This statement summarizes the U.S. Preventive Services Task Force (USPSTF) recommendations on genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility and the supporting scientific evidence. Explanations of the ratings and of the strength of overall evidence are given in Tables 1 and 2, respectively. The Research Gaps and Recommendations of Other Groups sections that are usually included in USPSTF recommendation statements are available in the complete recommendation statement on the USPSTF Web site athttp://www.ahrq.gov/clinic/uspstf05/brcagen/brcagenrs.htm. The complete information on which this statement is based, including evidence tables and references, is included in the systematic evidence review for the USPSTF¹ and in the evidence synthesis² on this topic, available on the USPSTF Web site athttp://www.uspreventiveservicestaskforce.org. The recommendation also is posted on the Web site of the National Guideline Clearinghouse athttp://www.guideline.gov.

Summary of Recommendations

The USPSTF recommends against routine referral for genetic counseling or routine breast cancer susceptibility gene (BRCA) testing for women whose family history is not associated with an increased risk for deleterious mutations in breast cancer susceptibility gene 1 (BRCA1) or breast cancer susceptibility gene 2 (BRCA2). D recommendation.

The USPSTF found fair evidence that women without certain specific family history patterns, termed here “increased-risk family history” (see Clinical Considerations for a definition), have a low risk for developing breast or ovarian cancer associated with BRCA1 or BRCA2 mutations. Thus, any benefit of routine screening of these women for BRCA1 or BRCA2 mutations, or routine referral for genetic counseling, would be small or zero.

The USPSTF found fair evidence regarding important adverse ethical, legal, and social consequences that could result from routine referral and testing of these women. Interventions such as prophylactic surgery, chemoprevention, or intensive screening have known harms. The USPSTF estimated that the magnitude of these potential harms is small or greater.

The USPSTF concluded that the potential harms of routine referral for genetic counseling or BRCA testing in these women outweigh the benefits.

The USPSTF recommends that women whose family history is associated with an increased risk for deleterious mutations in BRCA1 or BRCA2 genes be referred for genetic counseling and evaluation for BRCA testing. B recommendation.

The USPSTF found fair evidence that women with certain specific family history patterns (“increased-risk family history”) have an increased risk for developing breast or ovarian cancer associated with BRCA1 or BRCA2 mutations. The USPSTF determined that these women would benefit from genetic counseling that allows informed decision-making about testing and further prophylactic treatment. This counseling should be done by suitably trained health care professionals. There is insufficient evidence to determine the benefits of chemoprevention or intensive screening in improving health outcomes in these women if they test positive for deleterious BRCA1 or BRCA2 mutations. However, there is fair evidence that prophylactic surgery for these women significantly decreases breast and ovarian cancer incidence. Thus, the potential benefits of referral and discussion of testing and prophylactic treatment for these women may be substantial.

The USPSTF also found insufficient evidence regarding important adverse ethical, legal, and social consequences that could result from referral and testing of high-risk women. Prophylactic surgery is associated with known harms. The USPSTF estimated that the magnitude of these potential harms is small.

The USPSTF concluded that the benefits of referring women with an increased-risk family history to suitably trained health care professionals outweigh the harms.

Clinical Considerations

• These recommendations apply to women who have not received a diagnosis of breast or ovarian cancer. They do not apply to women with a family history of breast or ovarian cancer that includes a relative with a known deleterious mutation in BRCA1 or BRCA2 genes; these women should be referred for genetic counseling. These recommendations do not apply to men.

• Although there currently are no standardized referral criteria, women with an increased-risk family history should be considered for genetic counseling to further evaluate their potential risks.

• Certain specific family history patterns are associated with an increased risk for deleterious mutations in the BRCA1 or BRCA2 gene. Both maternal and paternal family histories are important. For non-Ashkenazi Jewish women, these patterns include two first-degree relatives with breast cancer, one of whom was diagnosed at 50 years or younger; a combination of three or more first- or second-degree relatives with breast cancer, regardless of age of diagnosis; a combination of breast and ovarian cancer among first- and second- degree relatives; a first-degree relative with bilateral breast cancer; a combination of two or more first- or second-degree relatives with ovarian cancer, regardless of age of diagnosis; a first- or second-degree relative with breast and ovarian cancer, at any age; and a history of breast cancer in a male relative.

