J Genet Counsel (2007) 16:241–260 DOI 10.1007/s10897-007-9090-7
PROFESSIONAL ISSUES
Risk Assessment and Genetic Counseling for Hereditary Breast and Ovarian Cancer: Recommendations of the National Society of Genetic Counselors Janice L. Berliner & Angela Musial Fay
Received: 24 January 2007 / Accepted: 25 January 2007 / Published online: 17 May 2007 # National Society of Genetic Counselors, Inc. 2007
Abstract These cancer genetic counseling recommendations describe the medical, psychosocial and ethical implications of identifying at-risk individuals for hereditary breast and ovarian cancer (HBOC) through cancer risk assessment, with or without genetic susceptibility testing. They were developed by members of the Practice Issues Subcommittee of the National Society of Genetic Counselors’ Familial Cancer Risk Counseling Special Interest Group. The information contained in this document is derived from extensive review of the current literature on cancer genetic risk assessment as well as the professional expertise of genetic counselors with significant experience in education and counseling regarding hereditary breast and ovarian cancer. Critical components of the process include the ascertainment of medical and family histories, determination and communication of cancer risk, assessment of risk perception, education regarding the genetics of HBOC, discussion of molecular testing for HBOC if appropriate (including benefits, risks and limitations) and any necessary follow-up. These recommendations do not dictate an exclusive course of management or guarantee a specific outcome. Moreover, they do not replace the professional judgment of a health care provider based on the clinical situation of a client.
J. L. Berliner (*) Saint Barnabas Medical Center, 94 Old Short Hills Rd, Livingston, NJ 07039, USA e-mail:
[email protected] A. M. Fay Meridian Health, Brick, NJ, USA
Keywords BRCA1 . BRCA2 . Hereditary breast cancer . Hereditary ovarian cancer . Cancer genetic counseling . Risk assessment . Genetic testing . Family history . Psychosocial assessment . Medical management
Purpose The National Society of Genetic Counselors (NSGC) has previously published recommendations for Genetic Cancer Risk Assessment and Counseling (Trepanier et al. 2004), which provide a detailed description of the components of the process and are applicable to all hereditary cancer syndromes. This document is intended to provide guidelines specifically for the evaluation of hereditary breast and/or ovarian cancer risk, and is to be used in conjunction with the previously published NSGC document to educate health care providers regarding the process of cancer genetic counseling and risk assessment, and current medical management options for individuals with hereditary breast and ovarian cancer (HBOC) syndrome. Psychosocial issues involved with identifying and counseling individuals at risk for HBOC will also be discussed. These recommendations were developed by genetic counselors who are members of the Practice Issues Subcommittee of the NSGC Familial Cancer Risk Counseling Special Interest Group. The information was derived from extensive review of the current literature on cancer genetic risk assessment as well as the professional expertise of genetic counselors with significant experience in the education and counseling of individuals at high risk for breast and ovarian cancer. This document has been reviewed by additional cancer genetic counselors, members of the American College of Medical Genetics(ACMG) and the Oncology Nursing Society (ONS), consumer groups,
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NSGC general membership, and the Board of Directors and Genetic Services Committee of the NSGC.
Disclaimer Genetic counseling recommendations of the NSGC are developed by members of the NSGC to assist practitioners and patients in making decisions about appropriate management of genetic concerns. Each practice recommendation focuses on a clinical or practice issue and is based on a review and analysis of the professional literature. The information and recommendations reflect scientific and clinical knowledge current as of the submission date and are subject to change as advances in diagnostic techniques, treatments, and psychosocial understanding emerge. In addition, variations in practice, taking into account the needs of the individual patient and the resources and limitations unique to the institution or type of practice, may warrant approaches, treatments or procedures alternative to the recommendations outlined in this document. Therefore, these recommendations should not be construed as dictating an exclusive course of management, nor does use of such recommendations guarantee a particular outcome. Genetic counseling recommendations are never intended to displace a health care provider’s best medical judgment based on the clinical circumstances of a particular patient.
Methodology The authors consisted of a working group of the Practice Issues Subcommittee of the NSGC Familial Cancer Risk Counseling Special Interest Group. The authors searched via MEDLINE the relevant English language medical and psychosocial literature between 1992 and 2006, and incorporated information from several key seminal articles from earlier years. Key words included BRCA1, BRCA2, hereditary breast cancer, hereditary ovarian cancer, cancer genetic counseling, risk assessment, genetic susceptibility testing, family history, medical management and psychosocial assessment. Previously published guidelines and policy statements published by the American Society of Clinical Oncology (American Society of Clinical Oncology 1996, 2003), the American College of Medical Genetics Foundation (American College of Medical Genetics Foundation 1999), the National Comprehensive Cancer Network (NCCN), and the National Society of Genetic Counselors (Trepanier et al. 2004) were also reviewed. This literature is based on clinical experience, descriptive studies and/or reports of expert committees. The literature was reviewed and evaluated for quality according to the
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categories outlined by the U.S. Preventive Services Task Force (1995): I. Evidence obtained from at least one properly designed randomized controlled trial II-1. Evidence obtained from well-designed controlled trials without randomization II-2. Evidence obtained from well-designed cohort or case-control-analytic studies, preferably from more than one center or research group II-3. Evidence obtained from multiple time series with or without the intervention III. Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees The rating of supporting literature for this recommendation includes II-2, II-3 and III. A draft of this document was made available to the 2,024 full members of the NSGC for comment in October, 2006. The revised document was reviewed by the NSGC attorney and the NSGC Ethics Subcommittee. The NSGC Board of Directors reviewed and approved the final document on January 16, 2007.
Clinical Overview Approximately half of all men and one third of all women in the United States will develop cancer in their lifetimes, according to the American Cancer Society. Among women, breast cancer is the second leading cause of cancer deaths after lung cancer and ovarian cancer is the fourth leading cause of cancer deaths (American Cancer Society 2006). In the United States, women face a 12.8% chance of developing breast cancer and a 1.4% chance of developing ovarian cancer by the age of 90 (National Cancer Institute 2006a). However, some women are at much greater risk. Although reproductive, demographic, and lifestyle factors affect the risk of both breast and ovarian cancer, the most significant risk factor after gender and aging is a family history of the disease (Schildkraut and Thompson 1988; Daly and Lerman 1993; McTiernan et al. 1997). The potential hereditary nature of breast and ovarian cancer has been recognized for many years. In the early 1990s, studies demonstrated the existence of an autosomal dominant form of breast and ovarian cancer risk, and led to the identification of two highly penetrant genes: BRCA1 on chromosome 17 (Hall et al. 1990) and BRCA2 on chromosome 13 (Wooster et al. 1994). A germ-line mutation in either gene leads to a significantly increased risk of breast and ovarian cancer (Miki et al. 1994; Wooster
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et al. 1995). Inherited mutations in BRCA1 and BRCA2 are relatively uncommon in the general population (estimates of the carrier frequency range from 1 in 300 to 1 in 800), but are thought to account for up to 7% of breast cancer and up to 14% of ovarian cancer cases overall (Pal et al. 2005). Mutations are more common in individuals and families that display a clustering of early-onset breast and ovarian cancer, multiple primary cancers, male breast cancer, Ashkenazi Jewish ancestry and evidence of autosomal dominant transmission. BRCA1 and BRCA2 mutations account for over 90% of families with multiple cases of breast and ovarian cancer (Ford et al. 1998). However, a client presenting for cancer risk assessment more often has a family history of only breast cancer, usually confined to females. BRCA1 and BRCA2 mutations are responsible for approximately 40% of families with a pattern of sitespecific female breast cancer (Ford et al. 1998). For Ashkenazi Jews, the prevalence of BRCA mutations is approximately 2.5% in the unselected population, in the form of three founder mutations, two of which are in the BRCA1 gene and one of which is in the BRCA2 gene (Roa et al. 1996). Jewish individuals have a disproportionately high likelihood of carrying a BRCA mutation, such that Jewish women with breast cancer diagnosed at any age have about a 10% likelihood of carrying a mutation, and Jewish women diagnosed by the age of 40 have a 21–30% likelihood (Rubinstein 2004). The BRCA1 and BRCA2 protein products are involved in the cellular response to DNA damage and doublestranded DNA repair. Women with a germline mutation in BRCA1 or BRCA2 face a 50–87% risk of developing breast cancer and a 27–44% risk of developing ovarian cancer to age 70 (Ford et al. 1994, 1998). Furthermore, within 10 years of an initial breast cancer diagnosis, the risk of developing a second primary breast cancer is 35–43% and the risk of ovarian cancer is 7–13% (Metcalfe et al. 2004, 2005). Men with BRCA mutations have a 5–10% lifetime risk of developing breast cancer, which is much higher than the average man’s risk of 0.1% (Brose et al. 2002) and an increased risk for earlier onset prostate cancer, and both men and women have a somewhat increased risk for pancreatic cancer (Breast Cancer Linkage Consortium 1999; Thompson et al. 2002; van Asperen et al. 2005). Finally, several publications have reported modest increases in the risk of other cancers among female and male carriers of BRCA1 and BRCA2 mutations, including colon cancer, uterine cancer, and melanoma, but the results have not been consistent among studies (Brose et al. 2002; Thompson et al. 2002). Clearly, the most clinically significant risks for female carriers of BRCA mutations are for breast and ovarian cancer. Over the last several years, published literature on the medical
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management of identified BRCA1 and BRCA2 mutation carriers has documented effective strategies for risk-reduction and enhanced surveillance. Therefore, it is crucial that appropriate candidates for breast and ovarian cancer risk assessment are identified and referred for these services.
