The U.S. Preventive Services Task Force (USPSTF) makes recommendations about the effectiveness of specific preventive care services for patients without related signs or symptoms.

It bases its recommendations on the evidence of both the benefits and harms of the service, and an assessment of the balance. The USPSTF does not consider the costs of providing a service in this assessment.

The USPSTF recognizes that clinical decisions involve more considerations than evidence alone. Clinicians should understand the evidence but individualize decisionmaking to the specific patient or situation. Similarly, the USPSTF notes that policy and coverage decisions involve considerations in addition to the evidence of clinical benefits and harms.

Importance

Potentially harmful mutations of the BRCA1 and BRCA2 genes are predominantly related to breast, ovarian, peritoneal, fallopian tube, and pancreatic cancer in women.^1-6 In the United States, breast cancer is the most common cancer in women and the second leading cause of cancer death in women.⁷ In the general population, BRCA1 and BRCA2 mutations occur in an estimated 1 in 300 to 500 women and account for 5% to 10% of breast cancer cases and 15% of ovarian cancer cases.^8-11 A woman's risk for breast cancer increases to 45% to 65% by age 70 years if she has clinically significant mutations in either BRCA gene.^12,13 Mutations in the BRCA1 gene increase ovarian cancer risk to 39% by age 70 years, and mutations in the BRCA2 gene increase ovarian cancer risk to 10% to 17% by age 70 years.^12,13

Detection

Genetic risk assessment and BRCA mutation testing is a multistep process that begins with identifying patients with family or personal histories of breast, ovarian, tubal, or peritoneal cancer; family members with known harmful BRCA mutations; or ethnicity or ancestry associated with harmful BRCA mutations. Risk for clinically significant BRCA mutations can be further evaluated with genetic counseling by suitably trained health care providers, followed by genetic testing of selected high-risk individuals and posttest counseling about results. The USPSTF found adequate evidence that familial risk stratification tools are accurate in identifying women with BRCA mutations. These tools can be used by primary care providers to guide referrals to genetic counseling.

The USPSTF has previously established that there is adequate evidence that current genetic tests can accurately detect known BRCA mutations.

Benefits of Screening, Genetic Counseling, and Genetic Testing

The USPSTF found adequate evidence that the benefits of screening, genetic counseling, and genetic testing are moderate in women whose family history is associated with an increased risk for harmful mutations in the BRCA1 or BRCA2 genes.

The USPSTF found adequate evidence that the benefits of screening, genetic counseling, and genetic testing are small to none in women whose family history is not associated with an increased risk for harmful mutations in the BRCA1 or BRCA2 genes.

Harms of Screening, Genetic Counseling, and Genetic Testing

The USPSTF found adequate evidence that the harms associated with screening, genetic counseling, genetic testing, and interventions are small to moderate.

USPSTF Assessment

The USPSTF concludes with moderate certainty that the net benefit of screening for increased risk of BRCA mutations, testing for BRCA mutations, and early intervention is moderate in women whose family or personal history is associated with an increased risk for potentially harmful mutations in the BRCA1 or BRCA2 genes.

The USPSTF concludes with moderate certainty that the harms of screening for increased risk of BRCA mutations, testing for BRCA mutations, and early intervention outweigh the benefits in women whose family or personal history is not associated with an increased risk for potentially harmful mutations in the BRCA1 or BRCA2 genes.

Patient Population Under Consideration

This recommendation applies to asymptomatic women with unknown BRCA mutation status. It includes women who have never been diagnosed with BRCA-related cancer, as well as those with a previous breast, ovarian, or peritoneal cancer diagnosis; women who have completed treatment; and women who are considered cancer free.

Assessment of Risk

Mutations in the BRCA genes cluster in families, showing an autosomal dominant pattern of transmission in the mother’s or father’s family. When taking medical and family history information from patients, primary care providers should ask about specific types of cancer, primary cancer sites, which family members were affected, relatives with multiple types of primary cancer, and the age at diagnosis and sex of affected family members.

