Final Research Plan
BRCA-Related Cancer: Risk Assessment, Genetic Counseling, and Genetic Testing
April 11, 2024
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.
*Clinically significant pathogenic mutations in the BRCA1 and BRCA2 genes associated with increased risk for breast cancer, ovarian cancer, or both.
†The population includes cisgender women and may be applicable to individuals who are transgender, non-binary, or otherwise gender-expansive. The population also includes women who may have a previous diagnosis of breast or ovarian cancer but have completed treatment and have not been previously evaluated for BRCA1/2 mutation status.
‡Pretest genetic counseling, scope of services, and appropriate providers are described in the Research Approach.
§Genetic testing may be done on the index patient, a relative with cancer, or a relative with highest risk for cancer, as appropriate.
║Posttest counseling includes interpretation of results, determination of eligibility for risk-reducing interventions, and patient decision making.
¶Risk-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), and risk-reducing surgery (e.g., mastectomy, salpingo-oophorectomy) when performed for prevention purposes.
1. In women with unknown carrier status for pathogenic BRCA1/2 mutations, does risk assessment, genetic counseling, and genetic testing reduce the incidence of BRCA-related cancer and cause-specific and all-cause mortality?
2a. What is the accuracy of familial cancer risk assessment methods to identify women with pathogenic BRCA1/2 mutations when performed by a non-specialist in genetics in a clinical setting? What are the optimal ages and intervals for risk assessment?
2b. What are the benefits of genetic counseling in determining eligibility for genetic testing for pathogenic BRCA1/2 mutations?
2c. What are the benefits of posttest counseling to interpret results and determine eligibility for interventions to reduce risk of BRCA1/2-related cancer?
3. What are the adverse effects of: 3a) risk assessment, 3b) genetic counseling, 3c) genetic testing, and 3d) posttest genetic counseling for BRCA1/2-related cancer?
4. In women with pathogenic BRCA1/2 mutations, do interventions reduce the incidence of BRCA-related cancer and mortality?
5. What are the potential adverse effects of interventions to reduce risk for BRCA1/2-related cancer in women with pathogenic BRCA1/2 mutations?
Contextual Questions will not be systematically reviewed and are not shown in the Analytic Framework.
- How does risk assessment for pathogenic BRCA1/2 mutations in women without BRCA1/2-related cancer in primary care practice settings vary across socioeconomic, racial, and ancestry groups? Are there differences in access to risk assessment in primary care settings among groups with lower educational levels, socioeconomic status, or access to care?
- Among women with increased risk for BRCA1/2-related cancer, what are the benefits and harms of testing family members to determine the presence of BRCA1/2 mutations? This may include testing other family members at higher risk before testing the index patient, including men, in addition to the potential benefits and harms of testing family members of the index case.
- What is the diagnostic accuracy of single vs. multigene panel testing for detecting pathogenic BRCA1/2 mutations?
- What is the prevalence of pathogenic BRCA1/2 mutations in common ancestry groups in the United States?
To the extent possible, we plan to describe the participant characteristics and major intervention components of the included studies. Data on population characteristics will help us explore the degree to which the findings are broadly representative of the U.S. population, including individuals in groups based on age; sex and gender; racial, ethnic, and cultural identity; socioeconomic status; and geographic region. As part of our effort to address health equity, we will search for and highlight risk assessment, counseling, and screening approaches that demonstrate effectiveness in groups of individuals who historically have higher rates of BRCA-related cancer and in traditionally stigmatized or underrepresented groups. Additionally, Contextual Question 1 is designed to address other important health equity considerations.
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.
| Category | Included | Excluded |
|---|---|---|
| Populations | KQs 1–3: Women* with unknown BRCA1/2 mutation status KQs 4, 5: Women* with pathogenic BRCA1/2 mutations |
All KQs: Women being treated for breast or ovarian cancer; women who are being tested to determine treatment rather than preventive interventions; men KQs 1–3: Women with known pathogenic BRCA1/2 mutations |
| Interventions | KQ 1: Risk assessment initiated by a non-specialist in genetics, pretest genetic counseling, genetic testing, and posttest counseling KQs 2a, 3a: Risk assessment initiated by a non-specialist 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 KQ 3c: Genetic testing KQs 2c, 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), and risk-reducing surgery or procedures (e.g. , mastectomy, salpingo-oophorectomy) performed for preventive purposes in patients identified with pathogenic BRCA1/2 mutations |
All KQs: Other interventions KQ 3c: BRCA1/2 testing of pathology or tissue samples; direct to consumer laboratory testing or samples; non-FDA approved tests |
| 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 non-specialist in genetics vs. usual care or alternative approaches KQs 2b, 3b: Pretest genetic counseling vs. usual care or alternative approaches KQ 3c: Genetic testing vs. usual care or alternative approaches KQ 2c, 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 BRCA1/2-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, health and psychological outcomes) KQ 2c: Patient outcomes of posttest counseling (improved patient knowledge, understanding of benefits and harms of risk-reducing interventions, risk perception, satisfaction, 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; 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; 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; 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; ethical, legal, and social implications KQ 5: Immediate and long-term harms associated with intensive breast imaging (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); ethical, legal, and social implications |
Other outcomes not listed, including cost |
| Setting | Primary care settings and clinical settings resulting from referral from primary care, including community health clinics and breast centers; settings in countries categorized as “Very High” on the Human Development Index (as defined by the United Nations Development Programme) | Other non-primary care–relevant or primary care–referable setting; settings and countries not categorized as “Very High” on the Human Development Index |
| Study Design | All KQs: Randomized, controlled trials; nonrandomized studies of interventions KQ 2a: Discriminatory accuracy studies KQ 3: Controlled or large, uncontrolled observational studies of harms KQs 4, 5: Observational studies with or without comparison groups |
Other study designs; modeling studies |
| Study Quality | Good- and fair-quality studies according to U.S. Preventive Services Task Force quality criteria | Poor-quality studies |
* The population includes cisgender women and may be applicable to individuals who are transgender, non-binary, or otherwise gender-expansive.
Abbreviations: FDA = U.S. Food and Drug Administration; KQ = Key Question.
The draft Research Plan was posted on the USPSTF website for public comment from January 18, 2024, to February 14, 2024. In response, the USPSTF revised the inclusion criteria to clarify gender terminology for the included population as “cisgender women and may be applicable to individuals who are transgender, non-binary, or otherwise gender-expansive.” Additional criteria were added in the Research Approach for “settings” to clarify that community health clinics and breast centers are considered primary care–relevant or primary care–referable settings. The USPSTF made no other changes.