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Focus on Female Cancers:
Hereditary Breast and Ovarian Cancer
American College of Obstetricians and Gynecologists, District II/NY
152 Washington Avenue, Albany, New York 12210
Telephone: (518) 436-3461 • Fax: (518) 426-4728
E-mail: [email protected] • Website: www.acogny.org
Hereditary Breast and Ovarian Cancer Task Force:
KERRY RODABAUGH, MD, FACOG, Chair
MOLLY A. BREWER, DVM, MD, MS, FACOG
EVA CHALAS, MD, FACOG, FACS
CAMILLE A. CLARE, MD, FACOG
MARK S. DeFRANCESCO, MD, MBA, FACOG
LUBA DJURDJINOVIC, MS
MARY EIKEN, RN, MS
LISA ENG, DO, FACOG
CAROLYN FARRELL, MS, RN, WHCNP, CGC
NEIL HOROWITZ, MD, FACOG
MOLLIE HUTTON, MS, CGC
EDMUND KAPLAN, MD, FACOG
NOAH D. KAUFF, MD, FACOG
MAUREEN KILLACKEY, MD, FACOG, FACS
ELLEN T. MATLOFF, MS
ELAINE MIELCARSKI, CNM, MS, NP, FACNM
MURRAY NUSBAUM, MD, FACOG
KENNITH OFFIT, MD, MPH
RICHARD N. WALDMAN, MD, FACOG
ELIZABETH WARNER, MD, FACOG
STERLING WILLIAMS, MD, MS, FACOG
STANLEY ZINBERG, MD, FACOG
Staff:
DONNA MONTALTO, MPP
KATHERINE L. CAMPBELL, MPH
SHAKIRA CRAMER
KATY STEVENSON
This initiative was a joint collaboration between District I and II
Compiled in July 2008
Focus on Female Cancers • ACOG District II/NY • 1 Dear Women’s Health Care Provider,
O
n behalf of the American College of Obstetricians and Gynecologists, District I and District II
(ACOG), we are pleased to provide you with the second chapter of Focus on Female Cancers,
a resource guide offering relevant cancer provider education. This chapter’s content focuses
on hereditary breast and ovarian cancer (HBOC), how to take a family history to identify
patients at risk of the HBOC syndrome, and how to appropriately refer patients for genetic
counseling and testing.
ACOG developed this chapter to respond directly to the needs of District I and II Fellows. Over the last three
decades, hundreds of families have participated in research studies to help understand the heritability of
cancer. To date, two genes, BRCA1 and BRCA2, account for a significant portion of families with inherited
HBOC. While only 5-10% of breast and ovarian cancer diagnoses are associated with inherited mutations
in cancer susceptibility genes, it is important for health care practitioners to be able to identify individuals
suggestive of hereditary cancer risk, as these individuals are at increased risk for multiple primary cancers
as well as early age onset. Once these individuals are identified, they can be offered genetic counseling
and testing services.
We would like to extend our sincere appreciation to the task force of medical experts who offered their
expertise throughout the creation of this resource guide chapter. Their knowledge and dedication to this
joint initiative was invaluable.
The HBOC resource guide chapter is the second installment in a series of comprehensive education and
resources on cancers in women. The first chapter addressed cervical cancer screening and management
guidelines, cytologic terminology and emerging technologies such as the HPV vaccine. ACOG will continue
developing additional chapters, which will be added to the resource guide in the future. If you have any
questions regarding the resource guide or ACOG’s cancer initiatives, please contact the ACOG District II
office at [email protected] or (518) 436-3461.
Sincerely,
Kerry Rodabaugh, MD, FACOG
Chair, Hereditary Breast and Ovarian Cancer Task Force
Richard N. Waldman, MD, FACOG
Chair, ACOG District II
2 • Focus on Female Cancers • ACOG District II/NY
Mark S. DeFrancesco, MD, MBA, FACOG
Chair, ACOG District I
❙ ❙ Introduction
Project Overview
I
n 2007, a joint collaboration was formed by ACOG Districts I and II to develop medical education that addresses
hereditary breast and ovarian cancer, increases ob-gyns’ knowledge of genetic counseling and testing, discusses
the role of the family history in cancer genetics, and outlines management strategies for women found to be at
an inherited risk. Ultimately the goal of this joint initiative is to ensure patients are evaluated appropriately and, if
needed, referred for genetic counseling and further testing.
Hereditary breast and ovarian cancer describes an inherited predisposition to breast and ovarian cancer. Approximately
5-10% of women with breast or ovarian cancer developed their malignancy as the result of an inherited risk. HBOC
typically presents with multiple affected family members, may occur at earlier ages, and may include the presence of
multiple and/or bilateral primary cancers.
Age is a primary risk factor in developing cancer in one’s lifetime. Over 95% of breast cancers are identified in women
over 40 years of age. The median age of breast cancer diagnosis is 61 years of age. In families with HBOC, the age of breast
cancer diagnosis is not uncommonly under 40 years of age. Importantly, in HBOC, ovarian cancer does not necessarily
occur at a particularly early age, with the mean age of ovarian cancer diagnosis being 54 in BRCA1 mutation carriers and
62 in BRCA2 mutation carriers.
The content of this resource guide chapter was developed by a panel of nationally recognized experts in women’s health
and cancer genetics. While this chapter provides up-to-date medical information, it is also important for individuals to
remain current with new advances in their field.
This resource guide chapter is aimed at addressing the needs of District I and II Fellows by increasing knowledge of HBOC
and genetic counseling and testing, emphasizing the utility of a family history to identify patients at risk, and stressing
appropriate referral for genetic counseling.
While this chapter serves to guide best practices, the most essential best practices are recognizing the need to evaluate
each patient individually and to always utilize sound clinical judgment. With this in mind, it is our hope that this chapter
provides a foundation from which ob-gyns can achieve optimal quality in patient care.
Focus on Female Cancers • ACOG District II/NY • 3 ❙ ❙ HBOC Overview
This hereditary breast and ovarian cancer chapter contains clinical information on tools for assessing cancer risk,
appropriately referring patients for counseling and further testing as well as management strategies. In addition,
relevant guidelines and other resources have been identified at the end of the chapter for your convenience.
Table of Contents
I. Background. .............................................................................................5
Approximately
5-10% of II. Risk Assessment.....................................................................................11
III. Genetic Counseling. ...............................................................................19
women with
IV. Genetic Testing. ......................................................................................27
breast or
V. Management Strategies.........................................................................33
ovarian
VI. Resources................................................................................................39
cancer developed
Objectives
their
malignancy
as the result
of an inherited
risk.
This guide is designed to enable participants to:
• Discuss the prevalence of BRCA1 and BRCA2 mutations and their relation to breast and ovarian cancer;
• Utilize risk assessment tools to identify appropriate patients for genetic counseling referral;
• Understand the benefits and limitations of genetic counseling and testing; and
• Identify management strategies for patients with an increased risk for developing breast and/or ovarian
cancer and the resources needed to achieve this level of care.
Reference to Myriad Genetics, Inc. and other pharmaceutical companies is not an endorsement of the companies
or their products by ACOG.
4 • Focus on Female Cancers • ACOG District II/NY
❙ ❙ Background
Introduction
Hereditary Syndromes
Hereditary breast and ovarian cancer describes an inherited predisposition
to these forms of cancer. Approximately 5-10% of women with breast or
ovarian cancer developed their malignancy as the result of an inherited
risk. Hereditary breast and ovarian cancer typically presents with multiple
affected family members, may occur at earlier ages, and may include the
presence of multiple and/or bilateral primary cancers.
There are other inherited cancer syndromes that also predispose women
to breast or ovarian cancer. They include Li-Fraumeni Syndrome, Cowden’s
Syndrome, and HNPCC. Li-Fraumeni Syndrome presents with multiple
affected family members with many different types of cancer, most
commonly breast cancer and sarcomas. Cowden’s Syndrome is marked by
multiple family members with breast, endometrial and/or thyroid cancers.
Colon and endometrial cancers are the hallmark cancers for HNPCC, which
also includes a risk for ovarian cancer in women.
Breast Cancer
Estimated New Cases, US (2007)
Women
178,480
Men
2,030
Lifetime Risk
Women
12.3% or 1 in 8
Men
0.1% or 1 in 1,000
Ovarian Cancer
Estimated New Cases, US (2007)
Women
22,430
Lifetime Risk
Women
1.4% or 1 in 71
American Cancer Society, Cancer Facts and Figures (2007)
Family cancer history is an important risk factor in identifying high risk families.
For most women with a family history of breast and/or ovarian cancer, their
personal lifetime risks may be somewhat higher than the general population
risk, but only a small subset of women have the risks associated with an
inherited cancer syndrome. A hallmark of inherited cancer syndromes is multiple
affected individuals in several generations, as well as cancer diagnosed at a
young age. The autosomal dominant inheritance pattern of most inherited
cancer syndromes allows us to understand that mutations in “cancer genes” can
be inherited from a father as well as a mother.
Prevalence
Over the last three decades, hundreds of families have participated in research
studies to help understand the heritability of cancer. The Human Genome Project
has offered many insights into sporadic and inherited cancers. To date, two
genes, BRCA1 and BRCA2, both of which are tumor suppressor genes critical
to maintaining DNA integrity, account for a significant portion of families with
inherited HBOC. In the mid 1990’s the BRCA1 gene was localized to chromosome
17 and BRCA2 to chromosome 13. In 1996, genetic testing was made available
for the BRCA1 and BRCA2 genes. Mutations in BRCA1 and BRCA2 increase the
lifetime risk for breast, ovarian, and certain other cancers. The lifetime risks for
breast and/or ovarian cancer in BRCA1 or BRCA2 mutation carriers have been
reported to range widely. Women with mutations in BRCA1 have a 65-85% risk
for breast cancer and a 36-45% risk for ovarian cancer by age 70. In addition,
women with mutations in BRCA2 have risks of breast and ovarian cancer by
age 70 of approximately 45-85% and 10-27%, respectively. Fallopian tube
and primary peritoneal carcinoma are also over represented in women with
mutations in BRCA1 and BRCA2 genes. Breast and ovarian cancer risks associated
with BRCA1 and BRCA2 mutations may be decreased through risk-reduction
strategies. Please see the table below.
Gene with Mutation
BRCA1
Risk Factors
Age is a primary risk factor in developing cancer in one’s lifetime. Over 95%
of new breast cancer cases are identified in women over 40 years of age. The
median age of breast cancer diagnosis is 61 years of age. In families with
hereditary breast and ovarian cancer the age of breast cancer diagnosis is
not uncommonly under 40 years of age - much younger than the general
population. Importantly, in HBOC, ovarian cancer does not necessarily occur
at a particularly early age, with the mean age of ovarian cancer diagnosis
being 54 in BRCA1 mutation carriers and 62 in BRCA2 mutation carriers.
