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Genetic Risk Assessment and BRCA Mutation Testing for Breast and Ovarian Cancer Susceptibility: Systematic Evidence Review for the U.S. Preventive Services Task Force H. Nelson, L. Huffman, R. Fu, E. Harris Clinically significant, or deleterious, mutations of BRCA1 and BRCA2 genes are associated with increased susceptibility for breast and ovarian cancer (1, 2). These mutations increase a woman's lifetime risk for breast cancer to 60% to 85% (3, 4) and… Clinically significant, or deleterious, mutations of BRCA1 and BRCA2 genes are associated with increased susceptibility for breast and ovarian cancer (1, 2). These mutations increase a woman's lifetime risk for breast cancer to 60% to 85% (3, 4) and risk for ovarian cancer to 26% (BRCA1) and 10% (BRCA2) (5-8). Specific BRCA mutations are clustered among certain ethnic groups, such as Ashkenazi Jews (9-11), and in the Netherlands (12), Iceland (13, 14), and Sweden (15). Additional germline mutations associated with familial breast or ovarian cancer have been identified, and others are suspected (16, 17). BRCA1 and BRCA2 mutations are also associated with increased risk for prostate cancer, and BRCA2 mutations are associated with increased risk for pancreatic and stomach cancer and melanoma (18). Screening for inherited breast and ovarian cancer susceptibility is a 2-step process: assessment of risk for clinically significant BRCA mutations followed by genetic testing of high-risk individuals. Guidelines recommend testing for mutations only when an individual has personal or family history features suggestive of inherited cancer susceptibility, when the test result can be adequately interpreted, and when results will aid in management (19, 20). Several characteristics are associated with an increased likelihood of clinically significant BRCA mutations, including young age at breast cancer diagnosis, bilateral breast cancer, history of both breast and ovarian cancer, multiple cases of breast cancer in a family, both breast and ovarian cancer in a family, and Ashkenazi Jewish heritage (21-24). Risk status requires reevaluation when personal or family cancer history changes. Genetic counseling is recommended before mutation testing (25). Several approaches are in practice, including educational; decision-making; and psychosocial support (26, 27) provided by genetic counselors (28-30), nurse educators (31-33), or other professionals. The type of mutation analysis required depends on family history. Individuals from families or ethnic groups with known mutations can be tested specifically for them. Several clinical laboratories in the United States test for specific mutations or sequence-specific exons. Individuals without linkages to others with known mutations undergo direct DNA sequencing. In these cases, guidelines recommend that testing begin with a relative who has known breast or ovarian cancer to determine whether a clinically significant mutation is segregating in the family (19). Myriad Genetic Laboratories provides direct DNA sequencing in the United States and reports analytic sensitivity and specificity exceeding 99% (34). Approximately 12% of high-risk families without a BRCA1 or BRCA2 coding-region mutation may have other clinically significant genomic rearrangements (34, 35). Test results include not only positive (denoting a deleterious mutation) and negative (no mutation found) interpretations but also variants of uncertain clinical significance; this last group represents up to 13% of results (21). The results of genetic testing could lead to prevention interventions for reducing risk or mortality in mutation carriers. Experts recommend earlier and more frequent cancer screening, chemoprevention, and prophylactic surgery (Table 1) (36-40). Table 1. Detection and Prevention Recommendations Although clinically significant BRCA mutations are estimated to occur in 1 in 300 to 500 persons in the general population (41-44), public interest in testing is growing, and physicians are increasingly faced with this issue while providing primary health care. Women often overestimate their risks for breast cancer or BRCA mutations (32, 45, 46), and most women responding to surveys, including women at average and moderate risk, report a strong desire for genetic testing (27, 47), even though only those at high risk would potentially benefit. Concerns about cancer, publicized scientific advances, incomplete understanding of testing and interventions, and direct-to-consumer advertising probably influence these perceptions, increasing demand for genetic testing services (47). The objective of this systematic evidence review is to determine the benefits and harms of screening for inherited breast and ovarian cancer susceptibility in the general population of women presenting for primary health care in the United States. This review was prepared for the U.S. Preventive Services Task Force (USPSTF) and examines a chain of evidence about genetic risk assessment in primary care settings; impact of genetic counseling; ability to predict cancer risk in women with average, moderate, and high risks for clinically significant mutations; benefits of prevention interventions; and potential adverse effects. A review of studies about Ashkenazi Jewish women specifically is reported elsewhere (48). Methods The analytic framework in Figure 1 outlines the patient population, interventions, and health outcomes. This report focuses on the following key questions: Figure 1. Analytic framework. KQ BRCA BRCA BRCA BRCA1 BRCA2 1. Do risk assessment and BRCA mutation testing lead to a reduction in the incidence of breast and ovarian cancer and cause-specific or all-cause mortality? 