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Cover of Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer

Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer

Systematic Review to Update the U.S. Preventive Services Task Force Recommendation

Evidence Syntheses, No. 101

Investigators: , MD, MPH, , PhD, , PhD, , BA, , MD, , MA, and , MBBS.

Author Information and Affiliations
Rockville (MD): Agency for Healthcare Research and Quality (US); .
Report No.: 12-05164-EF-1

Structured Abstract


To review new evidence on the benefits and harms of risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women for the U.S. Preventive Services Task Force.

Data Sources:

MEDLINE and PsycINFO (January 2002 to December 31, 2012), Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (4th Quarter 2012), Scopus, and reference lists were searched for English-language studies of benefits and harms of risk assessment, genetic counseling, genetic testing, and interventions to reduce BRCA-related cancer and mortality.

Data Synthesis:

Thirteen general risk models, such as the Gail model, are modest predictors of individual risk for breast cancer (c-statistic, 0.55 to 0.65). Five familial risk models for nongenetics specialists to guide referrals to genetic counseling accurately predict individual risk for BRCA mutations (c-statistic, >0.80). No studies reported harms of risk assessment. Sixteen studies indicated that genetic counseling decreases cancer worry, anxiety, and depression; increases the accuracy of risk perception; and decreases intention for mutation testing.

Thirty-two new studies and 38 earlier studies provided data for meta-analysis estimates of the prevalence and penetrance of BRCA mutations. Prevalence varies by population: 0.2 to 0.3 percent in general populations, 3 percent in women with breast cancer, 6 percent in women with breast cancer onset before age 40 years, 10 percent in women with ovarian cancer, and 20 percent in high-risk families. Among Ashkenazi Jewish women, prevalence is 2 percent in unselected populations and 10 percent in high-risk families. The penetrance of BRCA mutations differs by test result. Breast cancer penetrance to age 70 years if the test is positive is 46 to 71 percent for BRCA1 or BRCA2; ovarian cancer penetrance is 41 to 46 percent for BRCA1 and 17 to 23 percent for BRCA2. No estimates were available for women with variants of uncertain significance. The standardized incidence rate for breast cancer is 3.81 (95% CI, 3.06 to 4.75) for uninformative negative test results and 1.13 (95% CI, 0.81 to 1.58) for true negative results. Estimates for ovarian cancer were highly heterogeneous. Breast cancer worry and anxiety increased after testing in women with positive results and decreased in others, although results differed across studies. Risk perception improved after receiving test results.

No trials of the effectiveness of intensive screening for breast or ovarian cancer in women who are mutation carriers have been published. False-positive rates, unnecessary imaging, and unneeded surgery were higher in women undergoing intensive screening. Most women experienced no anxiety after screening with magnetic resonance imaging, mammography, or clinical breast examination, although women recalled for additional testing had transient anxiety. There are no trials of risk-reducing medications specifically in women who are mutation carriers. Tamoxifen and raloxifene reduced invasive breast cancer by 30 to 68 percent in placebo-controlled trials enrolling women with various levels of risk; tamoxifen had a greater effect than raloxifene in a head-to-head trial. Results suggested that reduction was greater in women with more relatives with breast cancer, but confidence intervals overlapped and results were not specific for women who are mutation carriers. Tamoxifen and raloxifene increased thromboembolic events and tamoxifen increased endometrial cancer and cataracts. In high-risk women and women who are mutation carriers, risk-reducing mastectomy reduced breast cancer by 85 to 100 percent and breast cancer mortality by 81 to 100 percent; risk-reducing salpingo-oophorectomy reduced breast cancer by 37 to 100 percent, ovarian cancer by 69 to 100 percent, and all-cause mortality by 55 to 100 percent. Some women experienced physical complications of surgery, postsurgical symptoms, or changes in body image; some had improved anxiety.


Including only English-language articles and studies applicable to the United States; varying number, quality, and applicability of studies.


Risk assessment using familial risk models to guide referrals is accurate. Genetic counseling reduces distress, improves risk perception, and reduces intention for testing. Genetic testing provides risk estimates for specific populations depending on test results. A true negative test indicates no increased risk for breast cancer. The effectiveness of intensive screening is not known, but it increases false-positive results and procedures. Tamoxifen and raloxifene reduce risk for breast cancer, but have adverse effects. Risk-reducing mastectomy and salpingo-oophorectomy are effective in reducing breast and ovarian cancer. Several evidence gaps remain and additional studies are necessary to better inform practice.


Acknowledgments: The authors acknowledge Andrew Hamilton, MLS, MS, for conducting literature searches and Amanda Brunton, BS, for assistance at the Oregon Health & Science University. We also thank AHRQ Officers Jennifer Croswell, MD, MPH, Karen Lee, MD, MPH, and Tess Miller, DrPH, and USPSTF leads Linda Baumann, PhD, RN, Joy Melnikow, MD, MPH, Virginia Moyer, MD, MPH, and Doug Owens, MD, MS, for their contributions to this report.

Prepared for: Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services1, Contract No. HHSA-290-2007-10057-I-EPC3, Task Order No. 13. Prepared by: Pacific Northwest Evidence-based Practice Center2

Suggested citation:

Nelson HD, Fu R, Goddard K, Mitchell JP, Okinaka-Hu L, Pappas M, Zakher B. Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: Systematic Review to Update the U.S. Preventive Services Task Force Recommendation. Evidence Synthesis No. 101. AHRQ Publication No. 12-05164-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2013.

This report is based on research conducted by the Pacific Northwest Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. 290-02-0024). The investigators involved have declared no conflicts of interest with objectively conducting this research. The findings and conclusions in this document are those of the author(s), who are responsible for its content, and do not necessarily represent the views of AHRQ. No statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services.

The information in this report is intended to help clinicians, employers, policymakers, and others make informed decisions about the provision of health care services. This report is intended as a reference and not as a substitute for clinical judgment.

This report may be used, in whole or in part, as the basis for the development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.


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Oregon Health & Science University, Mail Code: BICC, 3181 SW Sam Jackson Park Road, Portland, OR 97239


Bookshelf ID: NBK179201PMID: 24432435


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