BRCA2
Cancer Risk
65-85% risk for breast cancer
36-45% risk for ovarian cancer
Increased risk for other cancers
including prostate, colon, pancreas,
fallopian tube and melanoma
45-85% risk for breast cancer
10-27% risk for ovarian cancer
Increased risk for other cancers
including prostate, colon, pancreas,
fallopian tube and melanoma
Focus on Female Cancers • Background • 7 The prevalence of cancer-predisposing BRCA1 and BRCA2 mutations in the
general population is estimated to be between 1/345 and 1/800. Women
diagnosed with breast cancer prior to the age of 50 have a 6.4% chance of
carrying a mutation in either BRCA1 or BRCA2. This number increases to 9.5%
if breast cancer is diagnosed before the age of 40. Women who have ovarian
cancer at any age have a 1 in 10 chance of having a mutation.
Men and women of Ashkenazi descent, which includes the vast majority
of North American Jews, are at a greater risk for HBOC due to three founder
mutations in the BRCA1 and 2 genes found in this population. People of Jewish
ancestry have a 1 in 43 chance of carrying one of three common mutations. Two
mutations are in the BRCA1 gene (185 deletion AG and 5382 insert C) and one in
the BRCA2 gene (6174 deletion T). Given this increased prevalence of mutations,
1 in 10 Ashkenazi women with breast cancer at any age will have a detectable
BRCA1 or BRCA2 mutation. Similarly, Ashkenazi women with ovarian cancer
have a 35-40% chance of having one of the founder mutations.
Three Founder Mutations in the Ashkenazi Community
BRCA1 gene (185 deletion AG)
BRCA1 gene (5382 insert C)
BRCA2 gene (6174 deletion T)
Professional guidelines are available to assist with identification of HBOC
syndrome. Additionally, recommendations for selection of appropriate patients
for genetic testing have been published (references for these guidelines and
recommendations are located in the Resources section at the end of this guide).
Mathematical risk models and tables are available to assist in understanding
a woman’s unique risk and assist you in evaluating suitability for cancer
susceptibility testing. Guidelines and risk models are one step in a complex
process that aims to assure the patient fully appreciates the advantages and
possible risk of genetic testing for a mutation. Cancer genetic risk assessment
and genetic counseling are processes that have been extensively described
and advocated. For some individuals, cancer genetic risk assessments can
become quite complex and referral to experienced genetic professionals may be
appropriate.
The process begins with identification of risk through personal and family
cancer history and progresses through patient education, gene test selection,
informed consent, testing, and test result disclosure. The risk assessment and
genetic education related to risk is only part of the genetic counseling process.
The statistical risk information triggers a response, unique to each patient that
is informed by emotional, social and cultural context, beliefs and attitudes that
range from perceptions of risk, health beliefs, trust in the testing process and
privacy of testing information. A decision to proceed with testing is generally
not based on risk or probability statements. The decision to test brings into focus
several issues; the value of testing information, a consideration of a patient’s
8 • Focus on Female Cancers • ACOG District II/NY
desire “to know” or “not to know” if a mutation exists in the family, the impact
of testing decision on family relations and dynamics and whether testing
information would modify present surveillance and treatment strategy. Genetic
counseling does not always result in genetic testing. However,
genetic testing should not occur without genetic counseling. Those
initiating cancer genetic counseling need to recognize that there are stages
of readiness for some women. A women’s participation in genetic counseling
does not always indicate a willingness or readiness for testing. There is evidence
that genetic counseling can lead to reduction in cancer worry for women with
moderate risk. This means that cancer genetic counseling, even in the absence
of genetic testing, can benefit those with high risk and moderate risk for an
inherited cancer syndrome.
BRCA1 and BRCA2 Genetic Testing
Since the mid 1990’s, Myriad Genetics Laboratories in Salt Lake City, Utah has
been the primary provider of genetic testing for BRCA1 and BRCA2 in the United
States due to the enforcement of a patent on this testing. The laboratory offers
several testing options that include:
• Testing of coding regions of the BRCA1 and BRCA2 genes (DNA
sequencing)
• A three site panel for women and men of Ashkenazi descent which tests
for the three founder mutations
• A site-specific approach for a known family mutation
Genetic testing has its limitations and complexities. Not all mutations that may
exist in the BRCA1 or BRCA2 gene will be identified in the testing process. The
nature of this relatively new test is that approximately 10% of the time, testing
may identify “variants of uncertain significance” (VUS), or mutations of “unknown
clinical significance”. To date, there have been more than 1,500 different variants
reported. Such inconclusive test results can be challenging for the patient and
the physician. Disclosure of test results as part of the genetic counseling process
aims to provide the most current information to patients. In addition, strategies
can be developed to manage the uncertainty of test results and patients should
understand how the results relate to personal and family cancer history.
Strategies for management of risk for individuals with a deleterious mutation
continue to evolve. The availability of risk reduction strategies supports the
importance of early recognition of risk and mutation status.
The concept of genetic risk assessment for these hereditary cancer syndromes
may seem daunting for the obstetrician-gynecologist, especially given its timeconsuming nature. However, it is important to be able to identify women at
risk of HBOC syndrome, and refer appropriately for genetic counseling. There is
consensus that general population screening for BRCA1 and BRCA2 is premature.
ACOG Committees on Ethics and Genetics
Guidelines
References:
Genetic testing is attaining a greater role in the practice of obstetrics and
gynecology. To ensure patients the highest quality of care, providers should be
familiar with the following recommended guidelines published by the ACOG
Committees on Ethics and Genetics:
American Society of Clinical Oncology Policy Statement Update: Genetic testing
for cancer susceptibility. Journal of Clinical Oncology. 2003;21:2397-2406.
• Clinicians should be able to identify patients within their practices who are
candidates for genetic testing and should maintain competence in the face
of increasing genetic knowledge
• Obstetrician-gynecologists should recognize that geneticists and genetic
counselors are an important part of the health care team and should
consult with them and refer as needed
• Discussions with patients about the importance of genetic information
for their kindred, as well as a recommendation that information be shared
with potentially affected family members as appropriate, should be a
standard part of genetic counseling
With this resource guide, we hope to provide you with information to assist with
the identification of the appropriate patients to refer for genetic counseling,
inherited cancer risk assessment, and genetic testing for cancer susceptibility. By
tailoring screening and prevention strategies, the aim is to reduce morbidity and
mortality from these syndromes.
American Society of Clinical Oncology. American Society of Clinical Oncology
policy statement update: Genetic testing for cancer susceptibility. Journal of
Clinical Oncology. 2003; 21(12): 1-10.
Antoniou A, Pharoah PDP, Narod S, et al. Average risks of breast and ovarian
cancer associated with BRCA1 and BRCA2 mutations detected in case series
unselected for family history: A combined analysis of 22 studies. American
Journal of Human Genetics. 2003;72: 1117-1130.
Breast Cancer Facts and Figures 2007-2008: American Cancer Society. Atlanta:
American Cancer Society, Inc.
Breast-ovarian cancer screening. ACOG Committee Opinion 2000;239. ACOG:
Washington DC.
Couch FJ, DeShano ML, Blackwood MA, et al. BRCA1 mutations in women
attending clinics that evaluate the risk of breast cancer. New Engand Journal of
Medicine. 1997;336(20): 1409-1415.
Domchek SM and Weber BL. Clinical management of BRCA1 and BRCA2
mutation carriers. Oncogene. 2006;25:5825-5831.
Farrell C, Lyman M, Freitag K, Fahey C, Piver MS, Rodabaugh KJ. The role of
hereditary nonpolyposis colorectal cancer in the management of familial ovarian
cancer. Genetics in Medicine. 2006;10: 653-657.
Frank TS, Manley SA, Olopade OI, et al. Sequence analysis of BRCA1 and BRCA2:
Correlation of mutations with family history and ovarian cancer risk. Journal of
Clinical Oncology 1998;16(7): 2417-25.
Garber, JE and Offit K. Hereditary Cancer Predisposition Syndromes. Journal of
Clinical Oncology. 2005; 23(2): 276-292.
GeneTests: Medical Genetics Information Resource (database online). Copyright,
University of Washington, Seattle. 1993-2008. Available at www.genetests.org.
Accessed June 10, 2008.
Grann, VR and Jacobson, JS. Population screening for cancer-related germline
gene mutations. The Lancet Oncology. 2002;3(6):341-348.
Focus on Female Cancers • Background • 9 Karlan, BY, Berchuck, A, and Mutch, D.The role of genetic testing for cancer
susceptibility in gynecologic practice. Obstetrics and Gynecology 2007;110(1):
155-167.
King MC, Marks JH, Mandell JB. Breast and ovarian cancer risks due to inherited
mutations in BRCA1 and BRCA2. Science. 2003;302(5465): 643-646.
Moslehi R, Chu W, Karlan B, et al. BRCA1 and BRCA2 mutation analysis of 208
Ashkenazi Jewish women with ovarian cancer. American Journal of Human
Genetics. 2000;66(4):1259-1272.
Newman, B, Mu, H, Butler, L, Millikan, RC, Moorman, PG, and King, MC.
Frequency of breast cancer attributable to BRCA1 in a population-based series of
American women. Journal of the American Medical Association. 1998; 279:915921.
Peters JA. Genetic Counseling. In: Joules W and Hodgson, S, eds. Perspectives in
Inherited Cancer Syndromes. Cambridge,UK:Cambridge University Press; 1998.
Risch HA, McLaughlin JR, Cole DE, et al. Prevalence and penetrance of germline
BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian
cancer. American Journal of Human Genetics. 2001;68(3): 700-710.
Robson M and Offit K. Management of an inherited predisposition to breast
cancer. New Engandl Journal of Medicine. 2007; 357:154-162.
Role of the obstetrician-gynecologist in the screening and diagnosis of breast
masses. ACOG Committee Opinion. 2006;334. ACOG: Washington DC.
Rubinstein WS, O'Neill SM, Peters JA, Rittmeyer LJ, and Stadler MP. Mathematical
modeling for breast cancer risk assessment: State of the art and role in medicine.
Oncology (Huntingt). 2002;16(8):1082-1094.
New York State Department of Health and American College of Medical Genetics.
Genetic susceptibility to breast and ovarian cancer: Assessment, counseling, and
testing guidelines. 1999. Available at: www.health.state.ny.us/nysdoh/cancer/
obcancer/contents.htm. Accessed July 8, 2008.
Struewing JP, Coriaty ZM, Ron E, et al. [Letter to the Editor]. Founder BRCA1/2
mutations among male patients with breast cancer in Israel. American Journal of
Human Genetics. 1999;65e(6), 1800-1802.
O'Neill SM, Peters JA, Vogel VG, Feingold E, and Rubinstein WS. Referral to cancer
genetic counseling: Are there stages of readiness? American Journal of Medical
Genetics Part C: Seminars in Medical Genetics. 2006;142C(4):221-231.
Struewing JP, Hartge P, Wacholder S, et al. The risk of cancer associated with
specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. New England
Journal of Medicine. 1997;336(20): 1401-1408.
