Final Research Plan
Final Research Plan for BRCA-Related Cancer: Risk Assessment, Genetic Counseling, and Genetic Testing
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.
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 Report forms the basis of the USPSTF Recommendation Statement on this topic.
The draft Research Plan was available for comment from February 28 until March 27, 2012 at 5:00 p.m., ET.
This figure depicts the key questions. The figure illustrates how risk assessment for a BRCA mutation may result in classifying an individual at average or increased risk. Among patients with an increased risk of a BRCA mutation, testing will categorize individuals as BRCA positive, negative, or of unknown or uncertain status. Subsequent interventions among people that are BRCA positive, such as intensive early detection efforts like MRI or mammography or prophylactic medications or surgeries (mastectomy, oophorectomy) may result in improved intermediate outcomes such as a reduced incidence of breast or ovarian cancer; and/or long-term health outcomes such as reduced breast or ovarian cancer mortality and reduced all-cause mortality. Harms may occur at any point during the risk assessment and testing process, as well as with preventive interventions or treatment.
* Clinically significant deleterious mutations of BRCA1 or BRCA2.
** Testing may be done on the unaffected woman or her relative with cancer, as appropriate.
*** Interventions include intensive screening (earlier and more frequent mammography, breast magnetic resonance imaging [MRI]), use of medications (tamoxifen, raloxifene), and risk-reducing surgery (mastectomy, removal of fallopian tubes/ovaries).
---- Broken lines indicate the existence of links in the analytic framework that are not explicitly addressed by a key question. These include links indicating direct access to genetic counseling (e.g., women with relatives known to have deleterious mutations may come directly to genetic counseling); use of risk-reducing interventions by women identified at increased risk for deleterious mutations who do not undergo genetic testing; and the relationship between reduced incidence of BRCA-related cancer and mortality outcomes.
BRCA-related cancer = predominantly breast, ovarian, fallopian tube, and peritoneal cancer.
Genetic counseling = a service delivered by a qualified health professional that provides a comprehensive evaluation of familial risk for inherited disorders using kindred analysis and other methods, patient education, discussion of the benefits and harms of genetic testing, interpretation of results after testing, and discussion of management options.
True negative test = known confirmed deleterious genetic mutation in relatives, and none detected in the patient.
Uninformative negative test = no known deleterious genetic mutations in relatives, and none detected in the patient.
Variant of uncertain significance = an abnormality of the BRCA1 or BRCA2 gene, but it is not known whether it is associated with an increased risk for cancer.
Key Questions to be Systematically Reviewed
1. Does risk assessment, genetic counseling, and genetic testing lead to reduced incidence of BRCA-related cancer and reduced cause-specific and all-cause mortality?
2a. What is the accuracy of methods to assess familial cancer risk for BRCA-related cancer when performed by a nongenetics specialist in a clinical setting?
2b. 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, risk perception, satisfaction, and health/psychological outcomes.
2c. Among women with increased risk for BRCA-related cancer, what is the clinical validity* of genetic testing for deleterious mutations?
3. What are the potential adverse effects of a) risk assessment, b) genetic counseling, and c) genetic testing? Adverse effects include, but may not be limited to, inaccurate risk assessment, inappropriate testing, false-positive and false-negative results, adverse impact on the patient's relationships with family, false reassurance, incomplete testing, misinterpretation of the test result, anxiety, cancer worry, and ethical, legal, and social implications.
4. Do interventions reduce the incidence of BRCA-related cancer and mortality for women with increased risk? Interventions include intensive screening (earlier and more frequent mammography, breast MRI), use of medications (tamoxifen, raloxifene), and risk-reducing surgery (mastectomy, removal of fallopian tubes/ovaries).
5. What are the potential adverse effects of interventions to reduce risk for BRCA-related cancer? Adverse effects include, but may not be limited to, immediate and long-term harms associated with breast imaging, risk-reducing medications, and risk-reducing surgery and ethical, legal, and social implications.
*Clinical validity is the test's ability to accurately and reliably predict the future disorder, measured by clinical sensitivity and specificity and predictive values of positive and negative tests that take into account the disorder prevalence (from Teutsch SM, Bradley LA, Palomaki GE, et al; EGAPP Working Group. The Evaluation of Genomic Applications in Practice and Prevention [EGAPP] Initiative: methods of the EGAPP Working Group. Genet Med. 2009;11:3-14).
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).
|Population||Women without cancer or known deleterious BRCA mutations.|
|Setting||Clinical settings applicable to U.S. primary care practice.|
|Disease/Condition||Deleterious BRCA mutation carrier; BRCA-related cancer (predominantly breast, ovarian, fallopian, and peritoneal).|
|Screening (KQs 1–3)||Studies of risk assessment methods, outcomes of genetic counseling and testing, and potential adverse effects.|
|Treatment or Management Interventions (KQs 4–5)||Studies of interventions to reduce risk for BRCA-related cancer among women with deleterious mutations: intensive screening (e.g., earlier and more frequent mammography, breast MRI), use of medications (e.g., tamoxifen, raloxifene), and risk-reducing surgery (e.g., mastectomy, removal of fallopian tubes/ovaries).|
KQs 1 and 3: Risk assessment and genetic testing versus none.
KQs 2a and 3a: Accuracy of various risk assessment methods.
KQs 2b and 3b: Genetic counseling versus none; before versus after measures.
KQs 2c and 3c: BRCA mutation testing versus none; penetrance estimates of various population groups.
KQs 4 and 5: Treatment/intervention versus no treatment/intervention, placebo, or other treatment/intervention.
|Outcomes||Invasive breast cancer, invasive ovarian cancer, other BRCA-related cancer (fallopian tube, peritoneal), mortality (all-cause, cancer-specific).|
|Harms||Inaccurate risk assessment; inappropriate testing; false-positive and false-negative results; adverse impact on the patient's relationships with family members; false reassurance; incomplete testing; misinterpretation of the test result; anxiety; cancer worry; immediate and long-term harms associated with breast imaging, risk-reducing medications, and risk-reducing surgery; and ethical, legal, and social implications.|
|Study Designs||Randomized, controlled trials, prospective and retrospective cohort studies, case-control studies, cross-sectional studies (for KQs 3 and 5), systematic reviews, and meta-analyses.|
|Data Sources||OVID MEDLINE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Cochrane Methodology Register, Health Technology Assessment, National Health Sciences Economic Evaluation Database, and Database of Abstracts of Reviews of Effects; secondary referencing.|
MEDLINE: 2004 to June 2012 and updates.
Cochrane: 2005 to June 2012 and updates.
Health Technology Assessment, National Health Sciences Economic Evaluation Database, and Database of Abstracts of Reviews of Effects: 2nd Quarter 2012 and updates.
Internet Citation: Final Research Plan: BRCA-Related Cancer: Risk Assessment, Genetic Counseling, and Genetic Testing. U.S. Preventive Services Task Force. October 2014.