• For women of Ashkenazi Jewish heritage, an increased-risk family history includes any first-degree relative (or two second-degree relatives on the same side of the family) with breast or ovarian cancer.

• About 2 percent of adult women in the general population have an increased-risk family history as defined here. Women with none of these family history patterns have a low probability of having a deleterious mutation in BRCA1 or BRCA2 genes.

• Computational tools are available to predict the risk for clinically important BRCA mutations (i.e., BRCA mutations associated with the presence of breast cancer, ovarian cancer, or both), but these tools have not been verified in the general population. There is no empiric evidence concerning what level of risk for a BRCA mutation merits referral for genetic counseling.

• Not all women with a potentially deleterious BRCA mutation will develop breast or ovarian cancer. In a woman who has a clinically important BRCA mutation, the probability of developing breast or ovarian cancer by 70 years of age is estimated to be 35 to 84 percent for breast cancer and 10 to 50 percent for ovarian cancer.

• Appropriate genetic counseling helps women make informed decisions, can improve their knowledge and perception of absolute risk for breast and ovarian cancer, and often can reduce anxiety. Genetic counseling includes elements of counseling; risk assessment; pedigree analysis; and, in some cases, recommendations for testing for BRCA mutations in affected family members, the presenting patient, or both. Genetic counseling is best delivered by a suitably trained health care professional.

• A BRCA test typically is ordered by a physician. When done in concert with genetic counseling, the test ensures the linkage of testing with appropriate management decisions. Genetic testing may lead to potential adverse ethical, legal, and social consequences, such as insurance and employment discrimination; these issues should be discussed in the context of genetic counseling and evaluation for testing.

• Among women with BRCA1 or BRCA2 mutations, prophylactic mastectomy or oophorectomy decreases the incidence of breast and ovarian cancer; there is inadequate evidence for mortality benefits. Chemoprevention with selective estrogen-receptor modulators may decrease incidence of estrogen-receptor–positive cancers; however, it also is associated with adverse effects, such as pulmonary embolism, deep venous thrombosis, and endometrial cancer. Most breast cancer associated with BRCA1 mutations is estrogen-receptor–negative and thus is not prevented by tamoxifen. Intensive screening with mammography has poor sensitivity, and there is no evidence of benefit of intensive screening for women with BRCA1 or BRCA2 gene mutations. Magnetic resonance imaging (MRI) may detect more cases of cancer, but the effect on mortality rates is not clear.

• Women with an increased-risk family history are at risk not only for deleterious BRCA1 or BRCA2 mutations but potentially for other unknown mutations as well. Women with an increased-risk family history who have negative test results for BRCA1 and BRCA2 mutations also may benefit from surgical prophylaxis.

• The USPSTF has made recommendations on mammography screening for breast cancer, screening for ovarian cancer, and chemoprevention of breast cancer, that can be accessed online athttp://www.uspreventiveservicestaskforce.org/recommendations.htm.

Discussion

Breast and ovarian cancers are associated with a family history of these conditions. Approximately 5 to 10 percent of women with breast cancer have a mother or sister with breast cancer, and up to 20 percent have a first-degree or a second-degree relative with breast cancer.^2–7 Germline mutations in two genes, BRCA1 and BRCA2, have been associated with an increased risk for breast cancer and ovarian cancer.^8,9 Specific BRCA mutations (founder mutations) are clustered among certain ethnic groups, such as Ashkenazi Jews, and among families in the Netherlands, Iceland, and Sweden.²

Several characteristics are associated with an increased likelihood of BRCA mutations.^2,10–13 These include breast cancer diagnosed at an early age, bilateral breast cancer, history of both breast and ovarian cancer, presence of breast cancer in one or more male family members, multiple cases of breast cancer in the family, both breast and ovarian cancer in the family, one or more family members with two primary cancers, and Ashkenazi Jewish background. No direct measures of the prevalence of clinically important BRCA1 or BRCA2 mutations in the general, non-Jewish U.S. population have been published; however, models have estimated it to be about one out of 300 to 500.^14–17 Prevalence estimates in a large study of persons from referral populations with various levels of family history range from 3.9 percent (no breast cancer diagnosed in relatives younger than 50 years and no ovarian cancer) to 16.4 percent (breast cancer diagnosed in a relative younger than 50 years and ovarian cancer diagnosed at any age).¹⁸

