr. Fuchs (Lancet. 2014 Jan 4;383(9911):31-9.). “Immunotherapy represents an entirely new way to treat gastrointestinal cancers, but our approach to this treatment is based on scientific evidence of target mutations in these cancers,” said Dr. Fuchs. Genomic Analysis of Gastric Cancer Through The Cancer Genome Atlas (TCGA) program, medical oncologist Adam Bass, MD, co-chaired the largest ever project to map the genomic changes in gastric and esophageal cancers. A comprehensive genomic analysis of nearly 300 gastric cancers, performed by TCGA researchers, was published in Nature last year (Nature. 2014 Sep 11;513(7517):202-9.). The study showed the amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2) in a subtype Key features of gastric cancer subtypes. (Nature. 2014 Sep 11; 513(7517):202-9.) Combination Therapies with PD-1 Inhibitors In the Center for Immuno-Oncology, Dr. Hodi and Dr. Ott are leading several trials that are combining pembrolizumab (and other agents directed at PD-1 or PD-L1) with other therapies for the treatment of a range of cancers in order to assess safety and increase efficacy of treatment for these cancers. The Center features an immune assessment core for evaluation of patients on current immunotherapies and a pathology core for identification of biomarkers and analysis of immune therapies. Examples of current combination therapy studies in the Center for Immuno-Oncology are: • Phase 1 Trial of MK-3475 Plus Ziv-Aflibercept in Patients With Advanced Solid Tumors – This study, led by international Principal Investigator F. Stephen Hodi, MD, will examine the side effects and best dose of ziv-aflibercept when given together with pembrolizumab in treating patients with advanced solid tumors, including metastatic melanoma, metastatic renal cell carcinoma, recurrent colorectal cancer, recurrent ovarian cancer, recurrent renal cell carcinoma, stage IV ovarian cancer, stage IVA colorectal cancer, and stage IVB colorectal cancer. For more information regarding this trial, please contact Principal Investigator F. Stephen Hodi, MD, at (617) 632-5053 or [email protected]; Dana-Farber/Brigham and Women’s Cancer Center | 3 • Phase I/II Clinical Trial to Study the Safety and Tolerability of MK-3475 + Pegylated Interferon Alfa-2b (PEG-IFN) and MK-3475 + Ipilimumab (IPI) in Subjects With Advanced Melanoma and Renal Cell Carcinoma (KEYNOTE 029) –This study, led by site Principal Investigator F. Stephen Hodi, MD, is analyzing the safety, tolerability, and efficacy of treatment for advanced melanoma and renal cell carcinoma using combination regimens of pembrolizumab + pegylated interferon alfa-2b (PegIFN-2b) and pembrolizumab + ipilimumab (IPI). The primary hypothesis is that these combinations will be sufficiently well-tolerated to permit continued clinical investigation. For more information regarding this trial, please contact Christopher Graham, RN, at (617) 632-5960. “Our studies open new opportunities to patients with cancer by specifically manipulating the patient’s own immune system to recognize and destroy cancer. We are enabling clinicians to enroll patients in trials of novel agents when a dedicated study of the targeted approach for that specific cancer type is not available,” said Dr. Hodi. Tumor cell IFN-γR IFN-γ –mediated upregulation of tumor PD-L1 PD-L1/PD-1–mediated inhibition of tumor cell killing MHC-I PD-L1 T-cell receptor IFN-γ PD-1 TCR Shp-2 MHC-I Priming and activation of T cells Other NFκB PI3K CD28 B7.1 CD8ⴙ cytotoxic T lymphocyte Shp-2 Dendritic cell PD-L1 B7.1 PD-1 PD-L1 B7.1 PD-L1 PD-L1 PD-1 PD-1 PD-L1 PD-1 Treg cell PD-L1 Tumor-associated fibroblast M2 macrophage Stromal PD-L1 modulation of T cells T-cell polarization TGF-β PD-L2 PD-1 IL-4/13 Immune cell modulation of T cells TH2 T cell PD-L2–mediated inhibition of TH 2 T cells Can you generate tumor-killing T cells? Can the T cells get to the tumor? Can the T cells see the tumor? Can the T cells be turned off? Can the T cells be turned off? Antigen priming T-cell trafficking Peptide-MHC expression Inhibitory cytokines PD-L1 expression on tumor cells © 2012 American Association for Cancer Research Charles Fuchs, MD, MPH Director, Gastrointestinal Cancer Center, Dana-Farber/Brigham and Women’s Cancer Center F. Stephen Hodi, Jr., MD Director, Center for Immuno-Oncology, Director, Melanoma Center, Dana-Farber/Brigham and Women’s Cancer Center Patrick