The Cancer Risk Assessment and Genetic Counseling Process Cancer risks in mutation carriers differ depending upon the syndrome, the specific mutation being carried in the family, age, and sometimes, gender. Cancer risk assessment involves the process of identifying individuals at risk for hereditary cancer. Pedigree analysis is used in conjunction with available risk assessment models to determine whether a family is suspected of having hereditary cancer, familial cancer, or sporadically occurring cancer (see Table I). This classification can help in quantifying risks to individual family members and developing a plan for cancer screening, prevention, risk reduction and psychosocial support and counseling. Further, this classification helps in the determination of whether genetic testing is appropriate for the family, and if so, which relative(s) would be the appropriate individual(s) to test (Schneider 2002). Unfortunately, the separation of families into hereditary, familial, and sporadic cancer is often not precise. The features of these classifications are described in Table I. Genetic counseling is a key component of the cancer risk assessment process (Peters and Stopfer 1996; Stopfer 2000), and includes education regarding the genetics of cancer, the likelihood of developing cancer as well as the likelihood of carrying a genetic susceptibility mutation, the benefits, risks and limitations of genetic susceptibility testing, and appropriate cancer screening and prevention strategies. The goal is to empower the client to make informed decisions regarding screening, prevention and genetic testing by providing him or her with the necessary genetic, medical and psychosocial information. Attention to psychosocial issues is critical for effective genetic counseling (Lerman et al. 1995, 1997; Bernhardt et al. 2000; Lobb et al. 2001; Meiser and Halliday 2002; Pasacreta 2003). This document has been prepared to allow genetic counselors and other health care providers to identify clients who may benefit from cancer risk assessment and genetic counseling and to guide the practitioner in providing these services. Health care professionals should consider referring a client for cancer risk assessment and genetic counseling when the personal or family history is suggestive of familial or hereditary cancer. In order to
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Table I Characteristics of Hereditary, Familial and Sporadic Cancer Syndromes Classification of Family
Characteristics
Hereditary Cancer
Apparently autosomal dominant transmission of specific cancer type(s) Earlier age of onset of cancers than is typical Multiple primary cancers in an individual Clustering of rare cancers Bilateral or multifocal cancers First degree relatives of mutation carriers are at 50% risk to have the same mutation Incomplete penetrance and variable expressivity, such that obligate carriers of the family mutation may be cancer-free and the age of diagnosis of cancer among relatives will vary Those who do not have the familial mutation have the general population risk for cancer More cases of a specific type(s) of cancer within a family than statistically expected, but no specific pattern of inheritance Age of onset variable May result from chance clustering of sporadic cases May result from common genetic background, similar environment and/or lifestyle factors Does not usually exhibit classical features of hereditary cancer syndromes Cancers in the family are likely due to nonhereditary causes Typical age of onset Even if there is more than one case in the family, there is no particular pattern of inheritance Very low likelihood that genetic susceptibility testing will reveal a mutation; testing will likely not provide additional information about cancer risk
Familial Cancer
Sporadic Cancer
meet all of the client’s needs, cancer risk assessment ideally is offered in the context of a multidisciplinary team that includes expertise in both genetic counseling and oncology. The team may consist of a variety of different specialists including genetic counselors, medical geneticists, surgeons, oncologists, social workers, oncology nurses and psychologists. Referral for Cancer Risk Assessment and Genetic Counseling There are many publications, policy statements, and organizational recommendations that propose criteria for when an individual should be referred for genetic counseling regarding hereditary risk of breast and/or ovarian cancer, including the American Society of Clinical Oncology (ASCO), the National Comprehensive Cancer Network (NCCN), the U.S. Preventive Services Task Force (USPSTF) (1995, 2005), and the American College of Medical Genetics (ACMG). Although the specific criteria for genetic counseling referral vary among organizations, they are consistently based on the recognition of clinical features that increase the likelihood of hereditary susceptibility to breast and/or ovarian cancer, including: & &
Early-onset breast cancer, usually defined as before age 50 Ovarian cancer
& & & &
Individuals with two or more primary breast cancers, or breast and ovarian cancer in the same individual Male breast cancer Two or more individuals in the family with breast and/ or ovarian cancer Ashkenazi Jewish ancestry
Health care professionals providing cancer genetic counseling services should evaluate the current professional society guidelines for referral, and determine which criteria they will provide to referring physicians to facilitate the identification of appropriate patients. It is important to recognize that criteria for genetic counseling referral do not necessarily equate to referral for germ-line genetic testing. Less restrictive referral criteria will allow for a larger number of clients to benefit from risk assessment, and may identify appropriate candidates for genetic testing who would be missed using stringent criteria.
Intake and History An accurate personal and family history is essential to evaluate the possibility of hereditary cancer risk appropriately. This information may be obtained through a written questionnaire or during the consultation. Trepanier et al. (2004) provide a detailed description of how to obtain such a history, including a list of specific questions to ask about the client and relatives. When evaluating a client’s personal
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and family history for breast and/or ovarian cancer risk, a few issues warrant particular attention: 1. Clients should be questioned about relevant environmental exposures and reproductive factors that may affect cancer risk. A list of risk factors for breast and ovarian cancer is provided in Table II. The impact of the risk factors on women with a positive family history of breast and/or ovarian cancer or those who carry a BRCA1 or BRCA2 mutation is an active area of research. Most reproductive and lifestyle risk factors lead to less than a two-fold increase in cancer risk, and therefore, may not have an effect sufficient to alter medical management in women with a high genetic risk. Pathologic markers of risk on breast biopsy such as atypia and LCIS are important indicators of risk, and will lead to modified follow-up recommendations. 2. For the purpose of family history evaluation, surgeries that significantly reduce the risk of breast and/or ovarian cancer should be documented, as they may obscure an obvious pattern of hereditary cancer in the pedigree. Therefore, clients should be asked about surgical removal of the ovaries, fallopian tubes, and breast tissue, both in themselves and their relatives. Similarly, deaths at young ages due to other causes may lead to fewer cancers in the family than may be expected in a family with hereditary cancer risk. 3. Medical record confirmation of cancer diagnoses is ideal for accurate risk assessment, when possible. In clinical practice, it may be logistically difficult for clients to obtain medical records on their relatives’ cancer diagnoses. Clients should be advised that their risk assessments are based on the personal and medical histories they provide, and may change dramatically should any of the reported information prove to be
Table II Risk Factors for Breast and Ovarian Cancer Risk Factors for Breast Cancer
Risk Factors for Ovarian Cancer
Menarche before age 12 First live birth after age 30 Nulliparity Menopause after age 55 Atypical hyperplasia or LCIS diagnosed by breast biopsy Postmenopausal obesity Hormone replacement therapy Alcohol use (more than 2 drinks per day) Previous therapeutic radiation to chest or upper body Family history of breast cancer
Nulliparity Family history of ovarian cancer
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inaccurate. Studies evaluating the accuracy of selfreported cancer family histories have shown that reports of breast cancer are often accurate, while reports of ovarian cancer are more likely to be erroneous (Love et al. 1985; Theis et al. 1994; Parent et al. 1997; Douglas et al. 1999; Ziogas and Anton-Culver 2003). If the risk assessment depends on a particular family member’s specific diagnosis, medical records should be pursued. For example, the presence or absence of ovarian cancer in a family can significantly affect the estimated likelihood of a BRCA1 or BRCA2 mutation. Therefore, the primary site of reported “abdominal” or “female” cancer in a close female family member should be confirmed, if possible.