Penetrance is the probability of developing breast or ovarian cancer among women who have a BRCA1 or BRCA2 mutation. Published reports of penetrance describe estimates of BRCA1 and BRCA2 mutations ranging from 35 to 84 percent for breast cancer and 10 to 50 percent for ovarian cancer, calculated to 70 years of age, for non-Ashkenazi Jewish women or those unselected for ethnicity.^{2,14,15,19–23} Among Ashkenazi Jewish women, penetrance estimates range from 26 to 81 percent for breast cancer and 10 to 46 percent for ovarian cancer.^2,24–30 Estimates are higher for relatives of women with cancer diagnosed at younger ages, for women from families with greater numbers of affected relatives (when based on data from families selected for breast and ovarian cancer), and when certain methods of analysis are used.

A systematic review of the evidence found no population-based randomized controlled trials of risk assessment and BRCA mutation testing using the outcomes of incidence of breast and ovarian cancer or cause-specific mortality.² The USPSTF therefore examined the chain of evidence for accuracy of risk assessment tools, efficacy of preventive interventions, and the harms of screening and interventions.

Although several tools to predict risk for deleterious BRCA mutations have been developed from data on previously tested women, no studies of their effectiveness in a screening population in a primary care setting are available.³¹ These risk tools include the Myriad Genetic Laboratories model, the Couch model, BRCAPRO, and the Tyrer model.² Much of the data used to develop the models are from women with existing cancer, and their applicability to asymptomatic, cancer-free women in the general population is unknown. Three tools have been developed to guide primary care physicians in assessing risk and guiding referral: the Family History Risk Assessment Tool (FHAT), the Manchester scoring system, and the Risk Assessment in Genetics (RAGs) tool.³² The sensitivity and specificity of FHAT for a clinically important BRCA1 or BRCA2 mutation were 94 and 51 percent, respectively. The Manchester scoring system was developed in the United Kingdom to predict deleterious BRCA1 or BRCA2 mutations at the 10 percent likelihood level and had an 87 percent sensitivity and a 66 percent specificity.³³ The RAGs tool, a computer program designed to support assessment and management of family breast and ovarian cancer in primary care settings,³⁴ is used to assign patients to low-risk (less than 10 percent), moderate-risk (10 percent to 25 percent), or high-risk (greater than 25 percent) categories. Primary care physicians then can manage recommendations of reassurance, referral to a breast clinic, or referral to a geneticist on the basis of the patient’s respective risk category.³⁵

The interventions that can be offered to a woman with a deleterious BRCA1 or BRCA2 mutation or other increased risk for hereditary breast cancer include intensive screening, chemoprevention, prophylactic mastectomy or oophorectomy, or a combination. Overall, evidence on the efficacy of intensive surveillance of BRCA1 and BRCA2 carriers to reduce morbidity or mortality is insufficient. Recent descriptive studies report increased risk for interval cancer (cancer occurring between mammograms) in BRCA-positive patients with and without previous cancer who are receiving annual mammographic screening. This indicates that annual mammography may miss aggressive cancer in carriers of the BRCA mutation.²

Good evidence shows that MRI has higher sensitivity for detecting breast cancer among women with a BRCA1 or BRCA2 mutation than does mammography, clinical breast examination, or ultrasonography. One study compared these screening methods in 236 Canadian women 25 to 65 years of age who had BRCA1 or BRCA2 mutations.³⁶ The women underwent one to three annual screening examinations including MRI, mammography, and ultrasonography, and received clinical breast examinations every six months. The researchers found that MRI was more sensitive for detecting breast cancers (sensitivity, 77 percent; specificity, 95.4 percent) than mammography (sensitivity, 36 percent; specificity, 99.8 percent), ultrasonography (sensitivity, 33 percent; specificity, 96 percent), or clinical breast examination alone (sensitivity, 9 percent; specificity, 99.3 percent). However, use of MRI, ultrasonography, and mammography in combination had the highest sensitivity (95 percent). The effect of this increased detection on morbidity and mortality remains unclear. Expert groups recommend intensive screening for breast cancer in patients with BRCA mutation.³⁷