2A. How well does risk assessment for cancer susceptibility by a clinician in a primary care setting select candidates for BRCA mutation testing? 2B. What are the benefits of genetic counseling before testing? 2C. Among women with family histories predicting an average, moderate, or high risk for a deleterious mutation, how well does BRCA mutation testing predict risk for breast and ovarian cancer? 3. What are the adverse effects of risk assessment, genetic counseling, and testing? 4. How well do interventions reduce the incidence and mortality of breast and ovarian cancer in women identified as high risk by history, positive genetic test results, or both? 5. What are the adverse effects of interventions? We identified relevant papers from multiple searches of MEDLINE (1966 to 1 October 2004) and the Cochrane Library databases; we obtained additional papers by reviewing reference lists of pertinent studies, reviews, editorials, and Web sites and by consulting experts (Appendix Figure). Investigators reviewed all abstracts and determined eligibility by applying inclusion and exclusion criteria specific to key questions (Appendix Table). We then reviewed full-text papers of included abstracts for relevance. Studies about patients with current or past breast or ovarian cancer were excluded unless they addressed genetic testing issues in women without cancer. Data were extracted from each included study, entered into evidence tables, and summarized by using descriptive or statistical methods or both. Two reviewers independently rated the quality of studies using criteria specific to different study designs developed by the USPSTF (Appendix 1) (49). When reviewers disagreed, a final rating was determined by reevaluations by the 2 initial reviewers and a third reviewer if needed. Only studies rated good or fair in quality were included, although studies with designs that do not have quality rating criteria, such as descriptive studies, were also included if relevant to the key questions. To estimate risks for breast and ovarian cancer due to clinically significant BRCA mutations, the screening population was stratified into groups at average, moderate, and high risk for being a mutation carrier based on history of breast or ovarian cancer in first- and second-degree relatives. This approach allows use of published data that describe risks in similar terms. The following definitions were used: average riskno first-degree relatives and no more than 1 second-degree relative on each side of the family with breast or ovarian cancer; moderate risk1 first-degree relative or 2 second-degree relatives on the same side of the family with breast or ovarian cancer; and high riskat least 2 first-degree relatives with breast or ovarian cancer. On the basis of pooled data from more than 100000 women without breast cancer from 52 epidemiologic studies, approximately 92.7% of the screening population would be expected to be average risk, 6.9% moderate risk, and 0.4% high risk according to these definitions (50). Risks for breast and ovarian cancer in mutation carriers have been primarily calculated from families of women with existing breast and ovarian cancer. To determine benefits and adverse effects of genetic testing in average-, moderate-, and high-risk groups, we estimated mutation prevalence as well as the probability of developing cancer given the presence of the mutation (penetrance) for each risk group. Penetrance was calculated from data about the prevalence of BRCA mutations in women with and without breast and ovarian cancer; the probability of breast or ovarian cancer in the U.S. population estimated from Surveillance, Epidemiology, and End Result (SEER) data (51) by using DevCan software (52); and relative risks for breast and ovarian cancer in moderate- and high-risk groups. Penetrance estimates were based on the Bayes theorem and stratified by cancer type (breast or ovarian), risk group (average, moderate, and high), and age whenever data were available. Appendix 2 provides additional details of this method (48). We also performed a meta-analysis of chemoprevention trials to more precisely estimate effectiveness and adverse effects. All chemoprevention trials reported relative risk (RR) estimates, and the logarithm of the RR (logRR) and the corresponding standard errors were calculated for each trial and used in the meta-analysis. The overall estimates of RR were obtained by using a random-effects model (53). We developed an outcomes table to determine the magnitude of potential benefits and adverse effects of testing for BRCA mutations in the general population based on best estimates from published studies and results of analyses when available. Variation associated Published in Annals of Internal Medicine	30	8	2005