Psychosocial Assessment Risk assessment for cancer can raise a number of psychosocial issues. Clients will need to contend with an enhanced understanding of their specific cancer risks, potentially difficult decisions for managing their cancer risks, concerns about discrimination and worry about potential risks for their children and other family members. Thus, when providing genetic counseling for HBOC, a thorough evaluation is essential to understand better how genetic information will impact the individual and his or her family. Professionals performing cancer risk assessment and genetic counseling require proficiency in communication and counseling, psychosocial assessment and crisis intervention as well as the genetics of cancer and risk assessment. Psychosocial issues can be addressed by utilizing the principles and practices of genetic counseling as well as psychology and psycho-oncology (Baker et al. 1998). Even when presented with numerical risks, clients’ cancer risk perceptions remain largely based on the emotional responses and psychosocial outcomes of their previous cancer experiences. These experiences ultimately drive behaviors related to cancer screening, genetic counseling and testing, and medical management (Patenaude 2005; Schneider 2002; Weil 2000). Although a thorough psychosocial analysis may be difficult, there are several key factors which can provide a better understanding of the client’s overall psychological state. An awareness of the client’s socioeconomic, ethnic, educational, and religious backgrounds may provide information about how he or she will interpret and utilize the genetic information (Lynch et al. 1996; Mitchell 1998; Trepanier et al. 2004). This information can be gained either through completion of an intake form prior to the counseling session or through informal questioning during the session.
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In addition to the patient’s demographic and educational information, it is valuable to assess briefly the patient’s overall pre-test psychological and emotional state. It is important to remember that genetic counselors are not trained to perform a full psychological analysis or provide psychological counseling and should refer to appropriate mental health professionals when necessary. Having a broad understanding of the following components may be useful in identifying those patients who would benefit from contact with a mental health professional (Patenaude 2005; Schneider 2002; Trepanier et al. 2004). &
&
&
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Current emotional well-being: The perception of being at increased cancer risk can result in a range of emotional responses which can influence many areas of the individual’s life. It may be useful to evaluate for signs of depression or anxiety by asking about any recent changes in eating, sleeping or overall emotional state. Mental health history: An individual with a history of mental health issues may be more emotionally vulnerable to a genetic test result, particularly a positive test result confirming the perception of increased cancer risk. It may be valuable to integrate direct questions about the client’s mental health history and previous therapeutic interventions. These questions may help pave the way to recommending counseling intervention if necessary. Emotional response to family history of cancer: It is important during the counseling session to understand not only the genetic impact, but also the psychological impact of a cancer family history on the client. It may be useful for both client and counselor to address questions about the impact of a family member’s illness and how the client views his or her increased risk status. Coping strategies: Clients will have developed different coping methods for dealing with their increased risk (real or perceived) of developing cancer. To understand these coping strategies better so that they can work to their best advantage, it is important both to ask clients how they perceive themselves coping with the cancer in the family, and to observe their reactions and coping skills directly throughout the session. Reactions/responses during the counseling session: HBOC counseling sessions typically include discussions about family cancer history and estimates of cancer and mutation risks. These discussions have the potential to bring out unpleasant emotions, making it essential that the counselor continually monitor the client’s reactions and adjust the focus and content of the session accordingly.
In addition to having an understanding of the psychological and emotional state of a patient, it may be valuable
in a pre-test counseling session to identify any potential psychological barriers to testing that the client may be experiencing. These barriers might include any of the following: fear of a positive result in an unaffected individual, guilt associated with passing a mutation to children, survivor guilt, fear of discrimination/stigmatization due to a positive result, fear of insurance discrimination, or avoidance of the medical management decisions that would be necessary with a positive result (Fine 1999; Foster et al. 2004; Patenaude 2005). In addition to the discussion of psychological barriers to testing, it is important to ask the client about his or her perceived benefits of or motivations for testing. These potential benefits might include relieving the anxiety of not knowing, allowing mental focus on proactive medical management, and the potential to inform and educate other at-risk family members (Croyle 1997; Fine 1999; Lerman et al. 2002). The following pre-test questions may help both the counselor and client identify and process any potential psychological factors related to testing (Fine 1999): & & & & & &
Do you want to know more about your risk of developing breast/ovarian cancer? If so, how will the results of the test affect you? If a mutation is detected, how will you cope with knowing that you have an increased risk of developing cancer? Will you change your surveillance practices? Will you consider prophylactic surgery? If you test positive for a mutation, how will you feel about sharing this information with family members who may be at risk? What plans might you make in light of a negative/ positive test result? Do you want to pursue this testing? Now? Perhaps in the future?
Cancer Risk Assessment Risk assessment models have improved since genetic testing became available in 1996. Which model(s) a practitioner uses depends upon the personal and family characteristics of the individual(s) seeking the information, and available information about the family. Many families who present for cancer risk assessment exhibit some features of a hereditary cancer syndrome without clear evidence of single-gene dominant inheritance. Several factors can make it difficult to assess hereditary risk from a pedigree, including small family size, reduced penetrance, a paucity of individuals of the susceptible gender for sexinfluenced or sex-limited cancers, prior prophylactic surgeries in at-risk individuals, and inaccurate or incomplete
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information on family members (Trepanier et al. 2004). It is important for clients to report any new cancer diagnoses or newly gathered information on former diagnoses so that the pedigree can be reassessed over time. Risk can be assessed in many ways, and clients may be presented with several risk estimates, including the likelihood of developing certain types of cancers or the probability of carrying a genetic mutation related to increased cancer risk. Because individuals differ in their experiences and educational background, it is important to assess the client’s understanding of the information being presented, and if necessary, explain it in different ways. Since data can vary from one study to another, presenting the range of risks along with how those risks were derived is illustrative and may help the client understand that a specific numerical risk is not usually available. Pointing out how the client’s risk compares with that of the general population may also be helpful. Finally, assessing the potential impact of the risk estimate on the medical management and health behaviors of the client is essential. Population estimates of the likelihood of having a mutation within the BRCA1 or BRCA2 genes can help determine who might benefit most from a referral to a cancer genetic counselor and consideration of genetic susceptibility testing. Personalized risk assessment based on the individual’s medical and family history characteristics will provide a more accurate estimate of the likelihood that a client is carrying a BRCA mutation. Determining cancer risk involves two processes. One is the estimation of the absolute risk that the client will develop cancer based on the family history (see Trepanier et al. 2004 for detailed explanations of the models available for estimating cancer risk in the absence of a known heritable genetic mutation) and the assessment of whether the history is indicative of a hereditary, familial or sporadic pattern. The genetic counselor can be instrumental in sorting out families who fall into these categories through careful pedigree assessment. In general, a pedigree that shows an autosomal dominant pattern of inheritance of a specific constellation of tumors, especially at earlier ages of onset, may suggest an inherited cancer syndrome. However, because most hereditary cancer syndromes demonstrate incomplete penetrance, a family that does not show a typical autosomal dominant transmission pattern may still have a single cancer predisposing mutation. Familial cancers are those that do not generally exhibit the features of hereditary cancers as far as inheritance patterns or onset age, but occur in more individuals in the family than statistically expected. These may be the result of several factors, such as shared environment, chance clustering, small family size, and many others. Finally, sporadic cancers are those that can be defined by lack of (or limited) family history of cancer, older ages of onset, and a lack of
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an autosomal dominant pattern of inheritance. Most of the time clients with sporadic cancers will not benefit from molecular genetic testing for hereditary cancer syndromes. The exceptions include those cancers that are rare and/or may have a fairly high de novo mutation rate. The genetic counselor or other trained health professional can be instrumental in identifying these types of syndromes in an otherwise sporadic looking family, which could have important ramifications for the client and his/her family members. The second part of the risk assessment process is estimating the probability that there is a heritable genetic mutation (or family-specific mutation) in the family that the client may have inherited. The most effective models to determine this probability are compared in Table III. Clinical scenarios describing the strengths and weaknesses of some of the older models as well as the importance of determining which model is the most appropriate for the family in question are offered by Domchek et al. 2003 and Rubinstein et al. 2002. The sensitivity and specificity of some of the more recently described models are compared by Marroni et al. 2004 and Barcenas et al. 2006. Models for determining the probability of a BRCA1 or BRCA2 mutation in a family take into account some or all of the following factors: & & & & & &
Age of onset of cancer or age achieved cancer-free Number of affected relatives Degree of biological relationships of affected relatives Ratio of affected to unaffected relatives Presence/absence of associated malignancies Ethnic background
Given that each risk assessment model takes different factors into account, accurately assessing a client’s probability requires knowledge of which model(s) applies most closely to the personal and family characteristics. Because many people overestimate their risks, knowing the probability that genetic testing will reveal a mutation is often useful for those considering testing (Burke et al. 2000). It is important to recognize that risk assessment models are tools to enhance the clinician’s risk assessment, but should not be used in place of clinical judgment. Rubinstein et al. (2002) provide examples of case studies which illustrate the importance of using the appropriate model(s) and the interpretation of the results for the client. Because mutations in the BRCA1 and BRCA2 genes have explained only some of the genetic determinants of breast cancer risk, Tyrer et al. (2004) have developed a model incorporating the BRCA genes, a hypothetical low penetrance gene and personal risk factors. Though not widely used currently, this model is designed to incorporate a woman’s personal and family history in conjunction with
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Table III Risk Models for Estimating the Likelihood of Carrying a BRCA1 or BRCA2 Mutation Model
Characteristics
Limitations
Couch (Couch et al. 1997)
Probability of detecting a BRCA1 mutation on the basis of average age of breast cancer onset in the family, the presence of ovarian cancer, and the presence of breast and ovarian cancer in the same person. Probabilities are separated for those of Ashkenazi Jewish and non-Ashkenazi descent.
