Final Research Plan
BRCA-Related Cancer: Risk Assessment, Genetic Counseling, and Genetic Testing
August 24, 2017
Recommendations made by the USPSTF are independent of the U.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.
aClinically significant pathogenic mutations in the BRCA1 and BRCA2 genes associated with increased risk for breast cancer, ovarian cancer, or both.
bIncludes women who have a previous diagnosis of breast or ovarian cancer but have completed treatment.
cPretest genetic counseling, scope of services, and appropriate providers are described in the text.
dGenetic testing may be done on the index patient, a relative with cancer, or a relative with the highest risk for cancer, as appropriate.
ePosttest counseling includes interpretation of results, determination of eligibility for risk-reducing interventions, and patient decisionmaking.
fRisk-reducing interventions include early detection through intensive screening (earlier and more frequent screening, use of additional screening methods), use of risk-reducing medications (aromatase inhibitors, tamoxifen, raloxifene), and risk-reducing surgery (mastectomy, salpingo-oophorectomy, other procedures) performed for preventive purposes.
Figure 1 is a flow diagram of risk assessment, genetic counseling, and genetic testing. Women with unknown BRCA mutation status, including women who have a previous diagnosis of breast or ovarian cancer but have completed treatment, are assessed for BRCA mutation risk. These women may experience adverse effects as they are determined to have either no increased risk or increased risk for BRCA mutations. Women with an increased risk are referred for genetic counseling, during which they may experience adverse effects. Following genetic counseling, women are determined to have either no increased risk or increased risk for BRCA mutations. Women with an increased risk are referred for genetic testing, during which they may experience adverse effects. Women with increased risk for BRCA mutations may be referred directly to genetic testing, with no genetic counseling prior to testing. Testing may be done on the index patient, a relative with cancer, or a relative with highest risk, as appropriate. Women who undergo genetic testing may have benign results or likely benign, or they may have a result that is pathogenic, likely pathogenic, or of uncertain significance. Women may undergo posttest counseling, which includes interpretation of results, determination of eligibility for risk-reducing interventions, and patient decisionmaking. Women eligible for risk reduction may be referred for interventions, which may include increased early detection through intensive screening (earlier and more frequent mammography, breast MRI), risk-reducing medications (aromatase inhibitors, tamoxifen), and risk-reducing surgery (mastectomy, salpingo-oophorectomy). Women who undergo interventions may experience adverse effects. Women who undergo interventions may also have reduced incidence of BRCA-related cancer and reduced cause-specific and all-cause mortality.
The final Research Plan is used to guide a systematic review of the evidence by researchers at an Evidence-based Practice Center. The resulting Evidence Review will form the basis of the USPSTF Recommendation Statement on this topic.
The draft Research Plan was available for comment from March 16 to April 12, 2017.
1. Does risk assessment, genetic counseling, and genetic testing result in reduced incidence of BRCA-related cancer and cause-specific and all-cause mortality in women with unknown BRCA mutation status?
2a. What is the accuracy of familial risk assessment for BRCA-related cancer when performed by a nonspecialist in genetics in a clinical setting? What are the optimal ages and intervals for risk assessment?
2b. What are the benefits of pretest genetic counseling in determining eligibility for genetic testing for BRCA-related cancer? (Benefits include improved accuracy of risk assessment and pretest probability for testing and improved patient knowledge, understanding of benefits and harms of risk-reducing interventions, risk perception, satisfaction, and health and psychological outcomes.)
2c. What are optimal testing approaches to determine the presence of pathogenic BRCA mutations in women at increased risk for BRCA-related cancer? (Approaches include testing other high-risk family members, including men, before testing the index patient; using specific types of tests or multiple-gene panels.)
2d. What are optimal posttest counseling approaches to interpret results and determine eligibility for risk-reducing interventions for BRCA-related cancer? (Benefits include improved patient knowledge, understanding of benefits and harms of risk-reducing interventions, risk perception, satisfaction, and health and psychological outcomes.)
3. What are the adverse effects of a) risk assessment, b) pretest genetic counseling, c) genetic testing, and d) posttest counseling for BRCA-related cancer? (Adverse effects include inaccurate risk assessment; inappropriate testing; false-positive and false-negative results; adverse effects on family relationships; overdiagnosis and overtreatment; false reassurance; incomplete testing; misinterpretation of test results; anxiety; cancer worry; and ethical, legal, and social implications.)
4. Do interventions reduce the incidence of BRCA-related cancer and mortality in women at increased risk? (Interventions include intensive screening [earlier and more frequent screening; use of additional screening methods], use of risk-reducing medications [aromatase inhibitors, tamoxifen, raloxifene], and risk-reducing surgery [mastectomy, salpingo-oophorectomy, other procedures] performed for preventive purposes.)
5. What are the adverse effects of risk-reducing interventions for BRCA-related cancer? (Adverse effects include immediate and long-term harms associated with screening, risk-reducing medications, and risk-reducing surgery and ethical, legal, and social implications.)