For women who have family members with breast, ovarian, or other types of BRCA-related cancer or have a personal history of these types of cancer, primary care providers may use one of several brief familial risk stratification tools to determine the need for in-depth genetic counseling. Although several risk tools are available, the tools evaluated by the USPSTF include the Ontario Family History Assessment Tool, Manchester Scoring System, Referral Screening Tool, Pedigree Assessment Tool, FHS-7, and brief versions of BRCAPRO. All of these tools are clinically useful predictors of the likelihood of potentially harmful BRCA mutations and can be used to guide referrals to genetic counseling for more definitive risk assessment.¹⁴ General breast cancer risk assessment models (e.g., the National Cancer Institute Breast Cancer Risk Assessment Tool, which is based on the Gail model) are not designed to identify BRCA-related cancer risk and should not be used for this purpose.

In general, these brief familial risk stratification tools produce information about factors associated with increased likelihood of BRCA mutations. Family history factors associated with increased likelihood of potentially harmful BRCA mutations include breast cancer diagnosis before age 50 years, bilateral breast cancer, presence of breast and ovarian cancer, one or more male family members with breast cancer, multiple cases of breast cancer in the family, one or more family members with two primary types of BRCA-related cancer, and Ashkenazi Jewish ethnicity. The USPSTF recognizes that each risk assessment tool has advantages and limitations and found insufficient evidence to recommend one over another.

Genetic Counseling

The process of genetic counseling includes detailed kindred analysis and risk assessment for potentially harmful BRCA mutations. It also includes identification of candidates for testing, patient education, discussion of the benefits and harms of genetic testing, interpretation of results after testing, and discussion of management options. Genetic counseling about BRCA mutation testing should be done by trained health professionals, including trained primary care providers. Several professional organizations describe the skills and training necessary to provide comprehensive genetic counseling.

Genetic Testing

Testing for BRCA mutations should be done only when an individual has personal or family history that suggests an inherited cancer susceptibility, when an individual is willing to see a health professional who is trained to provide genetic counseling and interpret test results, and when test results will aid in decisionmaking. Clinical practice guidelines recommend that BRCA mutation testing begin with a relative with known BRCA-related cancer, including male relatives, to determine if a clinically significant mutation is detected in the family before testing individuals without cancer.¹⁵ If an affected family member with a BRCA-related cancer is not available, then the relative with the highest probability of mutation should be tested. The type of mutation analysis required depends on family history. Individuals from families with known mutations or from ethnic groups in which certain mutations are more common (e.g., Ashkenazi Jewish women) can be tested for these specific mutations. Because risk assessment is primarily based on family history, it is unclear how women with an unknown family history should be assessed for BRCA mutation risk and potential referral to counseling or genetic testing.

The availability of testing options has changed since the 2013 U.S. Supreme Court ruling that determined human genes are not patentable (Association for Molecular Pathology et al. v. Myriad Genetics).¹⁶ Previously, BRCA mutation testing in the United States was mainly conducted by one laboratory. Since the ruling, the number of testing options has significantly increased, with more than 80 multigene panels that include BRCA1 and BRCA2.¹⁷

Tests for BRCA mutations are highly sensitive and specific for known mutations, but interpretation of results is complex and generally requires posttest counseling. Guidelines from the American College of Medical Genetics and Genomics, which were updated in 2015, recommend new standard terminology for reporting BRCA mutations identified by genetic tests. These include a 5-tier terminology system using the terms “pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign.”¹⁸

Treatment and Interventions

Management of BRCA mutations to reduce risk of future cancer is beyond the scope of this recommendation statement. In general, women with BRCA mutations are managed with a variety of interventions, including intensive screening, hormonal risk-reducing medications, and prophylactic mastectomy and salpingo-oophorectomy.