Myriad II (Frank et al. 2002)
Provides estimation of mutation prevalence in Ashkenazi and non-Ashkenazi Jewish individuals. Incorporates those with breast and/ or ovarian cancer, and separates those with breast cancer diagnosed before age 50 and at or after 50. Very similar to Myriad II, and incorporates male breast cancers.
Study is based on families with an average of 4 affected relatives (must have ≥2), which may not be helpful for smaller families or those with fewer affected members. Does not provide risk estimates for BRCA2 and does not account for bilateral or male breast cancers. Not applicable for families with ovarian cancer only. Further calculations are needed for unaffected relatives. May overestimate probabilities for women who have only one affected relative versus those with larger family histories. May underestimate probabilities in families with early onset breast cancer.
Myriad Prevalence Tables (myriadtests. com/provider/brca-mutationprevalence.htm) BRCAPro (Berry et al. 1997; Euhus 2001; Parmigiani et al. 1998)
Manchester (Evans et al. 2004, 2005)
BOADICEA (Breast and ovarian analysis of disease incidence and carrier estimation algorithm) (Barcenas et al. 2006)
Modeled probabilities based on family history of breast and ovarian cancer in 1st and 2nd degree relatives and cancer rates in BRCA mutation carriers derived from previous studies. Incorporates client’s age and number and ages of unaffected relatives. Incorporates all affected and unaffected 1st and 2nd degree relatives, bilateral breast cancer and Ashkenazi Jewish ancestry. Age of onset and age of unaffected relatives are considered, as are breast, ovarian and male breast cancers. Performs slightly better in non-Ashkenazi individuals. The most sensitive model in predicting mutations in both BRCA genes, although works better for BRCA2. Outperforms Myriad II and BRCAPro with better overall prediction of the number of mutations. Incorporates pancreatic cancer. Takes minimal time and does not require computer data input. Susceptibility to BRCA1 and 2 is examined along with polygenic component reflecting joint effects of multiple genes with small effects on breast cancer risk. Includes extended family data. Performs better than other models in Ashkenazi Jewish families. Slightly better results with extended family history information than with limiting information to second degree relatives. Performs as well as BRCAPro when applied to data from first and second degree relatives.
Bayes’ theorem to determine the probability that she carries a significant genetic predisposition to breast cancer. The model has been incorporated into a computer program that calculates a personalized risk estimate.
Data obtained from laboratory requisition forms and has not been independently verified. Proband and family history information based on that listed on the form by the clinician. Assumes that BRCA1 and BRCA2 are the only predisposition genes for breast cancer. May overestimate the probability of a mutation in families with bilateral breast cancer and underestimate risk in families with early-onset breast cancer. Doesn’t include information on multiple marriages or extended family history.
May need modification to include pathology data to calculate whether to screen for BRCA1. Results in over-referral for genetic testing. Was developed from non-Ashkenazi Jewish families and affected probands.
May underestimate the observed risk at low estimated probabilities and over-estimate it at higher probabilities. Does not account for male breast cancer, double primary cancers or bilateral breast cancers.
Other Risk Factors All existing risk models incorporate only diagnoses of invasive breast cancer, not ductal carcinoma in situ (DCIS).
Risk Assessment and Genetic Counseling
Since DCIS may be a precursor to invasive breast cancer, using the age at diagnosis of DCIS may lead to a bias that increases the prior probability calculations. Some centers correct for this potential bias by adding 10 years to the age of diagnosis of a DCIS for the purpose of incorporating it into BRCA mutation probability models, but there is no published data to support this practice. Some centers consider DCIS equivalent to invasive breast cancer due to the increasing number of women with DCIS who are found to be carriers of BRCA mutations. One recent study (Claus et al. 2005) reported on the prevalence of BRCA1 and BRCA2 mutations among 369 cases of DCIS, unselected for age, family history, or ethnicity. The authors concluded that DCIS is, in fact, part of the HBOC syndrome, with mutation rates similar to those found for invasive breast cancers. However, in a previous study of 10,000 consecutive samples analyzed to identify mutations in BRCA1 and BRCA2 that were correlated with personal and family history of cancer, ancestry, invasive versus noninvasive breast cancers and sex, mutations were significantly less prevalent in women diagnosed before 50 years of age with DCIS (13%) than with invasive breast cancer (24%) (Frank et al. 2002). Many clients are concerned about a history of lobular carcinoma in situ (LCIS) and its impact on breast cancer risk. LCIS is a histologic risk factor, but not a premalignant lesion per se. The lifetime risk to develop breast cancer after a finding of LCIS is approximately 30% in the same (ipsilateral) or opposite (contralateral) breast. Generally women are given a breast cancer risk estimate of 1% per year after the finding of the LCIS. Because LCIS is not detectable on physical examination or mammogram, it is difficult to estimate its prevalence. It may be a serendipitous finding in a biopsy performed for other indications, but it should not be incorporated into any of the current BRCA1/2 mutation probability models. There are also other types of cancers that may raise suspicion of a BRCA mutation in the family, which are generally not incorporated into the mutation probability models. These include pancreatic cancer, early-onset prostate cancer and second primary breast cancers. It is common to treat secondary primary breast cancer as bilateral breast cancer in the mutation probability models. Fallopian tube cancers and primary peritoneal cancers are often treated as being equivalent to ovarian cancer using these models because the fallopian tubes are part of the coelemic epithelium. Male breast cancers are incorporated only into the BRCAPro model thus far. Limitations of Risk Assessment Models There are some global limitations to all of the available models, based on the fact that the studies are largely based on Caucasian women from North America and
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Northern Europe. Probability estimates for other populations are difficult to determine. It can also be difficult to assess risk if there is a lack of family history information, a small family size, deaths at young ages in at-risk individuals, a dearth of women in the family or a lack of verifiable cancer diagnoses in the family. It is imperative to tell the family that the risk assessment information provided is only as accurate as the family history data provided. Each risk model has its optimal applications, based on the methods by which it was developed, the populations studied, and the characteristics of the family being assessed. Therefore, the clinical judgment of the health care provider is critical.
