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Draft Research Plan

Draft Research Plan for BRCA-Related Cancer: Risk Assessment, Genetic Counseling, and Genetic Testing

This opportunity for public comment expired on April 12, 2017 at 8:00 PM EST

Note: This is a Draft Research Plan. This draft is distributed solely for the purpose of receiving public input. It has not been disseminated otherwise by the USPSTF. The final Research Plan will be 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.

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.

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Draft: Proposed Analytic Framework

Text Description is below the image.

Text Description.

Figure 1 is a flow diagram of risk assessment, genetic counseling, and genetic testing. Women without cancer and with unknown BRCA mutation status, which are clinically significant mutations of the BRCA1 and BRCA2 genes, are assessed for their familial cancer 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 for potentially harmful mutations are referred for genetic counseling, during which they may experience adverse effects. Women with known BRCA mutations in their family may be referred directly to genetic counseling. Following genetic counseling, women are determined to either have no increased risk or increased risk for BRCA mutations. Women with an increased risk for BRCA mutations are referred for genetic testing, during which they may experience adverse effects. Testing may be done on the unaffected woman, her relative with cancer, or her relative with highest risk, as appropriate. Women who have genetic testing may have benign or likely benign results, which means that the genetic test showed no indication of a harmful mutation; or they may have a result that is pathogenic, likely pathogenic, or uncertain significance. Women with a result that is not benign or likely benign may be referred for interventions, which may include intensive screening (earlier and more frequent mammography, breast MRI), risk-reducing medications (aromatase inhibitors, tamoxifen, raloxifene), 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.

Draft: Proposed Key Questions to Be Systematically Reviewed

  1. In women without breast or ovarian cancer whose BRCA mutation carrier status is unknown, does risk assessment, genetic counseling, and genetic testing reduce the incidence of BRCA-related cancer and disease-specific and all-cause mortality?
  2. a.  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?
    b.  What are the benefits of genetic counseling in determining eligibility for genetic testing for BRCA-related cancer? (Potential benefits include improved accuracy of risk assessment and pretest probability for testing and improved patient knowledge, understanding of potential benefits and harms of interventions to reduce risk, risk perception, satisfaction, and health and psychological outcomes.)
    c.  What are the optimal testing approaches to determine the presence of potentially harmful 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 and using specific types or panels of tests.)
  3. What are the potential adverse effects of a) risk assessment, b) genetic counseling, and c) genetic testing for BRCA-related cancer? (Adverse effects include, but are not limited to, inaccurate risk assessment; inappropriate testing; false-positive and false-negative results; adverse effects on the patient’s 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 mammography or breast magnetic resonance imaging], risk-reducing medications [aromatase inhibitors, tamoxifen, or raloxifene], and risk-reducing surgery [mastectomy or salpingo-oophorectomy].)
  5. What are the potential adverse effects of interventions to reduce risk for BRCA-related cancer? (Adverse effects include, but are not limited to, immediate and long-term harms associated with breast imaging, risk-reducing medications, and risk-reducing surgery and ethical, legal, and social implications.)

Draft: Proposed Research Approach

The Proposed 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).

Category 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 without preexisting breast or ovarian cancer whose BRCA mutation carrier status is unknown

KQs 4, 5: Women without preexisting breast or ovarian cancer with potentially harmful mutations in the BRCA1 or BRCA2 genes
All KQs: Women with breast or ovarian cancer

KQs 1–3: Women with known BRCA mutation carrier status
Interventions KQ 1: Risk assessment by a nonspecialist in genetics, genetic counseling, and genetic testing

KQs 2a, 3a: Risk assessment by a nonspecialist in genetics

KQs 2b, 3b: Genetic counseling

KQs 2c, 3c: Genetic testing

KQs 4, 5: Intensive screening (earlier and more frequent mammography [digital, tomosynthesis] or breast magnetic resonance imaging), risk-reducing medications (aromatase inhibitors, tamoxifen, or raloxifene), and risk-reducing surgery (mastectomy or salpingo-oophorectomy)
Other interventions
Comparisons KQ 1: Risk assessment, genetic counseling, and genetic testing vs. usual care

KQs 2a, 3a: Risk assessment by a nonspecialist in genetics vs. usual care or risk assessment by another approach

KQs 2b, 3b: Genetic counseling vs. usual care

KQs 2c, 3c: Genetic testing vs. usual care or an alternate approach to genetic testing (to compare effectiveness)

KQs 4, 5: Intensive screening, risk-reducing medications, or risk-reducing surgery vs. no intervention or an alternate intervention (to compare effectiveness)
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 genetic counseling (improved accuracy of risk assessment and pretest probability for testing and improved patient knowledge, understanding of potential benefits and harms of interventions to reduce risk, risk perception, satisfaction, and health and psychological outcomes)

KQ 2c: Patient health and psychological outcomes of testing

KQ 3a: Inaccurate risk assessment, false-positive and false-negative results; adverse effects on the patient's 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 the patient's family relationships; overdiagnosis and overtreatment; false reassurance, anxiety; cancer worry; and ethical, legal, and social implications

KQ 3c: Inappropriate testing; false-positive and false-negative results; adverse effects on the patient's family relationships; overdiagnosis and overtreatment; false reassurance; incomplete testing; misinterpretation of test results; anxiety; cancer worry; and ethical, legal, and social implications

KQ 5: Immediate and long-term harms associated with breast imaging (false-positive and false-negative results, overdiagnosis, and overtreatment); risk-reducing medications (thromboembolic and cardiovascular events, metabolic disorders, musculoskeletal symptoms, ophthalmologic disorders, quality of life, and others); risk-reducing surgery (surgical complications and 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 (except for efficacy)

KQ 2: Discriminatory accuracy studies

KQ 2c: Modeling studies
Other study designs
Study Quality Good- and fair-quality studies for meta-analyses Poor-quality studies
Current as of: March 2017

Internet Citation: Draft Research Plan: BRCA-Related Cancer: Risk Assessment, Genetic Counseling, and Genetic Testing. U.S. Preventive Services Task Force. March 2017.
https://www.uspreventiveservicestaskforce.org/Page/Document/draft-research-plan/brca-related-cancer-risk-assessment-genetic-counseling-and-genetic-testing1

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