A. Ott, MD, PhD Clinical Director, Center for Immuno-Oncology, Clinical Director, Melanoma Center, Dana-Farber/Brigham and Women’s Cancer Center Tumor immunology and the PD-L1/PD-1 pathway. (Clin Cancer Res. 18(24):6580-7.) Refer a Patient to the Center for Immuno-Oncology For more information or consultation, please call 1-877-332-4294 to speak with one of our experienced referral coordinators. We now offer next business day access for first appointments at our main campus in Boston. Leaders in Cancer Treatment and Research 1-877-DFCI-BWH • www.dfbwcc.org (1-877-332-4294) 4 | Oncology Advances New Study Finds Many Patients Choose Mastectomy, Despite Eligibility for Breast Conserving Therapy At the American Surgical Association’s 135th Annual Meeting in April 2015, Mehra Golshan, MD, a breast surgeon at Brigham and Women’s Hospital and Medical Director of International Oncology Programs at Dana-Farber/Brigham and Women’s Cancer Center,, presented findings of a multicenter study evaluating the impact of neoadjuvant chemotherapy in Stage II-III triple negative breast cancer on eligibility for breast conserving surgery and breast conservation rates (Ann Surg. 2015 Jul 28; E-pub ahead of print). Figure 2 “Neoadjuvant systemic therapy is often used to induce tumor regression and enable breast conserving therapy in patients with breast cancer who were to have a mastectomy if they had surgery first,” said Dr. Golshan, who is lead author of the study. “Our goal in this study was to quantify this benefit.” Alliance for Clinical Trials in Oncology Companion Study As part of a surgical companion study to CALGB 40603 (Figure 1), the treating surgeons prospectively evaluated breast conserving therapy (BCT) candidacy before and after neoadjuvant systemic therapy (NST) using clinical and radiographic information. Surgery was performed at surgeon and patient discretion. The presence of genetic mutations was not considered. The researchers measured: Among these patients, 70 percent chose BCT, which was successful in 94 percent of cases. Of the patients who were not initially eligible for BCT prior to NST, 42 percent converted to BCT eligibility. Of these patients, 68 percent chose BCT with a 91 percent success rate (Figure 3, back cover). • Conversion from BCT ineligibility to BCT eligibility; A Range of Significant Results • Surgical choices in BCT candidates; • Rates of successful BCT with tumor-free margins. Among 404 patients who were assessable for surgical outcomes, 54 percent were BCT candidates prior to NST. After NST, 90 percent remained candidates for BCT (Figure 2). The study led to substantial findings, including: • 31 percent of patients who were eligible for BCT still chose mastectomy; • 42 percent of patients who were initially deemed ineligible for BCT were found to be eligible following neoadjuvant systemic therapy. Conversion was highest among patients who received NST with carboplatin, bevacizumab, or both; Figure 1 • 47 percent of patients in the study overall underwent BCT, compared with 75 percent of patients with similar tumor types in a recent German study (von Minckwitz et al.); continued on back cover Mehra Golshan, MD Breast Surgeon, Brigham and Women’s Hospital; Medical Director, International Oncology Programs, Dana-Farber/Brigham and Women’s Cancer Center Dana-Farber/Brigham and Women’s Cancer Center | 5 New Clinic Studies Innovative Approaches to Prevent the Progression of Blood Cancer in Patients with Precursor Conditions The new Blood Cancer Prevention of Progression Clinic is an extensive research program designed to better understand the progression and clonal evolution of blood cancers in order to provide targeted approaches to prevent the development of blood cancers in patients with precursor conditions. These conditions include monoclonal B cell lymphocytosis (MBL), monoclonal gammopathy of undetermined significance (MGUS), and early cases of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). “In the majority of cases, there are no effective disease-modifying therapies available for patients with precursor conditions to blood cancers,” said Irene Ghobrial, MD, Co-Principal Investigator of the Clinic. “We are left waiting until the patient’s condition progresses to initiate treatment.” Experts in the Clinic are aiming to: • Promote earlier detection of precursor conditions; • Identify patients that are most