Other Hereditary Syndromes with Breast and/or Ovarian Cancer If other cancers or clinical findings are present in the patient or family, consideration of a hereditary breast or ovarian cancer predisposing syndrome other than BRCA1 or BRCA2 may be warranted. A detailed review of the clinical features and genetic testing recommendations for these syndromes is outside the scope of this document, but there are some excellent resources available for this purpose (Eng et al. 2001; GeneTests 2006; National Cancer Institute 2006b). A brief review of other possible syndromes follows:
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Cowden Syndrome: A rare autosomal dominant disorder characterized by the development of multiple hamartomas, a high risk of benign and malignant tumors of the breast, thyroid, and endometrium, and particular physical manifestations. Most patients meeting the clinical criteria for Cowden syndrome have a detectable mutation in the PTEN gene. Li Fraumeni Syndrome: A rare autosomal dominant disorder characterized by a predisposition to several cancers, including childhood cancers, soft-tissue sarcoma, breast cancer, leukemia, osteosarcoma, melanoma, and cancer of the colon, pancreas, adrenal cortex, and brain. The breast cancer associated with LFS sometimes presents at extraordinarily early ages, such as the early 20s. Many patients meeting the clinical criteria for Li Fraumeni syndrome have a detectable mutation in the p53 gene. Peutz Jeghers Syndrome: A rare autosomal dominant disorder characterized by the development of hamartomatous polyps throughout the gastrointestinal tract, mucocutaneous hyperpigmentation, an increased risk of gastrointestinal malignancies, breast cancer and ovarian sex cord tumors in females and testicular tumors in males. Approximately 70% of families meeting the
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clinical criteria for Peutz Jeghers syndrome have a detectable mutation in the STK11 gene. Hereditary Non-Polyposis Colorectal Cancer (HNPCC or Lynch Syndrome): an autosomal dominant disorder characterized by a significantly increased risk of colorectal, endometrial, ovarian, and gastric cancers. The majority of genetically characterized HNPCC is due to mutations in the MLH1 or MSH2 mismatch repair (MMR) genes. Other MMR genes, such as MSH6 and PMS2, are less commonly involved. Low Penetrance Genes: it is likely that the clustering of breast cancer in many families is due to the effect of genetic variations in any of a number of low-penetrance genes, which moderately increase cancer risk. One such example is the 1100delC mutation in the CHEK2 gene, which has been shown to increase the risk of breast cancer by twofold. The effect of this type of mutation on a woman’s lifetime risk of breast cancer is much smaller than with a BRCA1 or BRCA2 mutation, but may account for a proportion of familial breast cancer in the population.
Genetic Susceptibility Testing for HBOC Since genetic testing of the BRCA1 and BRCA2 genes first became clinically available in 1996, the published literature on appropriate medical management for patients who test positive has evolved dramatically. Similarly, the approach to offering genetic testing has also evolved. Professional society guidelines outlining when to offer a client genetic testing for the BRCA1 and BRCA2 genes vary among organizations. The American Society of Clinical Oncology’s position statement (American Society of Clinical Oncology 2003) on genetic susceptibility testing for cancer is the most often cited professional society guideline. ASCO recommends that genetic testing be offered when: & & &
The individual has personal or family history features suggestive of a genetic susceptibility condition The genetic test can be adequately interpreted The test results will aid in diagnosis or influence the medical management of the patient or family members at hereditary risk of cancer.
Initially, genetic testing of the BRCA1 and BRCA2 genes was only offered to clients with a high probability of testing positive. In such families, genetic test results often confirm the underlying molecular cause of cancer risk in the family, so that high-risk and average-risk relatives can be distinguished by testing for the family-specific mutation. However, clients with less significant personal or family histories of cancer may also be appropriate candidates for
genetic testing, such as a woman diagnosed with breast cancer at age 40 with no family history of cancer. In fact, a positive genetic test result may alter the course of medical management more dramatically for a client who presents with a moderate clinical history. In its 2003 policy statement on genetic testing for cancer susceptibility, ASCO suggested that the clinical judgment of a healthcare provider experienced in cancer genetics should be relied upon to determine the appropriateness of genetic testing, as opposed to a numerical threshold. This is consistent with the guidelines of other professional organizations, most of which provide criteria for outlining which clients should be offered further education and counseling, so that they can make informed decisions about genetic testing.
Approach to BRCA1 and BRCA2 Testing Once a client has been identified as an appropriate candidate for BRCA testing, the testing options should be explained in more detail. It is imperative for the genetics professional to explain why the test is being offered, how the results might affect the client’s risk for cancer, and what medical management options may be offered depending upon the results. At a minimum, discussion of the following elements would constitute informed consent: & & & & &
Details of the genetics of cancer in general The medical and family history of the client and the specific syndromes being considered (if any) The likelihood of a mutation being present in the family Possible test outcomes and the implications of these outcomes Medical management options
It is most informative for testing of the BRCA1 and BRCA2 genes to begin with the relative who is most likely to test positive, typically an individual who had breast cancer at a young age or ovarian cancer. For individuals who are not of Ashkenazi Jewish descent, the first individual tested will need to undergo comprehensive analysis of both genes, in order to determine if a mutation can be identified. At present, this analysis generally involves full sequencing of both genes and analysis of common large rearrangements in BRCA1 (e.g. Myriad Genetic Laboratories BRACAnalysis® Technical Specifications 2006 http://www.myriadtests.com/provider/doc/ tech_specs_brac.pdf, accessed 2/12/06). Clients who are of Ashkenazi Jewish ancestry should initially be offered testing for three founder mutations,185delAG and 5382insC in BRCA1 and 6174delT in BRCA2, that are most common in that ethnic group. Testing for these three
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mutations is offered as a panel, and is far less expensive than comprehensive sequencing. Some individuals of Ashkenazi Jewish ancestry carry a different BRCA1 or BRCA2 mutation, which will only be detected by comprehensive analysis of the genes (Kauff et al. 2002a, b; Phelan et al. 2002). Further testing may be indicated based on family cancer history and high pre-test probability. Once a specific mutation has been identified, at-risk relatives may be offered testing for the family-specific mutation only. Exceptions to this strategy include individuals who present with a significant family history of breast and/or ovarian cancer on both sides of the family. For these clients, the potential of a different mutation on the opposite side of the family should be addressed, either by offering comprehensive analysis of BRCA1 and BRCA2 to the client or the most appropriate affected relative from the opposite side of the family. Similarly, in Ashkenazi Jewish families in which one of the three founder mutations has been identified, relatives pursuing genetic testing should be tested for all three founder mutations based on the high prevalence of all three mutations in this population (Ramus et al. 1997). Interpretation of BRCA1 and BRCA2 Test Results Positive Result A positive test result means that a deleterious mutation was found in either the BRCA1 or BRCA2 gene, indicating an increased risk for breast, ovarian and other cancers. If the client has already been diagnosed with cancer, a positive result indicates an increased risk for a second primary cancer. Published literature provides recommendations for medical management for clients found to carry a BRCA1 or BRCA2 mutation (see “Medical Management Options for Patients” Section below). In order to determine which side of the patient’s family is at risk for carrying the mutation, the parents or other relatives, particularly women affected with cancer or offspring of women with breast or ovarian cancers, should be offered testing for the familial mutation to determine their status. For many clients, it may be possible to assume which side of the family is at risk, based on the history of cancer in the family. Whenever possible, the suspected parent’s carrier status should be confirmed through genetic testing. No Mutation Detected–No Mutation Previously Identified in Family When a mutation has not been previously identified in the family, a “no mutation detected” result in an affected patient means that the current technology did not find a mutation in BRCA1 or BRCA2. The cause of the pattern of cancer in the
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client and the family is still undetermined, and the risk assessment must be based on the clinical history. There are three possible explanations for a “no mutation detected” result; for an individual patient, it is necessary to consider which is most likely by reviewing the patient’s personal and family histories of cancer, and considering the pre-test probability of detecting a mutation in BRCA1 or BRCA2. First, the cancer history may be due to the combined effects of chance, environmental factors, and lifestyle factors, as opposed to a mutation in a single gene. Second, a BRCA1 or BRCA2 mutation is present, but current technology is not able to detect such a change. Berry et al. (2002) found that genetic testing missed an estimated 15% of mutations. More recently, Walsh et al. (2006) reported that among patients with breast cancer who had significant family histories of cancer and tested negative for BRCA1 and BRCA2 through typical commercial analysis, approximately 12% carried a large genomic deletion or duplication in one of these genes. When interpreting a “no mutation detected” test result, it is important for the healthcare provider to have an understanding of the testing methodology used by the laboratory and its estimated sensitivity. For clients that meet defined clinical criteria, it may be appropriate to request additional analysis to detect large genomic rearrangements in both BRCA1 and BRCA2 genes. (e.g. http://www.myriadtests.com/provider/ doc/tech_specs_ brac.pdf). Research opportunities may be available for families with a significant history of breast and ovarian cancer, in whom no mutation was found through clinical testing. Such families should be encouraged to contact their genetic counselor on a regular basis, to determine if additional technology has been added to the clinically available testing methods that may find a previously undetectable mutation. Third, the cancer history in the client or family may be due to a mutation in a different set of genes. Mutations in BRCA1 or BRCA2 are responsible for the majority of strong family histories of early-onset breast cancer and ovarian cancer. Among families with a clustering of only breast cancer, a smaller, but still significant, proportion is due to a BRCA1 or BRCA2 mutation. Other genes for breast and ovarian cancer susceptibility remain the subject of research, but are not available for testing at this time. If other specific cancers or clinical findings are present in the patient or family, consideration of a different hereditary cancer syndrome may be warranted, as described above. If a patient is affected with breast cancer or ovarian cancer and receives a “no mutation detected” result, it may be worthwhile for another family member to undergo genetic testing, as the patient may be a phenocopy. This possibility is more likely if the patient was diagnosed with breast cancer at a later age than is typical for hereditary cancer, or if the patient had a type of cancer other than breast or ovarian.