Papelard H, de Bock GH, van Eijk R, et al. Prevalence of BRCA1 in a hospital-based
population of Dutch breast cancer patients. British Journal of Cancer. 2000;83(6):
719-724.
Trepanier A, Ahrens M, McKinnon W, et al. Genetic cancer risk assessment and
counseling: Recommendations of the national society of genetic counselors.
Journal of Genetic Counseling. 2004;13(2):83-114.
Parmigiani G, Berry D, Aguilar O. Determining carrier probabilities for breast
cancer-susceptibility genes BRCA1 and BRCA2. American Journal of Human
Genetics. 1998;62(1): 145-58.
10 • Focus on Female Cancers • ACOG District II/NY
❙ ❙ Risk Assessment
Importance of Family History
Individuals with hereditary risk for cancer are at significantly increased risk to
develop cancer over the general population. While only 5-10% of breast and
ovarian cancer diagnoses are associated with inherited mutations in cancer
susceptibility genes, it is important for health care practitioners to be able to
identify individuals suggestive of hereditary cancer risk as these individuals
are at increased risk for multiple primary cancers as well as early age onset.
Thus, knowledge of hereditary cancer risk will impact medical management,
cancer screening, surveillance recommendations and consideration of
prophylactic surgery.
Although there is no singular tool that will identify all persons at hereditary
risk for cancer, the family history is the most useful and readily available factor
to take into consideration when evaluating possible hereditary risk. When
collecting the family medical history it is imperative to collect information
across three-generations and from both the maternal and paternal
perspective. Information important to performing a hereditary cancer risk
assessment includes type of cancer and age of diagnosis. Additionally,
confirmation of diagnoses with pathology reports should be done whenever
possible. Although not necessary, there are several forms/questionnaires
available online, including through the American Medical Association, United
States Department of Health and Human Services, and the American Society
of Human Genetics, to aid in family history collection. These, and other
relevant resources, are available at the following sites:
•
•
•
•
•
•
www.ama-assn.org/ama1/pub/upload/mm/464/adult_history.pdf
www.familyhistory.hhs.gov/
www.cdc.gov/genomics/activities/famhx.htm
www.nsgc.org/consumer/familytree/index.cfm
www.geneclinics.org
www.geneticalliance.org/ws_display.asp?filter=fhh
Red Flags
After documenting a family history it is necessary for health care practitioners
to evaluate the history for characteristics suggestive of hereditary risk. The
hallmark signs, or “red flags”, which warrant consideration of increased
hereditary risk for breast and/or ovarian cancer are as follows:
Alerts to possible inherited forms of common cancers:
• A high frequency of the same cancer within the family
• Early age of onset of cancer (usually less than age 50)
• Multiple primary cancers in a single individual
o Breast and ovary (HBOC-BRCA1 and BRCA2)
o Breast and sarcoma (Li-Fraumeni-p53)
o Colorectal, endometrial, ovary and stomach (HNPCC-MLH1,
MSH2, MSH6)
o Breast, endometrial, and thyroid (Cowden-pTEN)
Who should be referred for risk assessment? Persons with:
• A personal history of breast cancer such as:
o diagnosed at a young age
o breast cancer affecting both breasts
o both breast and ovarian cancers
• Two or more first or second-degree relatives who have developed breast or
ovarian cancer
• A family member who developed breast cancer before age 50 on either the
maternal or paternal side of the family
• A family history of breast cancer in more than one generation
• A male relative with breast cancer
• A family member (first or second degree relative) who has both breast and
ovarian cancer
• A family member with bilateral breast cancer
• A BRCA1 or BRCA2 “positive” genetic test result (known deleterious
mutation) in a relative
• Ashkenazi (Eastern European) Jewish ancestry, with or without a family
history of breast and/or ovarian cancer (2.5% incidence of a BRCA
mutation)
• HNPCC, also known as Lynch Syndrome which is characterized by an
increased incidence of the following cancers: colorectal, endometrium,
ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract,
brain and skin. Amsterdam criteria for clinical diagnosis of Lynch Syndrome
include:
o 3 or more family members with a confirmed diagnosis of
colorectal cancer, one of whom is a first degree (parent, child,
sibling) relative of the other two
o Two successive generations; and
o One or more colon cancers diagnosed under age 50
Please note:
o Familial adenomatous polyposis (FAP) has been excluded
o Modified clinical criteria for diagnosis: same as above, but
allows for inclusion of the more common other HNPCC cancers
such as endometrial (not just colorectal)
Risk Assessment Models
Currently, there are several models available for quantifying and/or stratifying an
individual’s breast cancer risk, with a family history of breast cancer being the
common variable included in all models. The available risk assessment models
are divided into two groups:
Focus on Female Cancers • Risk Assessment •13 • Models to calculate the risk for developing breast cancer in unaffected
individuals
• Models for calculating the likelihood of having a mutation in the BRCA1
and BRCA2 genes (the most common causes of hereditary breast and
ovarian cancer) in both affected and unaffected individuals
Note: No model currently exists for the quantification of the risk to develop
ovarian cancer.
These models can be useful during the risk assessment phase as they allow for
quantification of risk. However, whenever using these models it is important to
note the limitations of each individual model.
Please see the table included at the end of this section entitled “Breast Cancer
Risk Assessment: Models, Variables and Mutation Likelihoods” for information on
the models featured here.
Risk for Breast Cancer
The two most common and widely used models for quantifying breast cancer
risk are the Gail and Claus models.
The Gail Model
The Gail Model was developed using epidemiological data on 284,780 Caucasian
women from the Breast Cancer Detection Demonstration Project (BCDDP) in
an attempt to define at risk populations. Through analysis of a large number of
individual risk factors, as well as combinations of risk factors, five personal factors
plus family history were identified as important to defining at risk populations.
These factors include:
• Personal
o Age
o Age at menarche
o Age at first live birth
o Number of prior breast biopsies
o Presence of atypical hyperplasia on biopsy
• Family History
o Number of first degree relatives with breast cancer
Investigators with the National Surgical Adjuvant Breast and Bowel Project
(NSABP) modified the original Gail model to calculate the risk for invasive
breast cancer only, as well as to allow for inclusion of race, a factor that was not
included in the original model. However, it should be noted that although the
current model includes race, it only adjusts for Caucasian or African-American.
All other ethnic backgrounds are calculated as Caucasian. Another limitation of
the Gail model is that it may provide an inflated risk estimate in individuals with
a history of multiple breast biopsies. Additionally, the model does not allow
for inclusion of second degree relatives with breast cancer (thus cannot include
paternal family history), family history of ovarian cancer, or history of male
14 • Focus on Female Cancers • ACOG District II/NY
breast cancer. Despite these limitations, the current Gail model is a tool that can
be used to quantify an estimated five-year and lifetime risk for breast cancer in
an unaffected female.
The Claus Model
The Claus Model was derived from case-control data, obtained from the Cancer
and Steroid Hormone Study, to allow for quantification of age-specific breast
cancer probabilities in women with a family history of breast cancer. The
strength of this model is that it takes into consideration the family history of
breast cancer in first and second degree relatives, thus allowing for inclusion of
both the maternal and paternal family history. However, the limitations of the
Claus model are that it does not allow for inclusion of a family history of ovarian
cancer or history of male breast cancer. Further, the data were derived from a
Caucasian population and therefore it is unclear how accurate the model is for
women of other racial and ethnic backgrounds.
Likelihood of BRCA1 or BRCA2 Gene Mutations
While the above models are useful for estimating the probability for an
individual to develop breast cancer, they do not address the likelihood of an
individual harboring a mutation in the BRCA1 and BRCA2 genes; information
that is often important in making decisions surrounding genetic testing.
The BRCAPro Model
The BRCAPro Model was developed to allow for assessment of mutation
likelihood based on a personal and/or family history of breast and ovarian cancer.
Specifically, this model takes into consideration:
• Breast cancer (including bilateral diagnoses)
• Ovarian cancer in the individual and their first and second degree relatives
• Age of diagnosis
• Ashkenazi Jewish ancestry
• Age and exact relationship of unaffected relatives in the family
Consideration of the overall size of a family intuitively makes sense, as the
smaller a family is, the fewer the diagnoses of cancer one would expect to see.
The scientific basis of the BRCAPro model is founded on the autosomal dominant
inheritance pattern of BRCA1 and BRCA2 mutations and the use of Bayes’ analysis
to derive the probability of a BRCA gene mutation conditionally related to the
personal and family history. Through validation studies, the BRCAPro model has
proven to be a good tool for identifying individuals at high risk and low risk of
having a mutation in the BRCA1 or BRCA2 genes.
The Myriad Prevalence Tables
A second tool for calculating BRCA1 and BRCA2 mutation likelihood is available
through Myriad Genetic Laboratories, Inc. The Myriad prevalence tables are
currently based on personal and family history information collected on
approximately 50,000 individuals who have pursued BRCA1 and BRCA2 gene
testing through Myriad Genetic Laboratories, Inc. In addition to a history of
breast and ovarian cancer, the Myriad data and tables also allow for inclusion of
male breast cancer and Ashkenazi Jewish ancestry when quantifying mutation
likelihood. Of note, a primary limitation of these prevalence tables is that the
information is obtained through a potentially biased sample population, as only
individuals and families who actually pursue genetic testing are included in this
analysis.
The models mentioned are all available online at the following web addresses:
• Gail Model
o www.cancer.gov/bcrisktool/
o www4.utsouthwestern.edu/breasthealth/cagene/
• Claus Model
o www4.utsouthwestern.edu/breasthealth/cagene/
• BRCAPro Model
o www4.utsouthwestern.edu/breasthealth/cagene/
• Myriad Prevalence Table for BRCA mutations
o www.myriadtests.com/provider/brca-mutation-prevalence.
htm
• MMRPro Model
o www4.utsouthwestern.edu/breasthealth/cagene/
• Myriad Prevalence Table for HNPCC mutations
o www.myriadtests.com/provider/mutprevhnpcc.htm
Other Cancer Syndromes to Consider
Importantly, it should be noted that while the previously mentioned models
are useful for estimating the likelihood of identifying a BRCA1 or BRCA2 gene
mutation, these models do not allow for consideration of other hereditary breast
cancer syndromes, such as Cowden syndrome (associated with mutations in the
PTEN gene) and Li-Fraumeni syndrome (associated with mutations in the p53
gene). For this reason, it is important to obtain a complete family history and be
aware that there are other less common hereditary breast cancer syndromes that
should be considered in the differential diagnosis of some individuals/families.
Separately, it should be mentioned that a personal and/or family history of
ovarian cancer may also be associated with hereditary non-polyposis colorectal
cancer. HNPCC is more classically associated with early onset colorectal cancer
and endometrial cancer in addition to ovarian cancer. It is linked to mutations
in the mismatch repair genes, specifically MLH1, MSH2, MSH6 and PMS2. A
model exists for calculating the likelihood of identifying a mutation in an HNPCCassociated gene. The MMRPro model evaluates an individual and family history
of colorectal and endometrial cancer in first and second degree relatives in
determining the joint probability of identifying a mutation in the MLH1, MSH2 or
MSH6 genes. Additionally a prevalence table is available through Myriad Genetic
Laboratories, Inc., based on clinical information provided for individuals pursuing
HNPCC-gene testing through Myriad Genetics, for calculating the likelihood of
identifying a MLH1 or MSH2 gene mutation.