Additional Tools and Resources

The National Cancer Institute Cancer Genetics Services Directory provides a list of professionals who offer services related to cancer genetics, including cancer risk assessment, genetic counseling, and genetic susceptibility testing.¹⁹

Other Related USPSTF Recommendations

The USPSTF recommends that clinicians offer to prescribe risk-reducing medications such as tamoxifen, raloxifene, or aromatase inhibitors to women at increased risk for breast cancer and at low risk for adverse medication effects (B recommendation). It recommends against the routine use of medications for risk reduction of primary breast cancer in women not at increased risk for breast cancer (D recommendation).²⁰

The USPSTF recommends against screening for ovarian cancer in women (D recommendation). This recommendation does not apply to women with known genetic mutations that increase their risk for ovarian cancer (e.g., BRCA mutations).²¹ The USPSTF found insufficient evidence to assess the balance of benefits and harms of performing screening pelvic examinations in asymptomatic women for the early detection and treatment of a range of gynecologic conditions (I statement).²²

Research Needs and Gaps

Research on risk assessment and testing for BRCA mutations has focused on short-term outcomes for highly selected women in referral centers. In order to determine the best approaches for population-based risk assessment and testing, more research is needed about mutation prevalence and effects on the general population as well as ethnicities or ancestries associated with BRCA mutations. Because risk assessment is primarily based on family history, more research is needed to better understand how women with an unknown family history should be assessed for BRCA mutation risk. Additional studies are needed, including comparative effectiveness trials, of approaches to risk screening and strategies to improve access to genetic counseling and BRCA testing for high-risk individuals.

It would be helpful to understand which methods of delivery of genetic counseling are most effective, including those that can increase access to genetic counseling in rural or other settings. Trials comparing types of providers and protocols could address these questions. What happens after patients are identified as high risk in clinical settings is unknown. The consequences of genetic testing for individuals and their relatives require more study. Well-designed investigations using standardized measures and diverse study populations are needed.

An expanded database or registry of patients receiving genetic counseling for inherited breast and ovarian cancer susceptibility or who are tested for BRCA mutations would provide useful information about predictors of cancer and response to interventions. Additional data are needed from women of varying socioeconomic and racial/ethnic groups.

For women who are BRCA mutation carriers, studies about the effectiveness of intensive cancer screening and risk-reducing medications and the effects of age at intervention on improving long-term outcomes are needed. This research would increase knowledge of the relative benefits and harms of interventions that are provided on the basis of genetic risk information.

Burden of Disease

Breast cancer is the most common cancer in women in the United States and the second leading cause of cancer death in women.⁷ In 2018, an estimated 266,120 women developed breast cancer in the United States and 40,920 died from the disease.²³ Ovarian cancer is the fifth leading cause of cancer death in women in the United States.²³ In 2018, an estimated 22,240 women developed ovarian cancer and 14,070 died from the disease.²³ Mutations of the BRCA genes are estimated to occur in 1 in 300 to 500 women in the general population (0.2% to 0.3%) ^8-11 and account for 5% to 10% of breast cancer cases and 15% of ovarian cancer cases.^9,24

Estimates of the prevalence of potentially harmful BRCA mutations vary by population. The estimated prevalence is 0.2% to 0.3% in the general population of women, 6.0% in women with cancer onset before age 40 years, and 2.1% in the general population of Ashkenazi Jewish women.²⁵ In a meta-analysis of studies in which recruitment was based on family history of breast or ovarian cancer, BRCA1 mutation prevalence was 13.6%, BRCA2 mutation prevalence was 7.9%, and prevalence of either mutation was 19.8%.²⁵

Scope of Review

To update its 2013 recommendation, the USPSTF commissioned a systematic review on risk assessment, genetic counseling, and genetic testing for potentially harmful BRCA1 or BRCA2 mutations in asymptomatic women who have never been diagnosed with BRCA-related cancer, as well as those with a previous breast, ovarian, or peritoneal cancer diagnosis; women who have completed treatment; and women who are considered cancer free. The USPSTF also reviewed interventions aimed at reducing the risk for BRCA-related cancer in women with potentially harmful BRCA mutations, including intensive cancer screening (e.g., earlier and more frequent mammography or magnetic resonance imaging [MRI] of the breast), medications (e.g., tamoxifen, raloxifene, or aromatase inhibitors), and risk-reducing surgery (e.g., mastectomy or salpingo-oophorectomy).