likely to progress in order to focus treatment in this patient population; • Deliver targeted intervention, including the use of shortened duration of therapy with newer agents with low toxicity, to eliminate disease before symptoms appear. with age and is associated with an increased risk of hematologic malignancy. Current studies in the Clinic include: • Phase II Trial of Combination Elotuzumab and Lenalidomide +/- Dexamethasone in High-risk Smoldering Multiple Myeloma – This research study will determine the proportion of high-risk smoldering multiple myeloma patients who are progression free at two years after receiving elotuzumab and lenalidomide+/- dexamethasone combination therapy. For more information regarding this trial, please contact Principal Investigator Irene Ghobrial, MD, at [email protected]; • Study of Precursor Hematological Malignancies to Assess the Relationship between Molecular Events of Progression and Clinical Outcomes – This national observational study, led by Principal Investigator Irene Ghobrial, MD, is identifying molecular changes in cells of patients with precursor hematological malignancies using patients' bone marrow, blood, buccal swab or mouthwash, lymph node, urine, or other specimens. The study will link the participants’ molecular alterations with clinical information that has been generated during the course of clinical care in a large database with a goal to capture data on at least 10,000 patients. For more information regarding this trial, contact Adriana Perilla Glen at (617) 582-8664. “Prevention is the best way to eradicate disease,” said Robert Soiffer, MD, Co-Principal Investigator of the Clinic and Chief of the Division of Hematologic Malignancies at DanaFarber/Brigham and Women’s Cancer Center. “This clinic has the potential to change the trajectory of many blood cancers.” Robert Soiffer, MD Co-Principal Investigator, Blood Cancer Prevention of Progression Clinic; Chief, Division of Hematologic Malignancies; Co-Chief, Adult Stem Cell Transplantation Program; Dana-Farber/Brigham and Women’s Cancer Center Irene Ghobrial, MD, and colleagues have established the Blood Cancer Prevention of Progression Clinic to better understand the evolution of blood cancers in order to provide targeted preventive treatment for patients. Clonal Hematopoiesis Co-Principal Investigators Benjamin Ebert, MD, PhD, and David P. Steensma, MD, recently defined and outlined the nature and prevalence of clonal hematopoiesis of indeterminate potential (CHIP), which is characterized by acquisition of somatic mutations that drive clonal expansion in the absence of cytopenias and dysplastic hematopoiesis (NEJM. 2014 Dec 10; Blood. 2015 July 2;126(1).) CHIP increases in prevalence Irene Ghobrial, MD Co-Principal Investigator, Blood Cancer Prevention of Progression Clinic; Medical Oncologist, Jerome Lipper Multiple Myeloma Center, Dana-Farber/Brigham and Women’s Cancer Center Benjamin Ebert, MD, PhD Co-Principal Investigator, Blood Cancer Prevention of Progression Clinic; Medical Oncologist, Center for Hematologic Malignancies, Dana-Farber/Brigham and Women’s Cancer Center David P. Steensma, MD Co-Principal Investigator, Blood Cancer Prevention of Progression Clinic; Medical Oncologist, Adult Leukemia Program, Dana-Farber/Brigham and Women’s Cancer Center 6 | Oncology Advances Thyroid Cancer Center Focuses on Targeted Therapy, Tailored Approaches to Evaluation and Treatment The multidisciplinary team in the new Thyroid Cancer Center at Dana-Farber/Brigham and Women’s Cancer Center, led by Director Jochen Lorch, MD, is employing novel approaches to the evaluation, diagnosis, treatment, and management of all forms of thyroid cancer, as well as nodular disease. “Our Center delivers comprehensive evaluation and care using tailored approaches for each patient, from assessment of nodules and surgical treatment to targeted therapy for metastatic thyroid cancer,” said Dr. Lorch. Molecular and Genetic Analysis A variety of advanced techniques are employed to evaluate thyroid nodular disease, confirm a new thyroid cancer diagnosis, or assess recurrent or malignant disease. Endocrinologists and cytopathologists in the Center are leaders in the use of diagnostic molecular markers, including gene expression classification and gene mutation panels, to enhance the accuracy in distinguishing between benign or malignant disease. The team’s