Qualitative Risk Assessment
Genetic cancer risk assessment should include consideration of other genetic
syndromes in the differential diagnosis of breast and ovarian cancer etiology
(reference for the National Comprehensive Cancer Network guidelines is included
in the Resources section of this guide). Although a comprehensive discussion of
these syndromes is not the intent of this guideline, it is worthwhile for the health
care practitioner to have some awareness in order to understand the impact
on cancer screening and medical management. Some of these syndromes are
associated with benign conditions, physical findings and/or other medical
problems that can be identified as “red flags” for potential cancer etiology and
risk. Thus, inquiry about and ideally observation and examination of physical
characteristics in the patient and affected relatives regarding non-cancer medical
history is important.
The most common syndromes associated with genetic risk for breast and/or
ovarian cancer – other than BRCA gene mutations – are Cowden syndrome,
Li-Fraumeni syndrome, and HNPCC. Thus, to consider Cowden syndrome as one
example, the inquiry would include (but not be limited to) history of thyroid
disease (especially adenoma or multi-nodular goiter), fibrocystic breasts,
lipomas, uterine fibroids and genitourinary tumors. Physical evaluation for this
syndrome would include (but not be limited to) examination for macrocephaly,
trichilemmomas (benign lesions of the face which originate from the outer hair
sheath), papillomas of the oral mucosa, lipomas, and dysmorphology (structural
defects, especially congenital malformation). As an overall general rule, if the
personal and/or family history includes the following, the differential diagnosis
may include other than a BRCA mutation and make consideration of HBOC
secondary in the differential:
• Cancers other than breast or ovarian
• Medical problems such as those noted
• Dysmorphology
Medical records may be helpful in sorting out reported history influencing
medical assessment versus actual medical conditions. Communication,
consultation with and/or referral to a genetics expert are all appropriate for these
more complex cases.
Completing the Cancer Genetic Risk Assessment
Upon collection of a complete family history, which includes the maternal
and paternal lineage across three generations, the history should be assessed
for characteristics suggestive of hereditary cancer risk. This can be done by
evaluating the history for common characteristics associated with hereditary
cancer syndromes (i.e. multiple affected individuals in a family, across several
generations, and cancer diagnosed at a young age) as well as using the risk
assessment models previously discussed. It is important to note that in some
cases the only risk factor may be a singular affected individual with cancer at
Focus on Female Cancers • Risk Assessment • 15 an early age. These cases should not be ignored, especially if the family is of
limited size or relatives are predominantly males. Individuals identified to be at
increased risk for cancer using a risk assessment model should be offered genetic
consultation (if available) including genetic testing as appropriate. Importantly,
health care practitioners should be aware of and utilize genetic professionals
when questions arise regarding the appropriateness of an individual for genetic
consultation and/or testing, especially if the personal and family history is not
straightforward.
There is no singular model or
algorithm that will identify
all individuals at increased
genetic risk for breast and/or
ovarian cancer.
16 • Focus on Female Cancers • ACOG District II/NY
Focus on Female Cancers • Risk Assessment • 17 Breast Cancer Risk Assessment: Models, Risk Variables,
and BRCA Mutation Likelihoods
References:
American Medical Association. Adult Family History Form. Available at: www.
ama assn.org/ama1/pub/upload/mm/464/adult_history.pdf. Accessed
February 5, 2008.
Gail MH, Brinton LA, Byar DP, et al. Projecting individualized probabilities of
developing breast cancer for white females who are being examined annually.
Journal of the National Cancer Institute. 1989;81:1879-86.
Anderson SJ, Ahnn S, Duff K. NSABP Breast Cancer Prevention Trial risk
assessment program, version 2. NSABP Biostatistical Center Technical Report,
August 14, 1992.
National Comprehensive Cancer Network. NCCN clinical practice guidelines in
oncology – Genetic/familial high risk assessment: Breast and ovarian. 2008.
Available at http://www.nccn.org/professionals/physician_gls/PDF/genetics_
screening.pdf. Accessed July 15, 2008.
Berry DA, Iversen ES Jr, Gudbjartsson DF, et al. BRCAPro validation, sensitivity
of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer
susceptibility genes. Journal of Clinical Oncology. 2002;20:2701-12.
Berry DA, Parmigiani G, Sanchez J, Schildkraut J, Winer E. Probability of carrying
a mutation of breast-ovarian cancer gene BRCA1 based on family history. Journal
of the National Cancer Institute. 1997;89:227-38.
Chen S, Wang W, Lee S, et al. Colon Cancer Family Registry. Prediction of
germline mutations and cancer risk in the Lynch syndrome. Journal of the
American Medical Assocation. 2006;296:1479-87.
Claus EB, Risch N, Thompson WD. Autosomal dominant inheritance of earlyonset breast cancer. Implications for risk prediction. Cancer. 1994;73:643-51.
Costantino JP, Gail MH, Pee D, et al. Validation studies for models projecting the
risk of invasive and total breast cancer incidence. Journal of the National Cancer
Institute. 1999;91:1541-1548.
Eng C, Parsons R. Cowden Syndrome. In: Scriver CR, Sly WS, eds. The Metabolic
& Molecular Bases of Inherited Disease. New York: McGraw-Hill; 2001: 8.
Euhus DM, Smith KC, Robinson L, et al. Pretest prediction of BRCA1 or BRCA2
mutation by risk counselors and the computer model BRCAPRO. Journal of the
National Cancer Institute. 2002;94:844-51.
Frank TS, Deffenbaugh AM, Reid JE, et al. Clinical characteristics of individuals
with germline mutations in BRCA1 and BRCA2: Analysis of 10,000 individuals.
Journal of Clinical Oncology. 2002;20:1480-90.
18 • Focus on Female Cancers • ACOG District II/NY
Parmigiani G, Berry D, Aguilar O. Determining carrier probabilities for breast
cancer-susceptibility genes BRCA1 and BRCA2. American Journal of Human
Genetics. 1998;62:145-58.
United States Department of Health and Human Services. U.S. Surgeon General’s
Family History Initiative. My Family Health Portrait. Available at: https://
familyhistory.hhs.gov/ Accessed February 5, 2008.
❙ ❙ Genetic Counseling
Genetic Counseling
Genetic counseling is a process that has evolved over many years with many
publications defining practice. The definition of genetic counseling has been
recently revised.
As defined by the National Society of Genetic Counselors, genetic
counseling is the process of helping people understand and adapt to the
medical, psychological, and familial implications of genetic contributions to
disease. This process integrates the following:
• Interpretation of family and medical histories to assess the chance of
disease occurrence and recurrence
• Education about inheritance, testing, management, prevention,
resources, and research
• Promotes informed choices and adaptation to the risk or condition
Genetic counseling must precede the testing process. Genetic test results
have unique implications and practitioners must have a full appreciation of
the profound impact genetic test results can have on the patient and family,
as well as the associated ethical and legal implications. In this early phase of
introducing genetic testing into health care management, there needs to be
vigilance and caution in determining genetic risk and selecting appropriate
genetic tests, as well as a commitment to correctly interpret the genetic test
result. Careful genetic risk assessment, counseling, and informed consent
will assure that providers and their patients have the most current and
appropriate genetic test results to define a course of clinical care.
Cancer Genetic Counseling
Cancer genetic risk assessment and genetic counseling is an interactive
process that has been extensively described and advocated. The process
begins with identification of risk through assessment of personal and family
cancer history and continues with patient education, discussion of cancer
genetic syndromes, gene test selection as appropriate, informed consent,
test result disclosure, and interpretation.
Components of the Genetic Risk Assessment and Testing Process
• Create a three generation pedigree seeking to identify all affected
family members and ages of diagnosis
• Document the diagnosis in critical family members through review of
medical records
• Provide background about genes and mutations
• Use mathematical models and risk tables to define the patient’s
inherited risk of cancer
• Identify known or inherited cancer syndromes in the differential diagnosis
• Identify appropriate gene test (this may include more than one)
• Discuss the implication of genetic test information for medical
management
• Explore personal and family issues that may emerge from identification of
a mutation and confirmation of inherited risk
• Provide medical and/or risk management options if testing is not pursued
at time of referral
• Provide an informed consent process, including a written consent
• Discuss notification of test result
• Provide follow-up counseling, interpretation of test result and implications
for family members
• Evaluate need for alternate gene selection if there is a negative test result
• Provide medical management and cancer surveillance recommendations
based on gene test result
• Assess how the patient is responding to this cancer genetic experience and
the possible need for additional support
The Pedigree
The three generation family history or “pedigree” is fundamental to any genetic
risk assessment and is essential in evaluating the inherited cancer risk. There
are a number of ways to collect and review family history: questionnaires, lists
of family members with medical histories, or traditional diagrammatic genetic
pedigree. The pedigree diagram offers a rapid method to follow transmission of a
possible inherited cancer predisposition through the generations of a family and
to understand the relationships between affected family members.
There are a few simple steps to constructing a diagrammatic pedigree. The
symbols in a pedigree have been standardized. The designation for male and
female is presented as square and circle, respectively. Begin with your patient,
noting significant medical and cancer related concerns. Once you enter your
patient on a pedigree graph, add parents, siblings, maternal aunts, uncles
and cousins, paternal aunts, uncles and cousins and maternal and paternal
grandparents. If information is available, include the siblings of each of the
grandparents. As you note every family member and their significant medical or
cancer history, be sure to inquire about age of the relative and the age at which a
significant medical or cancer diagnosis was made. It is also important to include
the ethnic and racial background for both the maternal and paternal sides of the
family. Make special note of patients who report a relative of Ashkenazi Jewish
descent.
Construction and review of a three generation pedigree may be time-consuming
but is essential to documenting a pattern of inheritance of a suspected HBOC
predisposition syndrome. The process of pedigree construction or a detailed
Focus on Female Cancers • Genetic Counseling • 21 review of family history can offer insights into family relations and dynamics. This
may provide the patient and her medical provider an appreciation of the factors
that are prompting interest in genetic testing as well as barriers that may need to
be discussed as part of the genetic counseling process. An example of a pedigree
specific to HBOC can be viewed at the end of this section.
Initiating Cancer Risk Assessment
Initiating cancer genetic counseling needs to respect that there are stages of
“patient readiness” for accepting a referral for genetic risk assessment, counseling
and genetic testing. Practitioners need to assess the patient’s interest and
motivation to seek genetic risk information, as well as the practitioner’s own
reasons for requesting or considering genetics referral and testing. Additionally,
it is common for patients to raise questions about cost and concerns regarding
genetic discrimination.