Accuracy of Familial Risk Assessment

The USPSTF reviewed several tools that could be used in primary care settings to predict individual risk for breast cancer and potentially harmful BRCA mutations. Tools specifically designed to determine risk for BRCA-related cancer are primarily intended for use by nongeneticist health care providers to guide referral to genetic counselors for more definitive evaluation. In general, these tools elicit information about factors associated with increased likelihood of BRCA mutations, including family and personal history of cancer (including types of cancer and age of diagnosis) and ethnicity (Ashkenazi heritage). Because risk assessment is primarily based on family history, it is unclear how women with an unknown family history should be assessed for BRCA mutation risk.

Models that have been validated in studies include the Ontario Family History Assessment Tool,^26-29 Manchester Scoring System,^27-33 Referral Screening Tool,³⁴ Pedigree Assessment Tool,^35,36 FHS-7,³⁷ and the International Breast Cancer Intervention Study instrument.³⁸ The USPSTF found that these tools are clinically useful predictors of which individuals should be referred for genetic counseling. All have sensitivity estimates between 77% and 100%, and compared to other models or genetic testing, all had an area under the curve between 0.68 and 0.96,¹⁴ although some models have been evaluated in only one study.^34,37,38 The USPSTF reviewed brief versions of BRCAPRO (e.g., BRCAPROLYTE), designed for primary care clinicians, followed by the full BRCAPRO (used by genetic counselors) and found that the sequential testing scheme did not improve accuracy over brief versions alone.³⁹ The USPSTF recognizes that each risk assessment tool has advantages and limitations and found insufficient evidence to recommend one tool over another.

Effectiveness of Genetic Counseling, Genetic Testing, and Interventions

To understand the full benefits and harms of genetic counseling, the USPSTF reviewed studies on pretest and posttest counseling, BRCA mutation testing, and interventions.

Pretest and Posttest Counseling

The USPSTF reviewed 28 studies on pretest counseling.^40-69 Studies reported measures of distress associated with genetic counseling for BRCA-related cancer, including cancer worry (17 studies), anxiety (13 studies), and depression (eight studies). In general, pretest genetic counseling either decreased or had no effect on breast cancer worry, anxiety, and depression.¹⁴ Twenty-two studies examined risk perception, with most reporting either improved risk perception (14 studies)^{42,45,50,52-55,58,61,62,64-66,69,70} or no association (six studies),^{40,49,56,59,67,68} one study reporting decreased perception,⁵⁷ and one study reporting mixed results.⁴³ Five studies that evaluated the effects of genetic counseling on BRCA mutation testing intention found decreased intent to test in four studies^42,50,55,64 and increased intent in one study.⁷¹

The USPSTF found no studies on the benefits of posttest counseling.

BRCA Mutation Testing

One fair-quality study (n=1,034) of women and men of Ashkenazi Jewish ethnicity evaluated population-based BRCA mutation testing versus family history–based testing.⁷² It found that a strategy of population-based testing for founder mutations detected more BRCA mutation carriers than testing persons who met family history criteria. However, no clinical outcomes were reported and, because not all participants had BRCA mutation testing, the accuracy of this strategy could not be determined. Genetic testing generally improved risk perception, with increased perceived risk of breast and ovarian cancer risk in BRCA mutation carriers and decreased perceived risk in persons testing negative.⁷³

Interventions

Studied interventions to reduce risk for cancer in women who are BRCA mutation carriers include earlier, more frequent, or more intensive cancer screening (e.g., breast MRI or mammography); use of risk-reducing medications (e.g., selective estrogen receptor modulators or aromatase inhibitors); and risk-reducing surgery (e.g., mastectomy or salpingo-oophorectomy).