ongoing research into molecular analysis also is helping to better determine which patients require radioactive iodine or are at high risk for recurrence and to appropriately modify treatment decisions. The team completed the study of everolimus, which is being presented for FDA approval for appropriate patients with thyroid cancer. An investigator-initiated study of MLN0128, a new mTOR inhibitor, will soon become available for patients with anaplastic thyroid cancer and aggressive differentiated thyroid cancer. Tumor tissue sampling performed as part of the studies is linked with sequencing data to allow researchers to correlate clinical response with genetic information. A separate phase II study of the tyrosine kinase inhibitor (TKI) regorafenib is expected to open in fall 2015 as second or third line therapy for patients with metastatic medullary thyroid cancer. Histologic Findings and Computed Tomographic (CT) Scans in a Patient with Metastatic Anaplastic Thyroid Carcinoma. Thyroid Cancer Center endocrinologist Erik K. Alexander, MD, Chief of the Thyroid Section within the Division of Endocrinology, Diabetes and Hypertension at Brigham and Women’s Hospital (BWH), is a member of a panel of the American Thyroid Association that establishes guidelines for the management of thyroid nodules and thyroid cancer care. He was the lead author of a recent multicenter study published in the New England Journal of Medicine (N Engl J Med 2012; 367:705715) that found that patients with cytologically indeterminate nodules on fine needle aspiration that are benign according to gene-expression classification should be considered for a more conservative approach to management. Innovative Targeted Approaches for Advanced Thyroid Cancers Medical oncologists in the Center have introduced innovative trials of targeted therapies for patients with advanced thyroid cancer. Dr. Lorch and Nikhil Wagle, MD, led a recently published study that outlined response and acquired resistance to the mTOR inhibitor everolimus in a 57-year-old patient with metastatic anaplastic thyroid cancer (N Engl J Med 2014;371: 1426-33.). The patient had a near-complete response for 18 months before her disease progressed. As part of the study, whole exome sequencing was performed on samples of the pre-treatment and resistant tumors, demonstrating the mechanisms of cancer response and resistance. Hematoxylin and eosin staining of a total-thyroidectomy specimen (Panel A, top) shows anaplastic thyroid carcinoma; MIB-1 staining (Panel A, bottom) reveals the high proliferative rate of the tumor. A histologic section (hematoxylin and eosin) of an enlarged mediastinal lymph node, obtained after 18 months of a response to everolimus monotherapy, shows recurrent thyroid carcinoma (Panel B). Axial CT scans of the chest show a right-sided hilar mass (arrow) before treatment with everolimus (Panel C), 6 months after treatment initiation (Panel D), and at the time of everolimus resistance, 18 months after treatment initiation (Panel E). (N Engl J Med. 2014; 371:1426-33.) Dana-Farber/Brigham and Women’s Cancer Center | 7 Optimizing Surgical Outcomes Francis D. Moore, Jr., MD, Chief of the BWH Division of General and GI Surgery, leads a team of endocrine surgeons in the Center who perform more than 600 thyroid and thyroid-related procedures each year using advanced techniques. Internationally recognized for the development of team-driven protocols and checklists that have influenced surgery worldwide, the surgeons have reduced the rate of surgical complications to far below national averages for recurrent laryngeal nerve injury, one percent for bleeding, and two percent for parathyroid gland dysfunction. Innovative surgical developments include the use of the Advanced Multimodality Image Guided Operating (AMIGO) Suite at Brigham and Women’s Hospital for select patients with thyroid and parathyroid tumors. In the AMIGO suite, surgeons employ real-time imaging and 3D models to enhance navigation to identify small tumors, confirm complete resection, and avoid injury to key nerves and blood vessels. Endocrine surgeon Daniel T. Ruan, MD, was the first to utilize this technology during neck surgery and the first to describe MRI imaging of the recurrent laryngeal nerve during a thyroidectomy (N Engl J Med 2015; 373:96-98). Injury to this important nerve during thyroid and parathyroid surgery can