The Research Approach identifies the study characteristics and criteria that the Evidence-based Practice Center will use to search for publications and to determine whether identified studies should be included or excluded from the Evidence Review. Criteria are overarching as well as specific to each of the key questions (KQs).
| Included | Excluded | |
|---|---|---|
| Setting | Primary care settings or clinical settings referable from primary care; settings comparable to U.S. practice | Other settings |
| Populations | KQs 1–3: Women with unknown BRCA mutation status KQs 4, 5: Women with pathogenic BRCA mutations |
All KQs: Women being treated for breast or ovarian cancer; women who are being tested to determine treatment rather than preventive interventions KQs 1–3: Women with known pathogenic BRCA mutations, unless the study is designed to address questions for women with unknown BRCA mutation status (e.g., case-control, retrospective study) |
| Interventions | KQ 1: Risk assessment initiated by a nonspecialist in genetics, pretest genetic counseling, genetic testing, and posttest counseling KQs 2a, 3a: Risk assessment initiated by a nonspecialist in genetics KQs 2b, 3b: Pretest genetic counseling delivered by a provider trained in genetics using methods meeting current standards of practice in the United States KQs 2c, 3c: Genetic testing KQs 2d, 3d: Posttest counseling KQs 4, 5: Intensive screening (earlier and more frequent screening; use of additional screening methods), use of risk-reducing medications (aromatase inhibitors, tamoxifen, raloxifene), and risk-reducing surgery (mastectomy, salpingo-oophorectomy, other procedures) performed for preventive purposes |
Other interventions |
| Comparisons | KQ 1: Risk assessment, pretest genetic counseling, genetic testing, and posttest counseling vs. usual care or alternative approaches KQs 2a, 3a: Risk assessment by a nonspecialist in genetics vs. usual care or alternative approaches KQs 2b, 3b: Pretest genetic counseling vs. usual care or alternative approaches KQs 2c, 3c: Genetic testing vs. usual care or alternative approaches KQ 2d, 3d: Posttest counseling vs. usual care or alternative approaches KQs 4, 5: Intensive screening, risk-reducing medications, or risk-reducing surgery vs. no intervention or alternative approaches |
Other comparisons |
| Outcomes | KQs 1, 4: Incidence of BRCA-related cancer; disease-specific and all-cause mortality KQ 2a: Measures of test performance (sensitivity, specificity, positive and negative likelihood ratios, c-statistic) KQ 2b: Patient outcomes of pretest genetic counseling (improved accuracy of risk assessment and pretest probability for testing and improved patient knowledge, understanding of benefits and harms of risk-reducing interventions, risk perception, satisfaction, and health and psychological outcomes) KQ 2c: Patient health, implications of non-BRCA findings detected on multiple-gene panels, and psychological outcomes of testing KQ 2d: Patient outcomes of posttest counseling (improved patient knowledge, understanding of benefits and harms of risk-reducing interventions, risk perception, satisfaction, and health and psychological outcomes) KQ 3a: Inaccurate risk assessment; false-positive and false-negative results; adverse effects on family relationships; false reassurance; anxiety; cancer worry; and ethical, legal, and social implications KQ 3b: Inaccurate risk assessment; inappropriate testing; false-positive and false-negative results; adverse effects on family relationships; overdiagnosis and overtreatment; false reassurance; anxiety; decision regret; cancer worry; and ethical, legal, and social implications KQ 3c: Inappropriate testing; false-positive and false-negative results; adverse effects on family relationships; overdiagnosis and overtreatment; false reassurance; incomplete testing; misinterpretation of test results; anxiety; depression; cancer worry; and ethical, legal, and social implications KQ 3d: Inaccurate risk assessment; inappropriate testing; false-positive and false-negative results; adverse effects on family relationships; overdiagnosis and overtreatment; false reassurance; anxiety; decision regret; cancer worry; and ethical, legal, and social implications KQ 5: Immediate and long-term harms associated with screening (false-positive and false-negative results, overdiagnosis, overtreatment, nonadherence); risk-reducing medications (thromboembolic and cardiovascular events, metabolic disorders, musculoskeletal symptoms, ophthalmologic disorders, quality of life, others); risk-reducing surgery (surgical complications, sexual dysfunction, menopausal symptoms, mood changes, quality of life); and ethical, legal, and social implications |
Other outcomes not listed, including cost |
| Study Design | All KQs: Randomized, controlled trials; observational studies, with or without comparison groups KQ 2: Discriminatory accuracy studies KQ 2c: Modeling studies |
Other study designs |
| Study Quality | Good- and fair-quality studies according to USPSTF quality criteria | Poor-quality studies |
The draft Research Plan was posted for public comment on the USPSTF Web site from March 16 to April 12, 2017. Some comments suggested that the target population should be expanded to include women who have a previous diagnosis of breast or ovarian cancer but have completed treatment, because these women may also benefit from preventive interventions. In response, the USPSTF revised the target population and the inclusion criteria for studies accordingly. Additional comments suggested that pretest and posttest counseling are separate activities that may involve different services and types of providers. To address this, the USPSTF revised the analytic framework to explicitly consider pretest and posttest counseling as separate services. The USPSTF revised KQ 2b to address the benefits of pretest counseling specifically, and added KQ 2d to address optimal approaches to posttest counseling. The USPSTF made similar revisions to KQs 3b and 3d concerning the potential harms of pretest and posttest counseling.