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.

* 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.

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).