result in vocal cord paralysis, leading to problems with speech, swallowing, and breathing. “Real-time imaging during thyroid surgery can further reduce the risk of complications, including injury to nerves and other important structures,” said Dr. Moore. Refer a Patient to Dana-Farber/Brigham and Women’s Cancer Center For more information or consultation, please call 1-877-332-4294 to speak with one of our experienced referral coordinators. We now offer next business day access for first appointments at our main campus in Boston. Next Day Access in Boston for New Oncology Patients Dana-Farber/Brigham and Women’s Cancer Center in Boston now offers next business day access for first appointments. To facilitate this streamlined access, patients who are scheduled for next day access are contacted within a few hours by an oncology nurse to discuss their history and records. To refer a patient, or schedule a consultation with a member of our team, please call 1-877-332-4294. Jochen Lorch, MD, Francis D. Moore, Jr., MD, and Erik K. Alexander, MD, employ a multidisciplinary approach to the evaluation and treatment of patients with thyroid cancer and nodular disease. Jochen Lorch, MD Director, Thyroid Cancer Center, Dana-Farber/Brigham and Women’s Cancer Center Erik K. Alexander, MD Chief, Thyroid Section, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital; Endocrinologist, Thyroid Center, Dana-Farber/Brigham and Women’s Cancer Center Francis D. Moore, Jr., MD Chief, Division of General and GI Surgery, Brigham and Women’s Hospital; Surgeon, Thyroid Cancer Center, Dana-Farber/Brigham and Women’s Cancer Center Daniel T. Ruan, MD Surgical Director, Center for Adrenal Disorders, Brigham and Women’s Hospital; Surgeon, Dana-Farber/Brigham and Women’s Cancer Center See a Video of an Adrenal Tumor Surgery Visit mdvideocenter.brighamandwomens.org to see a video presentation of a Retroperitoneoscopic Right Adrenalectomy performed by Daniel T. Ruan, Surgical Director, Center for Adrenal Disorders. New Study Finds Many Patients Choose Mastectomy, Despite Eligibility for Breast Conserving Therapy… Upcoming CME Courses continued from page 4 Dana-Farber/Brigham and Women’s Cancer Center offers CME courses that cover the latest developments in clinical research and treatments. The courses are offered in conjunction with the Harvard Medical School Department of Continuing Medical Education and Partners Office of Continuing Professional Development, which are both accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. • 93 percent of patients who opted for BCT were able to successfully undergo BCT as part of the study. “Our study suggests that further investigation of the reasons behind these findings is warranted,” said Dr. Golshan. “It is important to better understand the factors that are influencing patients’ and surgeons’ decisions to opt for mastectomy in cases where breast conserving therapy is a viable option with a high likelihood of success.” Figure 3 Advances in the Management of Pancreatic and Biliary Tumors Saturday, October 31, 2015 Dana-Farber Cancer Institute, Boston, MA Advances in the Treatment of Genitourinary Cancers Saturday, November 21, 2015 Dana-Farber Cancer Institute, Boston, MA For more information on these and other CME courses, visit dfbwcc.org/cme. Tari King, MD, Appointed New Chief of Breast Surgery Dana-Farber/Brigham and Women’s Cancer Center is pleased to announce that Tari King, MD, has been appointed the new Chief of Breast Surgery. Dr. King has a national and international reputation as an outstanding breast surgeon, a thoughtful educator, a productive clinical/translational researcher, and an effective leader. Previously, Dr. King served as the Deputy Chief of Breast Surgical Services and Principal Investigator of the Breast Surgery Research Laboratory at Memorial Sloan-Kettering Cancer Center, where she was a faculty member for more than a decade. Her research has focused on the elucidation of the molecular genetics of breast cancer, focusing on high-risk populations, as well as on the mechanisms involved in the progression from non-invasive to invasive disease. Dr. King received her medical degree from the University of Colorado Health Sciences Center. She completed her residency at the Ochsner Medical Institutions in New Orleans and her clinical and research fellowships at Memorial Sloan-Kettering Cancer Center.