Psychosocial Dimension of Cancer Genetic Counseling
Psychosocial understanding of cancer worry and risk is central to facilitating
the process of genetic counseling and informed decision making. Personal
risk perception and beliefs about etiology of cancer in the family can shape
attitudes about testing and how test result information may be experienced. The
experience of genetic testing and confirmation of an inherited mutation has been
reported to be enabling in some patients and in others it can evoke conflicting
feelings. Patients who learn that they have a negative test result or those with an
uninformative DNA result may experience worry about the continued uncertainty
of their risk. The genetic testing process can have an emotional impact on
the family of origin and extended family members. Partners and spouses of
patients have emotional responses to knowledge of inherited risk and genetic
testing results. Each patient entering the genetic counseling process should be
offered the opportunity to discuss the possible psychological impact testing will
have on the patient and their families. Genetic counselors and genetics health
professionals are trained to address potential psychosocial conflicts and are able
to offer patient specific support in the genetic testing process.
Ethno-Cultural Perspectives
Exploration of beliefs and ethno-cultural perspectives on illness, risk and cancer
can be helpful in providing information and facilitating informed decisionmaking. How a patient responds to statistical risk information depends on his or
her emotional, social and cultural status. Beliefs and attitudes can range from
perceptions of risk, health beliefs, trust in the testing process and privacy of
testing information.
Patient Autonomy
Patient autonomy is a central tenet in genetic counseling, assuring that the
patient acts in a personally congruent manner. Historical pressures shaped early
genetic counseling discussions and autonomy was preserved through a practice
of “non-directiveness.” Currently, patient autonomy is maintained using the
22 • Focus on Female Cancers • ACOG District II/NY
genetic counseling experience which optimizes a decision-making climate.
Trained professionals utilize information, facilitated discussion, and available
preventive options in counseling patients.
Decision-Making Involving the Testing Option
The decision to participate in genetic testing requires time to inform patients
about cancer risk and inherited predisposition genes and to explore the role and
implications of genetic testing.
Participation in genetic counseling does not always indicate a willingness,
interest, or readiness for testing. The decision to test brings into focus several
issues:
• The value of testing information
• Consideration of the patient’s desire to know or not to know if a mutation
exists in the family
• The impact of testing decision on family relations and dynamics
• Consideration of whether testing information would modify present cancer
surveillance and medical management or treatment strategy
A decision to proceed with testing is generally not based on risk or probability
statements. The goal of genetic counseling is not genetic testing, but rather to
seek informed decisions based on accurate genetic assessment, understanding
of risks and options, and informed choices by the person in conjunction with
their health care provider. Genetic testing should never occur without genetic
counseling.
Informed Consent
Genetic testing needs to include an informed consent that provides information
to assure patient autonomy and assists in test disclosure.
Written informed consent is mandated by state law in New York State and
Massachusetts. See the websites below for information about genetics privacy
and informed consent law in New York State:
www.wadsworth.org/labcert/regaffairs/clinical/79-l_1_2002.pdf
and Massachusetts:
www.mass.gov/legis/laws/mgl/111-70g.htm
Common elements of informed consent include:
• Purpose of the test and specific genes to be tested
• Possible test results
• Test accuracy
• Laboratory testing procedure
• Cost of the test
• Questions about genetic discrimination
Informed consent (to sign a document to proceed with genetic testing) is not the
same as genetic consultation and counseling.
Questions About Genetic Discrimination
It is important to acknowledge the genetic discrimination concerns of
individuals and families exploring genetic testing. To date, the following
protections exist against genetic discrimination, which may be seen as a barrier
for testing for some patients:
In 1996, Congress passed the Health Insurance Portability and Accountability
Act (HIPAA). This legislation specifically recognizes and lists genetic information
as protected health information for group health insurance providers. In other
words, this information cannot be used as the basis for discrimination. In
addition, this legislation states that predictive genetic test results cannot be
considered a pre-existing condition. An example of this could include testing
of a cancer gene that is associated with increased susceptibility or risk, but not
certainty to develop cancer. These protections are in place and address most
concerns, although technically this legislation does not provide assurance that
group policies may not be cancelled due to the genetic status of one group
member. There are fewer protections for consumers that purchase individual
policies.
Several states in the US have attempted to protect their citizens from risk of
genetic discrimination with state laws. New York State has considered issues
of genetic privacy and discrimination. They offer some confidence that genetic
testing, as it relates to health insurance, has some protection under two New
York State laws. There was no consensus about possible implications for life
insurance or long term disability insurance. New York’s Task Force on Life and
Law’s recommendations can be viewed at:
www.health.state.ny.us/nysdoh/taskfce/screening.htm
On May 21, 2008, the President signed into law the Genetic Information
Nondiscrimination Act (GINA) that will protect Americans against discrimination
based on their genetic information when it comes to health insurance and
employment. The bill had passed the Senate unanimously and the House by
a vote of 414 to 1. The long-awaited measure, which has been debated in
Congress for 13 years, will pave the way for people to take full advantage of the
promise of personalized medicine without fear of discrimination
Special Considerations in Risk Assessment
and Testing
that can present in childhood is supported when early recognition is critical for
prevention or risk reduction treatment (e.g. Familial Adenomatous Polyposis
(FAP) or Multiple Endocrine Neoplasia (MEN II). For those disorders for
which the identification of gene carriers does not provide an avenue
for therapeutic or preventive treatment in prenatal or childhood
periods, genetic testing must be carefully considered.
Limited Family History
Cancer genetic risk assessment begins with an evaluation of a three generation
pedigree and number of affected family members. For patients who have limited
family history or who have gender skewed composition (few female relatives,
predominance of male relatives), it can be difficult to assess the likelihood of an
inherited cancer susceptibility mutation. Evaluation of single cases of breast or
ovarian cancer and limited family history needs to be carefully considered. The
patient with no access to family history due to an adoption and who has an early
diagnosis of breast or ovarian cancer may be a candidate for genetic counseling
and/or testing in the absence of a documented family history.
Consanguinity
On occasion patients report inter-relatedness in the family. It has been estimated
that possibly up to 1.5% of couples in the US are related prior to marriage. In
some ethnic communities around the world, 20-60% of couples may be interrelated. Consanguinity should therefore be explored and considered in the risk
evaluation process.
Underserved Racial and Ethnic Minorities
Current efforts are underway to better understand the factors that influence
the disparity in genetic testing for hereditary cancer susceptibility. Disparities
in the use of BRCA1 and BRCA2 testing are significant and do not appear to be
influenced by commonly cited barriers (perception or socioeconomic indicators).
Is there a role for prenatal testing or pre-implantation genetic
diagnosis for a known mutation?
Individuals and families that have witnessed the burden of inherited cancer
risk and early cancer diagnosis may be eager to identify ways to limit the
transmission of a family mutation. It is possible to test amniocytes for a known
family mutation in BRCA1 or BRCA2. In addition, pre-implantation genetic
diagnosis (PGD), testing polar bodies or blastocysts, offers families the possibility
to have a child free from a specific inherited genetic disease. These two testing
options raise ethical questions. To date, it appears that these testing options are
used rarely for HBOC.
Testing Minors
There is general consensus from many professional organizations that testing
of minors for HBOC is usually not warranted and should be delayed until the
minor reaches an age that they can make a decision for themselves. In contrast,
testing minors who are at risk for an inherited cancer susceptibility syndrome
Focus on Female Cancers • Genetic Counseling • 23 24 • Focus on Female Cancers • ACOG District II/NY
Pedigree: HBOC Originating from Paternal Side of the Family
References:
American Society of Clinical Oncology. American Society of Clinical Oncology:
Genetic testing for cancer susceptibility. Journal of Clinical Oncology.
1996;14:1730-40.
American Society of Clinical Oncology. American Society of Clinical Oncology
policy statement update: Genetic testing for cancer susceptibility. Journal of
Clinical Oncology. 2003;21:2397-406.
American Society of Human Genetics. Statement of the American Society of
Human Genetics on genetic testing for breast and ovarian cancer predisposition.
American Journal of Human Genetics. 1994;55:i-iv.
Armstrong K, Micco E, Carney A, Stopfer J, Putt M. Racial differences in the use of
BRCA ½ testing among women with a family history of breast or ovarian cancer.
Journal of the American Medical Association. 2005;293:1729-36.
Bennett RL, Motulsky AG, Bittles A, et al. Genetic counseling and screening of
consanguineous couples and their offspring: Recommendations of the National
Society of Genetic Counselors. Journal of Genetic Counseling. 2002;11:97-119.
Bennett RL, Steinhaus KA, Uhrich SB, et al. Recommendations for standardized
human pedigree nomenclature. Pedigree Standardization Task Force of
the National Society of Counselors. American Journal of Human Genetics.
1995;56:745-52.
d’Agincourt-Canning L. A gift or a yoke? Women’s and men’s responses to genetic
risk information from BRCA 1 and BRCA 2 testing. Clinical Genetics. 2006;70:46272.
Djurdjinovic L. 2008 Genetic Counseling. In press. Wiley Press.
Fasouliotis SJ, Schenker JG. Preimplantation genetic diagnosis: Principles and
ethics. Human Reproduction 1998; 13:2238.
Genetic Discrimination in Health Insurance, National Institute of Human Genome
Research. Available at www.genome.gov/10002328. Accessed July 22, 2008.
Hall MJ, Olopade OI. Disparities in genetic testing: Thinking outside the BRCA
box. Journal of Clinical Oncology. 2006;24:2197-203.
Lancaster JM, Wiseman RW, Berchuck A. An inevitable dilemma: Prenatal testing
for mutations in the BRCA1 breast/ovarian cancer susceptibility gene. Obstetrics
and Gynecology. 1996;87:306-309.
Lerman C, Peters JA, Ades T, et al.1997 American Cancer Society Workshop
on Heritable Cancer Syndromes and Genetic Testing. Workshop 2: Genetic
counseling issues. Cancer. 1997;80 Suppl 2:S628-629.
Menon U, Harper J, Sharma A, et al. Views of BRCA gene mutation carriers on
preimplantation genetic diagnosis as a reproductive option for hereditary breast
and ovarian cancer. Human Reproduction. 2007;22:1573-7.
National Society of Genetic Counselors’ Definition Task Force, Resta R, Biesecker
BB, et al. A new definition of Genetic Counseling: National Society of Genetic
Counselors’Task Force Report. Journal of Genetic Counseling. 2006;15:77-83.
National Society of Genetic Counselors 1995 Position Statement. Prenatal and
childhood testing for adult onset disorders. Available at www.nsgc.org/about/
position.cfm#Prenatal_two Accessed July 22, 2008.
O'Neill SM, Peters JA, Vogel VG, Feingold E, Rubinstein WS. Referral to cancer
genetic counseling: are there stages of readiness? American Journal of Medical
Genetics Part C: Seminars in Medical Genetics. 2006;142C:221-31.
Peters JA, Biesecker BB. Genetic counseling and hereditary cancer. Cancer.