The evidence also is insufficient to determine the morbidity and mortality effects of intensive screening for ovarian cancer among women with BRCA1 or BRCA2 mutations. One study in which 1,610 women with a family history of ovarian cancer were screened with transvaginal ultrasonography showed a high rate of false-positive results (only three of 61 women with abnormal scans had ovarian cancer).³⁸

Good-quality evidence from four randomized controlled trials^39,40 shows that prophylactic tamoxifen reduces the risk for estrogen-receptor–positive breast cancer in women without previous breast cancer. A meta-analysis of these trials showed a relative risk for total breast cancer of 0.62 (95% confidence interval [CI], 0.46 to 0.83).² Further analysis of the largest of these trials showed a possible reduction in breast cancer incidence for women with BRCA2 mutations but not those with BRCA1 mutations, possibly because women with BRCA1 mutations had predominantly estrogen-receptor–negative tumors. Conclusions are difficult to draw because of the small number of breast cancers in this analysis.⁴¹

Fair quality evidence is available on the effectiveness of prophylactic surgery to prevent breast and ovarian cancer. Cohort studies of prophylactic surgery have several methodologic limitations that should be considered when interpreting and generalizing their results, such as selection bias, retrospective study design, lack of a control group for estimation of benefit-attributable outcome in the untreated group, and inability to define risk reduction attributable to mastectomy in patients electing both mastectomy and oophorectomy.⁴² Four published studies (two of fair quality, two that did not meet USPSTF quality criteria) of prophylactic bilateral mastectomy in high-risk women showed a consistent 85 to 100 percent reduction in risk for breast cancer despite differences in study designs and comparison groups (e.g., sisters,⁴³ matched controls,⁴⁴ a surveillance group,⁴⁵ and penetrance models.⁴⁶ Four studies of prophylactic oophorectomy reported reduced risks for ovarian and breast cancer,^47–50 although the number of cases was small and the CIs for the only prospective study crossed 1.0 for both outcomes.⁵¹ Overall, oophorectomy reduced ovarian cancer risk by 85 to 100 percent and reduced breast cancer risk by 53 to 68 percent.

No studies have described cancer incidence or mortality outcomes associated with genetic counseling, although 10 fair- to good-quality randomized controlled trials reported psychological and behavioral outcomes.² These studies examined the impact of genetic counseling on worrying about breast cancer, anxiety, depression, perception of cancer risk, and intention to participate in genetic testing. Studies were conducted in highly selected samples of women and results may not be generalizable to a screening population. Five of seven trials showed that breast cancer worry decreased after genetic counseling, and two studies showed no significant effect.² Three studies reported decreased anxiety after genetic counseling, and three reported no significant effect. One study reported decreased depression after genetic counseling, and four found no significant effect.² Results of a meta-analysis show that genetic counseling significantly decreased generalized anxiety, although the reduction in psychological distress was not significant.⁴⁴ There is poor evidence (conflicting studies) regarding whether genetic counseling increases or decreases the accuracy of patients’ risk perception.

The USPSTF examined the available evidence on harms of screening and intervention. Approximately 12 percent of high-risk families without a BRCA1 or BRCA2 coding-region mutation may have other clinically important genomic rearrangements.⁴⁵ Approximately 13 percent of tests report mutations of unknown significance; however, the harms associated with such test results are not known.⁴⁶ Routine referral for genetic counseling and consideration of BRCA1 and BRCA2 testing clearly has important psychological, ethical, legal, and social implications, although they are not well quantified in the literature. Among these are the potential for burdening patients with the knowledge of mutations of unknown importance and the potential for affecting family members other than the individual patient. The potential harms of intensive screening include overdiagnosis and overtreatment. There is good-quality evidence on the harms of prophylactic tamoxifen,² including thromboembolic events, endometrial cancer, and hot flashes. Fair quality evidence shows that prophylactic mastectomy can cause hematoma, infection, contracture, or implant rupture (with reconstruction); and that prophylactic oophorectomy can cause infection, bleeding, urinary tract or bowel injury, and premature menopause. Overall, the USPSTF estimates that the magnitude of these potential harms is at least small.