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It is most informative to test a family member who has had breast cancer at a young age or ovarian cancer first. If a patient who has not had cancer receives a “no mutation detected” result, the most closely related affected family member should undergo comprehensive genetic testing. In the absence of a positive test result in the family, a “no mutation detected” result in an unaffected patient is uninformative. No Mutation Detected–Known Mutation in Family If a mutation in BRCA1 or BRCA2 is known to be the cause of cancer risk in a family, a negative result means that the client’s risk of developing breast or ovarian cancer is similar to that of the general population, assuming that there is no history on the other side of the family that might be suggestive of a hereditary cancer syndrome and that there are no other risk factors such as atypia. Genetic Variant of Uncertain Clinical Significance Genetic variants of uncertain significance are typically missense mutations of unknown functional significance. In the immediate sense, the client’s medical management should be based on the strength of her personal and family history of cancer, similar to the approach for a “no mutation detected” result in the absence of a known mutation in other relatives. Further research on the segregation of the variant with cancer in the family, or laboratory studies of a variant’s functional impact, may elucidate its clinical significance in the future. Past studies show that many genetic variants in BRCA1 and BRCA2 have been reclassified as harmless polymorphisms. However, a small number of uncertain variants have later been shown to be deleterious. Some variants are classified at the outset as “favor polymorphism” or “suspected deleterious,” such that based on the position and type of the alteration within the DNA, certain assumptions about the affect on the ultimate protein can be made. When an alteration is classified as “favor polymorphism,” it can generally be treated as a negative result, although not technically considered as such. No change in the client’s medical management would usually be warranted. Alternatively, a “suspected deleterious” result may warrant medical management recommendations similar to those for someone found to have a mutation, keeping in mind the personal and family history of cancer, the client’s position in the family, whether the client may have already had risk reducing surgeries, etc. Post-test Genetic Counseling and Results Disclosure Once a client opts to pursue genetic susceptibility testing and the sample is sent to the laboratory, the client’s anxiety
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regarding the test results may climb. Explaining the protocol for results disclosure at the time of testing can help to reduce the anxiety of receiving the phone call that the results are available. By scheduling a result appointment either in person or on the telephone, clients can arrange to have a support person (e.g. spouse, family member or close friend) if desired. Once the client has agreed to have the information and the results are given, a discussion of the significance of the results should ensue. This should include a review of the specificity and sensitivity of the testing, impact of the results on cancer risk and emotional state, medical management options (see section below as well as Table IV), referrals to other health professionals, and assistance in informing other family members if applicable. A discussion of the carrier risks for other family members and potential cancer medical management issues may also be helpful. Supportive counseling should be provided throughout, with referral to other health care professionals when indicated. Some clients who test positive find it helpful to speak with another individual in a similar circumstance, and can greatly benefit from being provided a contact. If a high-risk client tests negative in the absence of a known familial mutation, he or she should be encouraged to maintain contact with the healthcare provider in the event that a new gene is discovered or new family history information comes to light. Support resources should also be provided as appropriate (see Table V). A follow-up letter to the client is always helpful, as it can be used as a permanent reference and a summary of the cancer risk assessment and genetic testing process. This written summary can then be shared with other family members to help relay information about the significance of their family history and outcome of the assessment. Clients should provide written permission for copies of the letter or a separate consultation summary to be sent to other healthcare providers.
Medical Management Options for Patients Management of patients at risk for breast and ovarian cancer remains a challenge for both the physician and genetics professional. There are varying recommendations published for patients considered to be at high risk for breast and ovarian cancers. The rapid pace of research in this area and the lack of randomized studies means that the most recent best evidence should be used to determine the care for a particular individual. These recommendations were derived through review of the NCCN guidelines, ASCO guidelines and extensive review of the current literature addressing the efficacies of medical and surgical management for persons carrying either a BRCA1 or BRCA2 gene mutation. Recommendations include increased screening, the option
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Table IV Medical Management Options for Patients after Testing
High Risk (Women)
Surveillance
Chemoprevention Options
Prophylactic Surgery Options
Monthly breast self-exams starting at age 18; semiannual clinical breast exams, starting at age 25.
Drugs such as tamoxifen (used for 5 years) may significantly reduce the risk of breast cancer in women with BRCA mutations. Tamoxifen is estimated to reduce the risk of contralateral breast cancer by up to 60% in BRCA mutation carriers. Oral contraceptives have been associated with up to a 50% reduction in the risk of ovarian cancer in women with BRCA mutations. Studies reveal that this effect can persist for up to 15 years after discontinuing their use.
Prophylactic mastectomy reduces the risk of breast cancer by at least 90% in women with BRCA mutations.
Yearly mammography beginning at age 25.
High Risk (Men)
Moderate Risk (Women)
Breast ultrasound, digital mammography and MRI may also be considered, especially in younger women who may have limitations of imaging, e.g. due to increased breast density. Annual or semiannual transvaginal ultrasound, pelvic exam and testing for CA-125 to screen for ovarian cancer beginning at 25 years of age or ten years younger than the earliest age of diagnosis in the family. Monthly self-breast exam, annual clinical exams and consideration of mammography based on exam findings. Annual Digital Rectal Exam and a Prostate Specific Antigen (PSA) test consistent with NCCN guidelines. Monthly breast self-exams starting at age 18; semiannual clinical breast exams, starting at age 25.
Yearly mammography beginning at age 25.
Low Risk (Women)
If there is a family history of ovarian cancer, annual or semiannual transvaginal ultrasound, pelvic exam and testing for CA-125 to screen for ovarian cancer beginning between 30–35 years of age or ten years younger earlier than the earliest age of diagnosis in the family. No screening is warranted if there is no family history of ovarian cancer and no BRCA mutation has been documented. Monthly breast self-exams starting at age 18; annual clinical breast exams starting at age 25–35. Yearly mammography beginning at age 40.
Prophylactic BSO is estimated to reduce the risk of ovarian cancer by 80–96% and reduces the risk of breast cancer by up to 50% in pre-menopausal women with BRCA mutations.
None
None
Tamoxifen if appropriate.
Prophylactic mastectomy may be considered depending upon the quality of screening (e.g. if the breasts are dense and difficult to read) or for women with significant concern about their risks. Prophylactic BSO is estimated to reduce the risk of ovarian cancer and breast cancer substantially. This surgery is generally not offered if there is no known mutation and no family history of ovarian cancer.
Use of oral contraceptives for a period of 5 years may be considered for ovarian cancer risk reduction if there is a family history of ovarian cancer.