1997;80 Suppl 3:S576-86.
Peters JA. Genetic counseling. In: Joules W, Hodgson S, eds. Perspectives in
Inherited Cancer Syndromes. Cambridge, UK: Cambridge University Press; 1998.
Spits C, DeRycke M, Van Ranst N, et al. Preimplantation genetic diagnosis for
cancer predisposition syndromes. Prenatal Diagnosis. 2007;27:447-56.
Thompson HS, Valdimarsdottir HB, Duteau-Buck C, et al. Psychosocial predictor of
BRCA counseling and testing decisions among urban African American women.
Cancer Epidemiology Biomarkers and Prevention. 2002;11:1579-85.
Trepanier A, Ahrens M, McKinnon W, et al. Genetic cancer risk assessment and
counseling: Recommendations of the National Society of Genetic Counselors.
Journal of Genetic Counseling. 2004;13:83-114.
Van Dijk S, Timmermans DR, Meijers-Heijboer H, Tibben A, van Asperen CJ, Otten
W. Clinical characteristics affect the impact of an uninformative DNA test result:
The cause of worry and distress experienced by women who apply for genetic
testing for breast cancer. Journal of Clinical Oncology. 2006;24:3672-7.
Weitzel JN, Lagos VI, Cullinane CA, et al. Limited family structure and BRCA gene
mutation status in single cases of breast cancer. Journal of the American Medical
Association. 2007;297:2587-95.
Focus on Female Cancers • Genetic Counseling • 25
❙ ❙ Notes:
26 • Focus on Female Cancers • ACOG District II/NY
❙❙
Genetic Testing
Genetic Testing Process
DNA testing is now available for a variety of hereditary cancer syndromes.
However, testing is indicated for only a small percentage of individuals at
risk for cancer. It is important to order testing for the correct gene (there
are many). Testing is best when first directed to an individual affected by
cancer since testing an unaffected family member alone is not informative
or appropriate much of the time. If the correct test is not ordered on the
most informative family member, the results of the testing can easily be
misinterpreted or compromised.
When indicated, DNA testing offers the important advantage of presenting
patients with actual risks instead of the empiric risks derived from risk
calculation models. DNA testing can be very expensive (full BRCA1/BRCA2
testing currently costs >$3,200). Most insurance companies now cover
the cost of cancer genetic testing in families where the test is medically
indicated. Insurance authorization should therefore be obtained before
testing is ordered (although some persons may request to pay out-ofpocket). This authorization often requires a letter of medical necessity, the
process can take several weeks or months to complete, and is valid in many
cases only if cleared before the test is ordered.
The pretest counseling and disclosure of the results of DNA testing are
generally best provided in person. It may be comforting for patients to
bring a close friend or relative with them to these sessions. These additional
people can provide the patient with emotional support and assist them in
hearing and processing the information provided.
BRCA1 and BRCA2 Testing
It is imperative to test the appropriate gene and the appropriate person
in the family. Although the most common genes tested for hereditary
breast and ovarian cancer are the BRCA1 and BRCA2 genes, there are other
genes that confer risk as well. For example, BRCA1 and BRCA2 testing is
inappropriate in a patient with breast cancer who has a family history of
thyroid cancer and the oro-cutaneous manifestations of Cowden syndrome.
BRCA1 and BRCA2 testing is also inappropriate in a patient with early-onset
lobular breast cancer who has a strong family history of lobular breast
cancer and gastric cancer, as this more likely represents a mutation in a gene
called CDH1. Therefore, taking a three generation maternal and paternal
family history is critical, as is offering full informed consent before testing.
The family history should include all cancer diagnoses, ages of diagnoses,
and should be confirmed with pathology reports if possible. Some types of
cancer (e.g. medullary breast cancer) are more likely to be associated with
hereditary cancer syndromes while others (e.g. mucinous or borderline
ovarian cancer) are less likely. The family history should also include genetic
diseases (e.g. Fanconi Anemia, Ataxia Telengiectasia), birth defects, mental
retardation, multiple miscarriages, infant deaths, and consanguinity, as these can
influence cancer risk and direct genetic testing. Genetic counselors can provide
expertise in taking this detailed pedigree.
The ideal person to test first is the family member whose personal history is
most suggestive of a hereditary cancer syndrome (e.g. a personal history of
early-onset cancer, multiple cancers, etc.). This represents a challenge for the
clinician because advertisements from genetic testing companies encourage
unaffected and low-risk women to consider testing. This can often lead to
uninformative test results and may confuse the patient and the providers. Thus,
the person in a family to be tested first should be selected with care. As an
example, it is possible for a person to develop sporadic cancer in a hereditary
cancer family (e.g. one with an early-onset breast cancer), and thus it would
not be ideal to first test a woman diagnosed with breast cancer at age 65, as she
may represent a sporadic case.
Interpretation of test results is complex and can often be misinterpreted
(especially when no mutation or a variant of uncertain significance is found)
when genetic testing is not done in the context of genetic counseling.
Interpretation is becoming increasingly complicated as more tests become
available. For example, one study demonstrated that approximately 12% of
high-risk families who originally tested negative by standard BRCA1 and BRCA2
testing were found to carry a deletion or duplication in one of these genes or
a mutation in another gene. In these high-risk families, finding the mutations
requires ordering additional tests that are not generally included with standard
BRCA1 and BRCA2 testing.
Test results, Interpretation and Implications
True Positive
An individual is found to carry a mutation that is known to be deleterious. These
patients need to be referred for genetic counseling (if they haven’t already)
and to physicians with expertise in hereditary cancers to consider increased
surveillance, chemoprevention, or risk reductive surgery.
True Negative
An individual does not carry the deleterious mutation previously found in her
family, and therefore her cancer risks are consistent with that of the general
population; thus, risks and chemoprevention and/or risk reductive surgery are
not indicated.
Uninformative
In a family with a clear hereditary cancer syndrome by history, an affected family
member is tested and no mutation is found. It is possible that the cancer is
not hereditary, that there is an undetectable mutation within the gene, or the
family carries a mutation in a different gene altogether. It is also possible that
the person tested does not carry a mutation but that someone else in the family
Focus on Female Cancers • Genetic Testing • 29
at greater risk (e.g. with an earlier-onset cancer, a rare cancer such as ovarian
or male breast cancer) does carry a mutation and would have been the more
appropriate person to test first. Additional genetic testing may be warranted.
DNA banking can be offered to the proband (affected) for future testing. This
group should not be mistaken for true negative and should continue to be
considered at increased risk for development of breast and ovarian cancer.
Variant of Uncertain Significance
A genetic change is found whose significance is unknown. Variants occur in
approximately 8-13% of high-risk families and higher in minorities and nonCaucasians. These may or may not be associated with hereditary risk for cancer
and need to be evaluated by a genetic counselor (or a clinician with genetics
expertise) for further recommendations.
Note: Variants of uncertain significance and uninformative test results are those
most often misinterpreted by people not well-versed in hereditary cancer and
genetics.
If a deleterious mutation is detected, other family members should be offered
genetic counseling and testing for the same mutation. This information is critical
to confirming or ruling out inherited (increased) risk which impacts developing
a plan for surveillance, chemoprevention or risk reduction surgery. The patient
should be counseled to contact other relatives and the clinician may need to
conduct direct testing of family members to determine from which side of the
family the mutation originates.
Cancer Risk
Penetrance of mutations in cancer susceptibility genes may be difficult to
interpret and should be provided as a range of risks, instead of as a single figure.
Female carriers of BRCA1 and BRCA2 mutations have up to an 85% lifetime risk
to develop breast cancer and between a 10-45% lifetime risk to develop ovarian
cancer. It is important to note that the classification “ovarian cancer” also includes
cancer of the fallopian tubes and primary peritoneal carcinoma. BRCA2 carriers
also have an increased lifetime risk of male breast cancer and pancreatic cancer.
Separately, carriers of Hereditary Non-Polyposis Colorectal Cancer mutations
have a 65-85% lifetime risk to develop colon cancer, and female carriers have at
least a 40-60% lifetime risk of uterine cancer and as great as a 10-12% risk of
ovarian cancer.
Pre- and Post-Testing Procedures
Insurance discrimination is a common concern for patients who have not yet
secured life and disability insurance, particularly if they have not had a personal
diagnosis of cancer. Documented cases of insurance discrimination are rare,
however, the facts and risks of insurance concerns should be a part of the pretest genetic counseling discussion.
30 • Focus on Female Cancers • ACOG District II/NY
Genetic testing should be ordered only after thorough genetic counseling which
includes:
•
•
•
•
Taking a detailed pedigree
Deciding which gene is most likely mutated
Determining whom the best testing candidate in the family may be
Offering full informed consent to the patient.
Insurance preauthorization and a discussion of the risks, benefits and limitations
of testing should also precede a blood draw.
Testing should be followed by careful result interpretation and a plan for
long-term follow-up as information about management and options change.
Emotional and psychosocial support should also be provided following genetic
testing.
This section has been adapted with permission from:
Matloff ET. Genetic counseling. In DeVita VT, Hellman S and Rosenberg SA (eds).
Cancer: Principles and Practice of Oncology (8th ed.). Philadelphia, Lippincott,
Williams & Wilkins: 2008
DNA testing,
although widely
available, is
indicated for
only a small
percentage of
individuals with
cancer.
References:
Aarnio M, Mecklin JP, Aaltonen L, Nyström-Lahti M, Järvinen HJ. Lifetime risk
of different cancers in hereditary non-polyposis colorectal cancer (HNPCC)
syndrome. International Journal of Cancer. 1995;64:430-33.
Antoniou A, Pharoah PD, Narod S, et al. Average risks of breast and ovarian
cancer associated with BRCA1 or BRCA2 mutations detected in case series
unselected for family history: A combined analyses of 22 studies. American
Journal of Human Genetics. 2003;72:1117-30.
Struewing J, Hartge P, Wacholder S. The risk of cancer associated with specific
mutations of BRCA1 and BRCA2 among Ashkenazi Jews. New England Journal of
Medicine. 1997;336:1401-8.
van Asperen C, Brohet R, Meijers-Heijboer EJ, et al. Cancer risks in BRCA2
families: estimates for sites other than breast and ovary. Journal of Medical
Genetics. 2005;42:711-719.
Walsh T, Casadei S, Coats K, et al. Spectrum of mutations in BRCA1, BRCA2,
CHEK2, and TP53 in families at high risk of breast cancer. Journal of the American
Medical Association. 2006;295:1379-88.
Aziz S, Kuperstein G, Rosen B, et al. A genetic epidemiological study of carcinoma
of the fallopian tube. Gynecolic Oncology. 2001;80:341-5.
Cancer risks in BRCA2 mutation carriers. Breast Cancer Linkage Consortium.
Journal of the National Cancer Institute. 1999;91:1310-16.
Ford D, Easton D, Bishop D. Risks of cancer in BRCA1 mutation carriers. Breast
Cancer Linkage Consortium. Lancet Oncology. 1994;343:692-5.