None
None
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Table V Selected HBOC Resources for Clients and Professionals Client Resources
Professional Resources
American Cancer Society: http://www.cancer.org or (800) ACS-2345
Online Mendelian Inheritance in Man: http://www.ncbi.nlm.nih.gov/ Omim American Society of Clinical Oncology http://www.asco.org
Facing Our Risk of Cancer Empowered (FORCE): http://www. facingourrisk.org Genetic Alliance, Inc.: http://www.geneticalliance.org National Institutes of Cancer, Cancer Information Service: http://www. cancer.gov or (800) 4-CANCER National Society of Genetic Counselors: http://www.nsgc.org Myriad Genetic Laboratories, Inc: http://www.myriadtests.com
Sharsheret: a national organization of cancer survivors dedicated to addressing the unique concerns of young Jewish women facing breast cancer. http://www.sharsheret.org/ Breastcancer.org
of chemoprevention strategies, risk reducing surgeries, and potential lifestyle modifications. BRCA1/2 Mutation Positive Individuals Female Carriers Breast cancer surveillance should begin at 18–21 years of age with monthly breast self examination (after thorough training in proper technique), semi-annual clinical breast examination (CBE), mammography beginning at 25 years of age and magnetic resonance imaging (MRI). Some BRCA-associated breast cancers are not visible or palpable by mammography, especially in younger women who tend to have dense breasts. Thus, MRI can be especially helpful in younger women who are at an increased risk for breast cancer (Hartmann et al. 2001; Kriege et al. 2004; Robson 2004) and is becoming a common recommendation for those with BRCA mutations. Warner et al. (2004) studied 236 women with germ-line BRCA mutations who had annual breast cancer screening with CBE, mammography, ultrasound and MRI, and found that while mammography detected 36% of the identified cancers and ultrasound detected 33%, 77% were detected by MRI. Sensitivity was as high as 95% when using four modalities together including mammography, MRI, CBE and ultrasound. Of course the sensitivity and specificity of screening MRI are dependent upon the experience of the radiologist and the follow-up capabilities, such as MRguided biopsies. Plevritis et al. (2006) measured survival
BRCAPro: http://www.stat.duke.edu/~gp/brcapro.html Gene Tests and Gene Reviews: http://www.genetests.org Counseling About Cancer: Strategies for Genetic Counselors (2nd ed.), Katherine Schneider, Wiley-Liss; 2002 (ISBN: 0-471-37036-3) Cancer: Principles and Practice of Oncology (6th ed.), Vincent T. DeVita, Samuel Hellman and Steven A. Rosenberg (Eds.), Lippincott Williams and Wilkins; 2001 (ISBN: 0-781-72229-2) The Concise Handbook of Family Cancer Syndromes, Noralane Lindor, Mark Greene and the Mayo Familial Cancer Program. Journal of the National Cancer Institute, 90(14), 1039–1071, 1998 Clinical Cancer Genetics : Risk Counseling and Management, Kenneth Offit, Wiley-Liss; 1998 (ISBN 0-471-14655-2) NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian http://www.nccn.org/professionals/physicians.gls NCI Physicians Data Query (PDQ) http://www.nci.nih.gov/ cancertopics/pdq/genetics
benefit and cost-effectiveness of MRI for BRCA1 versus BRCA2 carriers by looking at screening strategies incorporating annual MRI with annual mammography and measuring the cost per quality adjusted life-year gained. They found that breast MRI screening is more costeffective for women with BRCA1 mutations than for women with BRCA2 mutations. Breast cancer chemoprevention may be implemented along with increased surveillance. Tamoxifen, a selective estrogen receptor modulator (SERM), has been shown to decrease the risk for breast cancer in high risk women by about 50% (Fisher et al. 1998). Few data exist on the ability of tamoxifen to reduce the risk of breast cancer in cancer-free BRCA1 and BRCA2 mutation carriers. King et al. (2001) demonstrated a 62% reduction in breast cancer risk among healthy BRCA2 carriers, but not among healthy BRCA1 mutation carriers. However, based on very small numbers, this study had no statistical significance. Tamoxifen has been shown to reduce the risk for contralateral breast cancer in women with BRCA mutations by at least 50% (Narod et al. 2000; Gronwald et al. 2006). Along with consideration of a patient’s age, race and personal risk for breast cancer, patients need to be informed of the risks and benefits of the use of tamoxifen. Prophylactic mastectomy has been shown to reduce a patient’s risk for breast cancer by about 90% (Rebbeck et al. 2002; 2004). Due to residual tissue left behind, it is generally not possible to eliminate the risk. However, breast cancer following prophylactic mastectomy has generally occurred in women undergoing subcutaneous
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mastectomy, which leaves the nipple-areolar complex intact along with more residual breast tissue, as compared with total or simple mastectomy. However, review of the literature suggests that breast cancer occurring at the nipple site is an uncommon event (Metcalfe et al. 2005), such that all options for prophylactic mastectomy (subcutaneous versus total) should be discussed with clients who are found to have BRCA mutations. Ovarian cancer surveillance is unfortunately still quite limited. Even with regular screening, the early diagnosis of ovarian cancer is rarely made (Rosenthal and Jacobs 1998), and false positive results from screening can lead to anxiety and unnecessary invasive procedures. Therefore, prophylactic bilateral salpingo-oophorectomy (BSO), with or without hysterectomy, should be done when a woman is sure she has completed childbearing, as it reduces the risk of ovarian cancer by 80–96% in BRCA1/2 carriers (Rebbeck et al. 2002; Finch et al. 2006). Women should not wait until menopause to have this surgery, especially in the setting of BRCA1, where the risk of ovarian cancer has been reported in women under the age of 40 (Antoniou et al. 2005). In addition, the earlier a pre-menopausal woman has BSO, the more risk reduction there is for development of a future breast cancer. Prior to BSO, screening may include annual or semi-annual recto-pelvic examination, transvaginal ultrasound with color Doppler, and CA-125 serum tumor marker testing beginning at 25–35 years of age. Cancer can still occur in the lining of the abdominal cavity (peritoneum) from the cells that are left after surgery, with an estimated cumulative incidence of 4.3% at 20 years after the BSO (Finch et al. 2006). Additionally, prophylactic BSO reduces the risk for breast cancer by about 50% (Rebbeck et al. 1999, 2002; Eisen et al. 2005). However, concern has arisen that women who have this surgery may need hormone replacement therapy (HRT) to mitigate the effects of an immediate surgical menopause, which is presumed to increase breast cancer risk. It has recently been shown that short-term use of HRT in BRCA1 and BRCA2 carriers does not substantially decrease the protective effect of the prophylactic BSO on breast cancer risk (Rebbeck et al. 2005). In addition, a recent study (Domchek et al. 2006) showed a survival benefit for BRCA carriers who elected to have prophylactic surgery. While risk-reducing surgeries confer survival benefits, they also affect a patient’s quality of life, so a thorough and frank discussion of risks, benefits and limitations of these surgical recommendations is essential. Moreover, it is critical to have appropriate pathologic evaluation of riskreducing BSO specimens of mutation carriers performed due to an occult cancer rate possibly as high as 17% (Powell et al. 2005). Chemoprevention for ovarian cancer is available in the form of oral contraceptives, which have been associated
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with up to a 60% reduction in the risk of ovarian cancer in women with BRCA mutations who used them for six or more years (Whittemore et al. 2004; Modan et al. 2001; Narod et al. 1998). However, this is controversial and it may be premature to use oral contraceptives for the chemoprevention of ovarian cancer in BRCA carriers, primarily out of concern that oral contraceptives may increase the risk of breast cancer in BRCA carriers (Narod et al. 2002; Haile et al. 2006). Male Carriers Breast cancer surveillance should include monthly breast self examination and annual clinical breast examination. Mammography may be considered if gynecomastia or parenchymal/glandular breast density is present or there are suspicious findings (Giordano 2005). Prostate cancer surveillance should include annual digital rectal examination and prostate specific antigen (PSA) testing, following the NCCN general population guidelines. BRCA1/2 Mutation Negative Individuals and those with Variants of Unknown Significance (VUS) with a Family History For unaffected women who test negative, clarification of their results may be possible if an affected family member is found to carry a mutation in either BRCA1 or BRCA2. In the absence of a known mutation in the family, the patient’s personal and family histories are used to assess risk. For an affected patient, this result does not explain why she is affected with cancer. Due to testing limitations, this result does not account for possible undetectable mutations in either the BRCA1 or BRCA2 cancer susceptibility gene. Likewise, there are likely to be other genes involved in hereditary breast and ovarian cancer that have not been discovered to date and therefore no clinical tests are available. Individuals (and their family members) in this category are considered to be between “high risk” and “moderate risk” depending on the extent of the personal and family history. Breast cancer screening recommendations should be made based on the number of family members affected and the age the cancer was diagnosed. For individuals who are found to have VUS, it is recommended that other family members with cancer be tested in an effort to characterize this finding further, although often this is not possible. If other family members are not available for testing, one can make recommendations based on the personal and family history (Daly et al. 2006). Patients and physicians need to remain updated on any reclassification of a VUS as they may be re-classified as either deleterious mutations or normal polymorphisms.
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For individuals with a strong personal and family history of cancer, participation in available research studies investigating other breast and/or ovarian cancer candidate susceptibility genes may be considered. Breast cancer screening recommendations should be made based on personal history, the extent of the family history, and the use of statistical models. For appropriate clients, the discussion of chemoprevention and prophylactic mastectomy may be considered. Limited studies have shown that there appears to be no statistically significant increased risk for ovarian cancer in families with female breast cancer but no known ovarian cancer cases (Kauff et al. 2005). Therefore, in the absence of a BRCA mutation, and without a family history of ovarian cancer, there is no strong recommendation for prophylactic BSO or screening for ovarian cancer. Women with breast cancer who have a family history of ovarian cancer can be counseled about the limitations of screening for ovarian cancer through transvaginal ultrasound and CA-125 levels (Kauff et al. 2005). Those over the age of 35 who are finished with child-bearing are usually counseled to consider risk-reducing BSO. BRCA1/2 Mutation True Negative Individuals who have known mutations in the family who are not found to carry the same mutation have a risk for breast and ovarian cancer similar to that of the general population. These clients are considered to be at average risk. It is, however, important to emphasize to these individuals that the general population is at risk for cancer, and that no testing will remove this background risk. For women in this category, the general screening recommendations include monthly breast self examination; clinical breast examination every 3 years from age 25–40 years of age and then annually beginning at 40 years of age; and annual mammograms beginning at 40 years of age. Ovarian cancer screening is generally not recommended for this group of patients.
Ethical and Legal Implications As with all genetic testing, HBOC testing has the potential to raise ethical and legal issues both within a family and for society as a whole. A variety of concerns has been expressed with respect to predisposition testing for a less than fully penetrant gene, as well as the potential for prenatal testing or testing of minors for an adult onset condition. Additionally, clients may express concern for the potential of genetic discrimination, particularly with regard to health and life insurance in the event of a positive test result. The ethical and legal challenges raised by HBOC testing are not exclusive to this testing situation and therefore should be guided by the overall ethical code of NSGC. The
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ethical responsibilities of genetic counselors with respect to presymptomatic genetic testing rest on four basic principles, namely autonomy, beneficence, confidentiality, and justice (Baumiller et al. 1996; Schneider 2002). The principle of autonomy in an HBOC test setting is essential to ensure that the client is making an informed, non-coerced testing decision. Given the nature of testing for a dominantly inherited, late onset condition, it is not uncommon for ethical dilemmas to arise in families related to the issue of autonomous testing. This can be particularly relevant in situations in which an unaffected individual is instigating testing for an affected family member. It is important in these situations to assess whether the affected family member is making an informed, autonomous decision and understands the benefits, risks and limitations of testing (Schneider 2002). The principle of beneficence and its counterpart, nonmaleficence, in HBOC testing relates to the goal that testing should cause no emotional or other harm to the client or family. Clients with increased levels of distress may not cope properly with the test process or their genetic results (Lerman et al. 1995; Audrain et al. 1998). If the genetic counselor has concerns about the client’s emotional wellbeing, it may be valuable to discuss these concerns with the client directly and consider referral for additional mental health services (Trepanier et al. 2004). Additionally, controversy may arise with respect to the goal of beneficence when considering testing for at-risk unaffected individuals, particularly with respect to testing minors. Although parents may wish to know the mutation status of their child in order to prepare for future medical needs, the widely accepted ethical opinion, as well as a recommendation from the ASCO Task Force, is that parents should not be able to test their children for late onset conditions until the children are able to give their consents (Fasouliotis and Schenker 2000; American Society of Clinical Oncology 2003). Similarly, as technology advances and public awareness increases, there will be more discussions about both prenatal testing and preimplantation genetic diagnosis for BRCA mutations. In these and other situations, the ultimate goal should be to provide as much information as possible while acting in an ethical context that minimizes harm to clients and their families. Given the nature of genetic testing within families, it is possible that ethical dilemmas may arise surrounding the issue of confidentiality. This may be particularly true for cases in which multiple family members are seen at the same clinic. Although it would be ideal to have members of a family communicating about their testing decisions and results, no assumptions can be made about intra-family communications. Thus, it is important that careful mechanisms are in place to ensure that results and other sensitive information are not inadvertently communicated to a third
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party (Schneider 2002). The principle of confidentiality can expand to the social level as well, given the potential for genetic discrimination. Studies have shown that although concern about discrimination is widespread, very few examples of it actually exist (Greely 2005). Nevertheless, in response to the potential risk, national and state legislation has been enacted restricting insurance companies’ access to and use of genetic information (Hall and Rich 2000). In the past 10 years or so, almost all states have adopted laws regarding genetic discrimination for health insurance plans and many states have fairly stringent rules regarding employment discrimination based on genetic testing (Greely 2005). Regardless of this legal reassurance, it is important that clinicians recognize and appropriately address the issues of disclosure of information and confidentiality with their clients (Fasouliotis and Schenker 2000), as the fear of discrimination is quite real. This fear may prevent at-risk individuals from having genetic testing, which could have health implications as well (Greely 2005). The principal of justice relates to fairness in the access of HBOC testing regardless of client demographic information and ability to pay (Baumiller et al. 1996). Although many insurers offer varying degrees of coverage for HBOC testing, there are certainly at-risk individuals who are not undergoing testing due to monetary limitations (Croyle 1997). To alleviate some of the burden in such cases, commercial laboratories may offer a financial hardship program that provides testing free of charge to patients who qualify. With the expansion of genetic counseling and testing in healthcare, access to these services should continue to increase.
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Special Cases/Exceptions to Practice Recommendations As stated above, genetic susceptibility testing for HBOC is not typically offered to minors because no alterations in medical management would be offered to individuals under the age of 18, as their risks for developing HBOC-related cancers are not increased above that of the general population until later in life. In addition, they may not be able to provide informed consent (MacDonald and Lessick 2000; NSGC Position Statement 1995, at http://www.nsgc. org). For the same reasons, some practitioners are unwilling to provide prenatal or preimplantation genetic susceptibility testing for HBOC gene mutations. Individuals with early-onset cancer who were adopted and have no details regarding family history should be evaluated on the basis of personal medical and psychosocial history alone (Trepanier et al. 2004). Acknowledgements The authors gratefully acknowledge the following individuals for their careful review and comments on drafts of this article: Michelle Martin, MS and Aimee Walter, MS of Myriad Genetic Laboratories, Inc., Dr. Sue Friedman (Executive Director of FORCE: Facing Our Risk of Cancer Empowered); Nettie Beyer, RN (Hematology/ Oncology Clinic Coordinator and BRCA Carrier); Dr. Mary Claire King; Dr. Olufunmilayo Olopade; Dr. Wendy S. Rubinstein; Cecelia Bellcross; Kathleen Blazer; Donna Blumenthal; Joann Bodurtha; Heather Creswick; Shelly Cummings; Agnes Masny; John Quillin; Courtney Rowe-Teeter; Jeff Shaw and Jill Stopfer. We also thank members of the NSGC Genetic Services Committee and the Ethics Subcommittee. At the time of publication and during the development of these recommendations, two of the authors (A.W. and M.M.) were employed by Myriad Genetic Laboratories, Inc. While the above NSGC recommendations do not necessarily reflect the opinions or policies of any corporate entity, the authors acknowledge the potential for the appearance of a conflict of interest.
Summary References The process of cancer risk assessment and genetic counseling requires many steps, including the gathering of personal medical and family history data, psychosocial assessment, a discussion of risk, how the risk factors were derived, the benefits, risks, limitations and applicability of genetic susceptibility testing, informed consent, results disclosure (if applicable) and options for medical management. Genetic counseling is a key factor of this process, as the genetic counselor ensures that each client understands the genetics of cancer, what his or her risks are, whether genetic testing is indicated, how the test results (if any) may impact decision-making, and provides assistance in coping with the emotional issues surrounding the process. The identification of clients who may need additional support is critical for referral to appropriate psychosocial professionals. A genetic counselor can be located in almost any geographical region by clicking on “find a counselor” in the NSGC website at http://www.nsgc.org.
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