Kandel M, Stadler Z, Masciari S, et al. Prevalence of BRCA1 mutations in triple
negative breast cancer (BC). In: 2006 42nd Annual ASCO Meeting, Atlanta,
Georgia, 2006, pp. 508.
Piver M, Jishi M, Tsukada Y, Nava G. Primary peritoneal carcinoma after
prophylactic oophorectomy in women with a family history of ovarian cancer.
A report of the Gilda Radner Familial Ovarian Cancer Registry Cancer. Cancer.
1993;71:2751-5.
Risch H, McLaughlin J, Cole D, et al. Population BRCA1 and BRCA2 mutation
frequencies and cancer penetrances: A kin-cohort study in Ontario, Canada.
Journal of the National Cancer Institute. 2006;98:1624-706.
Schmeler KM, Lynch HT, Chen LM, et al. Prophylactic surgery to reduce the risk of
gynecologic cancers in the Lynch Syndrome. New England Journal of Medicine.
2006;354:261-9.
Schrader K, Masciari S, Boyd N, et al. Hereditary diffuse gastric cancer:
association with lobular breast cancer. Familial Cancer. 2008;7:73-82.
Shinaman A, Bain L, Shoulson I. Preempting genetic discrimination and assaults
on privacy: Report of a symposium. American Journal of Medical Genetics.
2003;120A:589-93.
Focus on Female Cancers • Genetic Testing • 31 ❙ ❙ Notes:
32 • Focus on Female Cancers • ACOG District II/NY
❙ ❙ Management Strategies
Selection of Strategies
Women who have been identified to be at an increased risk of mutations due to strong
family or personal history, those with indeterminate findings at genetic testing and
those with a diagnosis of a genetic mutation associated with an increased lifetime risk
of developing breast and/or gynecologic malignancies should be offered intervention
aimed at risk reduction. The strategies currently include heightened surveillance,
chemoprevention and the use of risk reduction surgery. The selection of a strategy
is highly individualized and is based on a clear understanding of specific risk of
developing malignancy, the efficacy of the strategy, and patient-related factors such
as age, psychological concerns, presence of medical co-morbidities, and reproductive
desires. Often consideration of these issues evolves over time due to advances in
medical knowledge or a change in patient-related factors, such as a change in
reproductive desires. Thus counseling on clinical management is likely to represent an
ongoing conversation with the patient as needed.
Ovarian Cancer Risk-Reduction Strategies
Screening
The least invasive strategy involves heightened screening with pelvic examinations
once or twice per year, coupled with transvaginal ultrasound semi-annually, beginning
at age 30-35 for BRCA1 mutation carriers, and at age 35-40 for BRCA2 mutation
carries. CA-125 levels should be obtained twice per year also beginning at age 30-35
years old for BRCA1 mutation carriers and at age 35-40 years old for BRCA2 mutation
carriers. These recommendations are based on the fact that the risk of developing
ovarian cancer in women with BRCA1 mutations begins to increase in their late 30s,
and is already significantly higher than the general population by age 40. In contrast,
for women with BRCA2 mutations, this increase in risk is not seen until age 50.
Predicted Mean Cancer Risk: Breast and Ovarian Cancer
Currently Unaffected BRCA1 and 2 Mutation Carriers (% by Age)
Current Age (yrs) 30 yrs
40 yrs
50 yrs
BRCA1
BC OC BC OC BC OC
20
1.8 1
12 3.2 29 9.5
30
10 2
28 8.7
40
20 6.7
50
60
BRCA2
BC OC BC OC BC OC
20
1 0.19 7.5 0.7 21 2.6
30
6.6 0.52 20 2.4
40
15 1.9
50
60
Chen S and Parmigiani G. J Clin Oncol 2007;25:1329-1333
60 yrs
BC OC
44 23
44 22
38 20
22 15
BC
35
35
30
18
OC
7.5
7.4
7
5.7
70 yrs
BC OC
54 39
54 39
49 38
37 34
19 22
BC OC
45 16
45 16
42 16
32 14
17 9.8
Screening Limitations
The strategy of heightened screening is fraught with false positive and
false negative findings on sonograms and CA-125 testing in all women,
but particularly in the premenopausal population. Physiologic and
benign pathologic conditions, which are more commonly detected in
premenopausal women, adversely affect the accuracy of the testing
and can lead to unnecessary psychological stress and/or surgical
intervention. Furthermore there are no published studies which confirm
the efficacy of this strategy. While some studies have shown a shift to
diagnosis at an earlier stage of ovarian cancer, no studies have shown
a survival benefit. Women selecting this strategy must be aware of the
risk of unnecessary intervention due to false positive findings, and the
lack, to date, of a proven survival advantage.
Chemoprevention
The use of hormonal therapy in the form of oral contraceptives to
reduce the risk of ovarian cancer appears to decrease the incidence of
ovarian cancer by as much as 40 to 60%. Some concerns, however,
have been raised by observations of increased risk of up to 20% in
breast cancer in young women with BRCA1 mutations taking oral
contraceptive pills, although this is controversial and other studies
have shown little to no increased risk. The magnitude of protection
against ovarian cancer is related to the number of years of suppression
of ovarian function and persists for years after cessation of use. Women
selecting this option should be advised that this treatment strategy
remains under investigation.
Risk-Reducing Surgery
Performance of bilateral salpingo-oophorectomy is the only strategy
proven to be associated with a significant reduction of development of
ovarian, fallopian tube and primary peritoneal cancers. The magnitude
of reduction has been reported to be as high as 85-90%. In addition to
reducing the risk of gynecologic cancer, the risk of breast cancer is also
significantly decreased in premenopausal women. The impact of riskreducing surgery is affected by the penetrance and type of mutation
and age of the patient at the time of risk-reducing surgery. With less
than one quarter of women with BRCA1 mutations and up to 80% of
women with BRCA2 mutations having estrogen receptor positive breast
tumors, the protection against breast cancer development is estimated
to be approximately 40% and 70% respectively from the risk-reducing
salpingo-oophorectomy.
Focus on Female Cancers • Management Strategies • 35
Women considering this option should be counseled that in addition to the
standard risks of the surgical procedure, depending on the age of the patient, there
has been up to a 9% risk of finding an occult cancer reported. The surgeon should
be prepared to perform appropriate, immediate surgical staging or cytoreductive
surgery based on operative findings. The performance of hysterectomy in women
with BRCA mutations is not required, as increased risk of uterine malignancies
has not been adequately documented. The theoretical risk of fallopian tube
cancer arising in the interstitial portion of the fallopian tube has, thus far, not
been reported-likely due to the fact that the overwhelming majority of these
malignancies arise in the distal portion of the tube. In contrast, women with
HNPCC mutations have a 60% lifetime risk of developing a uterine malignancy
and hysterectomy should be offered along with risk-reducing bilateral salpingooophorectomy.
The timing of surgery should be determined by the estimated risk of developing
breast or gynecologic malignancies (see table titled Predicted Mean Cancer Risk
on page 35), evidence of penetrance of the mutation in the individual’s relatives,
and her desire to preserve fertility. However, delaying risk-reducing salpingooophorectomy after menopause will limit protection in risk of breast cancer,
particularly in women with BRCA2 mutations.
The performance of risk-reducing salpingo-oophorectomy requires completion of
the following steps:
• Surveillance of the abdomen and pelvis for occult disease
• Pelvic washings
• Removal of the entire tube and ovary bilaterally, usually via a retroperitoneal
approach to assure completeness of the procedure and decreased risk of
ureteral injury
• Communication with a pathologist regarding the indication for the
procedure
• Sectioning of the entire tube and ovary every 2-3 mm sections by an
experienced pathologist
These steps will help assure that the surgeon avoids the risk of failing to detect
occult cancer and the risk of cancer arising in residual ovarian tissue.
Following risk-reducing surgery, a lifetime risk of up to 6% of developing primary
peritoneal cancer has been reported. Optimal follow up of these women has
not been determined, and screening with CA-125 levels should be considered
investigational. Surgically induced premature menopause can increase the risk of
heart disease and osteoporosis, and may adversely affect the individual’s quality
of life. It has been reported that the use of hormone replacement therapy after
salpingo-oophorectomy may result in a decrease in magnitude of protection in
risk of development of breast cancer. However, several studies have suggested
that short-term use of hormone replacement therapy after salpingo-oopherctomy
does not significantly impact breast cancer risk.
36 • Focus on Female Cancers • ACOG District II/NY
Breast Cancer Reduction Strategies
Screening
Consensus recommendations state that each woman with a known or
suspected genetic mutation which raises her risk of breast cancer should
have monthly examinations starting at age 18, and have clinical breast
examinations semi-annually starting at age 25. Annual mammograms
should be initiated at the same time. However, dense breast tissue which
is often present in young women can limit the sensitivity of these studies.
Therefore, dedicated MRI screening beginning at age 25, alternating at 6
month intervals with mammography is now recommended.
Chemoprevention
Several studies have documented a reduction (50%) in contralateral breast
cancer risk in women with BRCA mutations treated with tamoxifen. A subset
analysis of the BRCA mutation carriers from the NSABP P-1 chemoprevention
trial showed this risk reduction only for BRCA2 carriers. This study, although
limited by small sample size, suggests that the risk reduction of tamoxifen
may be effective in breast cancer risk reduction regardless of BRCA mutation
status. Risks of treatment with tamoxifen include menopausal symptoms
such as hot flushes, thrombotic events and endometrial cancer.
The NSABP P-2 trial (STAR trial) showed that raloxifene was equivalent
to tamoxifen in reducing breast cancer risk in high risk post menopausal
women. There is not yet any published data on the subset of women with
BRCA mutations who participated in this study. The use of SERMs other than
tamoxifen and aromatase inhibitors has not yet been adequately studied
in women with known BRCA mutations. At this time, it is unknown if the
risks of use can be justified for this population in view of lack of evidence of
benefits.
Risk-Reducing Surgery
Performance of bilateral simple mastectomies offers a greater than 90%
reduction in development of breast cancer. This magnitude of reduction is
also associated with a significant reduction in anxiety. However, there have
been no published guidelines regarding appropriate medical follow-up
after mastectomy. Appropriate counseling preoperatively and follow up is
helpful in assisting each woman in maintaining an acceptable quality of life.
Women opting for salpingo-oophorectomy also decrease their risk of breast
cancer as discussed in the ovarian cancer risk reducing surgery section.
References:
Allain DC, Sweet K, Agnese DM. Management options after prophylactic
surgeries in women with BRCA mutations: A review. Cancer Control.
2007;14:330-337.
Brohet RM, Goldgar DE, Easton DF, et al. Oral contraceptives and breast cancer
risk in the international BRCA1/2 carrier cohort study: A report from EMBRACE,
GENEPSO, GEO-HEBON, and the IBCCS Collaborating Group. Journal of Clinical
Oncology. 2007;25:3831-6.
Hartmann LC, Sellers TA, Schaid DJ, et al. Efficacy of bilateral prophylactic
mastectomy in BRCA1 and BRCA2 gene mutation carriers. Journal of the National
Cancer Institute. 2001;93:1633-7.
Hogg R, Friedlander M. Biology of epithelial ovarian cancer: Implications
for screening women at high genetic risk. Journal of Clinical Oncology.
2004;22:1315-27.
Kauff ND, Barakat RR. Risk-reducing salpingo-oophorectomy in patients
with germline mutations in BRCA1 or BRCA2. Journal of Clinical Oncology.
2007;25:2921-7.
Kauff ND, Satagopan JM, Robson ME, et al. Risk-reducing salpingooophorectomy in women with a BRCA1 or BRCA2 mutation. New England
Journal of Medicine. 2002;346:1609-15.
King MC, Wieand S, Hale K, et al. Tamoxifen and breast cancer incidence among
women with inherited mutations in BRCA1 and BRCA2: National Surgical
Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial.
Journal of the American Medical Association. 2001;286:2251-6.
Kriege M, Brekelmans CT, Boetes C, et al. Efficacy of MRI and mammography for
breast-cancer screening in women with a familial or genetic predisposition. New
England Journal of Medicine. 2004;351:427-37.
Leach MO, Boggis CR, Dixon AK, et al. Screening with magnetic resonance
imaging and mammography of a UK population at high familial risk of breast
cancer: A prospective multicentre cohort study (MARIBS). Lancet Oncology.
2005;365:1769-78.
Liede A, Karlan BY, Baldwin RL, et al. Cancer incidence in a population of Jewish
women at risk of ovarian cancer. Journal of Clinical Oncology. 2002;20:1570-7.
Meijers-Heijboer H, van Geel B, van Putten WL, et al. Breast cancer after
prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation.
New England Journal of Medicine. 2001;345:159-64.
Modan B, Hartge P, Hirsh-Yechezkel G, et al. Parity, oral contraceptives, and
the risk of ovarian cancer among carriers and noncarriers of a BRCA1 or BRCA2
mutation. New England Journal of Medicine. 2001;345:235-40.
Narod SA, Brunet JS, Ghadirian P, et al. Tamoxifen and risk of contralateral breast
cancer in BRCA1 and BRCA2 mutation carriers: A case-control study. Hereditary
Breast Cancer Clinical Study Group. Lancet Oncology. 2000;356:1876-81.
Narod SA, Dubé MP, Klijn J, et al. Oral contraceptives and the risk of breast cancer
in BRCA1 and BRCA2 mutation carriers. Journal of the National Cancer Institute.
2002; 94:1773-9.
Narod SA, Risch H, Moslehi R, et al. Oral contraceptives and the risk of hereditary
ovarian cancer. Hereditary Ovarian Cancer Clinical Study Group. New England
Journal of Medicine. 1998;339:424-8.
National Comprehensive Cancer Network. Clinical Practice Guidelines in
Oncology- V.1.2007. Genetic/Familial High Risk Assessment: Breast and
Ovarian Cancer. Available at: www.nccn.org/professionals/physician_gls/PDF/
genetics_screening.pdf Accessed November 27, 2007.
Powell CB, Kenley E, Chen LM, et al. Risk-reducing salpingo-oophorectomy
in BRCA mutation carriers: Role of serial sectioning in the detection of occult
malignancy. Journal of Clinical Oncology. 2005;23:127-132.
Rebbeck TR, Friebel T, Lynch HT, et al. Bilateral prophylactic mastectomy reduces
breast cancer risk in BRCA1 and BRCA2 mutation carriers: The PROSE Study
Group. Journal of Clinical Oncology. 2004;22:1055-62.
Rebbeck TR, Friebel T, Wagner T, et al. Effect of short-term hormone replacement
Therapy on breast cancer risk reduction after bilateral prophylactic oophorectomy
in BRCA1 and BRCA2 mutation carriers: The PROSE Study Group. Journal of
Clinical Oncology. 2005;23:7804-10.
Rebbeck TR, Lynch HT, Neuhausen SL, et al. Prophylactic oophorectomy in
carriers of BRCA1 or BRCA2 mutations. New England Journal of Medicine.
2002;346:1616-22.
Robson M, Offit K. Clinical practice. Management of an inherited predisposition
to breast cancer. New England Journal of Medicine. 2007;357:154-162.
Focus on Female Cancers • Management Strategies • 37 Roukos DH, Briasoulis E. Individualized preventive and therapeutic management
of hereditary breast ovarian cancer syndrome. Nature Clinical Practice Oncology.
2007;4:578-590.
Society of Gynecologic Oncologists Clinical Practice Committee Statement on
Prophylactic Salpingo-Oophorectomy. Gynecologic Oncology. 2005;98:179–81.
Saslow D, Boetes C, Burke W, et al. American Cancer Society guidelines for breast
screening with MRI as an adjunct to mammography. CA: A Cancer Journal for
Clinicians. 2007;57:75-89.
Warner E, Plewes DB, Hill Ka, et al. Surveillance of BRCA1 and BRCA2 mutation
carriers with magnetic resonance imaging, ultrasound, mammography, and
clinical breast examination. Journal of the American Medical Association.
2004;292:1317-25.
Scheuer L, Kauff N, Robson M, et al. Outcome of preventive surgery and
screening for breast and ovarian cancer in BRCA mutation carriers. Journal of
Clinical Oncology. 2002;20:1260-8.
Whittemore AS, Belise RR, Pharoah PD, et al. Oral contraceptive use and ovarian
cancer risk among carriers of BRCA1 or BRCA2 mutations. British Journal of
Cancer. 2004; 91:1911-5.
Selection of
appropriate
modalities must
be tailored to the
individual patient.
38 • Focus on Female Cancers • ACOG District II/NY
❙ ❙ Hereditary Breast and Ovarian
The following resources are available to you to learn more about inherited
cancer predisposition syndromes, specifically, hereditary breast and
ovarian cancer. There are references for incidence, family history tools,
risk assessment, the process of genetic counseling, how to find genetic
counselors for referral or consultation, resources for individuals with a
mutation as well as resources for high risk individuals who test negative,
risk reduction strategies and studies.
Family Health History Tools:
Genetic Alliance Family Health Historywww.geneticalliance.org/ws_display.asp?filter=fhh
U.S. Surgeon General's Family History Initiative
www.hhs.gov/familyhistory
Genetic Counselors:
American Society of Human Genetics
www.ashg.org
American College of Medical Genetics
www.acmg.org
International Society of Nurses in Genetics
www.isong.org
National Cancer Institute’s Cancer Information Service
1-800-4-CANCER or www.cancer.gov
National Society of Genetic Counselors
www.nsgc.org
New York State Department of Health Cancer Services Program
1-866-442-CANCER
New York State Genetic Counselors
www.nysgeneticcounselors.org
Cancer Resources
Genetic Discrimination:
Genetics and Health Insurance: State Anti-Discrimination Laws. National
Conference of State Legislatures
www.ncsl.org/programs/health/genetics/ndishlth.htm
Genetic Testing and Screening in the Age of Genomic Medicine
(NYS report on genetic testing)*
www.health.state.ny.us/nysdoh/taskfce/screening.htm
National Human Genome Research Institute
www.genome.gov/10002077
National Human Genome Research Institute Policy and Legislation Database:
Genetic testing, information, privacy, counseling
www.genome.gov/PolicyEthics/LegDatabase/PubSearchResult.cfm
National Society of Genetic Counselors Patient Brochure
Genetic Information, Privacy and Discrimination: What you need to know
www.nsgc.org/client_files/consumer/gd_brochure2.pdf
The Secretary’s Advisory Committee on Genetics, Health and Society
www4.od.nih.gov/oba/sacghs.htm
*A hard copy of this report is available by contacting the Legislative Commission
on Science & Technology, Assembly, P.O. Box 167, Albany, NY 12248 and
requesting NYS Legislative Commission on Science and Technology, LCST Report
No. 94-1, September, 1994.
Guidance:
2007 State of the State of Gynecological Cancers: Fifth Annual Report to the
Women of America. Gynecological Cancer Foundation.
www.wcn.org/SOS_2007_FINAL081507.pdf
Ethical issues in genetic testing. ACOG Committee Opinion. 2008;410. ACOG:
Washington DC.
Genetic/Familial High-Risk Assessment: Breast and Ovarian. National
Comprehensive Cancer Network. 2008.
www.nccn.org/professionals/physician_gls/PDF/genetics_screening.pdf
Focus on Female Cancers • Resources • 41
National Cancer Institute
www.cancer.gov/cancertopics/pdq/genetics/breast-and-ovarian/
healthprofessional
Proposed International Guidelines on Ethical Issues in Medical Genetics and
Genetic Services. World Health Organization Human Genetics Programme. 1998.
http://whqlibdoc.who.int/hq/1998/WHO_HGN_GL_ETH_98.1.pdf
Role of the Obstetrician–Gynecologist in the Screening and Diagnosis of Breast
Masses. ACOG Committee Opinion No. 334. American College of Obstetricians
and Gynecologists. May 2006.
Center for Genetics and Public Policy
www.dnapolicy.org
Genetic Alliance
www.geneticalliance.org/ws_display.asp?filter=understanding.genetics
National Cancer Institute – Fact Sheets
www.cancer.gov/cancertopics/Genetic-Testing-for-Breast-and-Ovarian-Cancer-Risk
www.cancer.gov/cancertopics/factsheet/Risk/BRCA
National Cancer Institute: Genetics of Breast and Ovarian Cancer
www.cancer.gov/cancertopics/pdq/genetics/breast-and-ovarian/healthprofessional
Routine Cancer Screening. ACOG Committee Opinion No. 356. December 2006.
Statement on Prophylactic Salpingo-Oophorectomy. SGO Clinical Practice
Committee. Society of Gynecologic Oncologists. 2005.
www.sgo.org/WorkArea/showcontent.aspx?id=306
National Institute of Health-Genetics Through a Primary Care Lens: A Web-Based
Resource for Faculty Development
www.genetests.org (click on “Genetic Tools” in the right hand tool bar)
The Role of the Generalist Obstetrician–Gynecologist in the Early Detection of
Ovarian Cancer. ACOG Committee Opinion No. 280. December 2002.
Society of Gynecological Oncologists
www.sgo.org
U.S. Preventive Services Task Force
www.ahrq.gov/clinic/uspstf/uspsbrgen.htm
Journals:
Guttmacher A, Collin FS. Genomic medicine: A primer. New England Journal of
Medicine 2002;347(19):1512-1520. Accessed July 20, 2008.
Available at http://content.nejm.org/cgi/reprint/347/19/1512.pdf
Websites:
American College of Medical Genetics
www.acmg.net
American College of Obstetricians and Gynecologists
www.acog.org
Centers for Disease Control and Prevention
www.cdc.gov/genomics/training/perspectives/factshts/breastcancer.htm
42 • Focus on Female Cancers • ACOG District II/NY