The USPSTF reviewed 11 randomized clinical trials of selective estrogen receptor modulators and aromatase inhibitors, although none were conducted specifically in women who were BRCA mutation carriers. Results of meta-analysis⁷⁴ indicated clinically significant reductions in invasive breast cancer with the use of tamoxifen, raloxifene, and aromatase inhibitors, with 7 fewer events per 1,000 women for tamoxifen (four trials),^75-78 9 fewer events per 1,000 women for raloxifene (two trials),^79,80 and 16 fewer events per 1,000 women for aromatase inhibitors (two trials),^81-85 assuming 5 years of treatment. Tamoxifen reduced invasive breast cancer more than raloxifene in the head-to-head trial (relative risk [RR], 1.24 [95% CI, 1.05 to1.47]).⁸⁶ Risk reduction persisted at least 8 years after discontinuation in the two tamoxifen trials providing long-term followup data. All medications reduced estrogen receptor-positive, but not estrogen receptor-negative, invasive breast cancer. Breast cancer–specific and all-cause mortality were not reduced.⁷⁴

In cohort studies of high-risk women and women who were BRCA mutation carriers, risk-reducing surgery such as mastectomy (six studies),^87-93 oophorectomy (seven studies),^94-100 or salpingo-oophorectomy (two studies)^87,101 substantially reduced risk for breast or ovarian cancer. Bilateral mastectomy reduced breast cancer incidence by 90% to 100% and breast cancer mortality by 81% to 100%. Oophorectomy reduced ovarian cancer risk by 69% to 100%. In general, there was no association between oophorectomy or salpingo-oophorectomy and reduced breast cancer risk, although some studies showed reduced risk in younger women (age <51 years).¹⁴

The USPSTF found no studies on the benefits of intensive screening for BRCA-related cancer on clinical outcomes in women who are BRCA mutation carriers.

Harms of Genetic Counseling, Genetic Testing, and Interventions

The USPSTF reviewed the psychological effects of test results. Nine studies evaluated breast cancer worry or distress after genetic testing. Increased worry was found in seven studies,^102-108 particularly in women who are BRCA mutation carriers, and two studies reported decreased worry.^109,110 Studies reporting anxiety related to genetic testing were mixed, with three reporting increased anxiety,^102,110,111 two reporting decreased anxiety,^108,112 and six reporting no association.^{72,105,109,113-115} Three studies noted higher anxiety in women who did not get tested compared with those who were tested.^108,116,117 Of the eight studies evaluating depression, none reported increases in anxiety after genetic testing.^{72,105,108,109,112,114,115,117}

Intensive screening for breast and ovarian cancer is associated with false-positive results, unnecessary imaging tests, and unneeded surgery. In a retrospective analysis of a cohort of women with potentially harmful BRCA mutations or first-degree relatives with BRCA mutations, women who were screened with mammography were more likely to have unneeded imaging tests than those who were screened with MRI.¹¹⁸ In two studies comparing mammography to MRI for breast cancer screening in which 18% to 100% of study participants were BRCA mutation carriers, MRI was associated with higher false-positive rates (14% vs. 5.5% in the first round of screening; p<0.001;¹¹⁹ 15% vs. 11% in another study¹¹⁸). Intensive screening for ovarian cancer demonstrated high false-positive rates (3.4%) using transvaginal ultrasound.¹²⁰ A second study in women who were BRCA mutation carriers found an unneeded diagnostic surgery rate of 55% with annual screening with transvaginal ultrasound and serum tumor marker cancer antigen 125 (CA-125) measurements.¹²¹ Most women did not experience anxiety after screening with MRI, mammography, or clinical breast examination, although women recalled for additional testing reported transient anxiety.¹²²

Eight placebo-controlled trials and one head-to-head trial of tamoxifen and raloxifene reported harms of risk-reducing medications. Raloxifene and tamoxifen increased the risk for thromboembolic events in one trial, and raloxifene caused fewer events in the head-to-head trial.^74,123,124 An increased risk of endometrial cancer was seen with tamoxifen (4 cases per 1,000 women) but not with raloxifene or aromatase inhibitors. Women using tamoxifen had more cataract surgeries compared to placebo and raloxifene.^75,86 The most common side effects were vasomotor symptoms and vaginal discharge, itching, or dryness for tamoxifen and vasomotor symptoms and leg cramps for raloxifene.¹⁴

Twelve studies of mastectomy^125-137 and five studies of oophorectomy/salpingo-oophorectomy^138-142 reported harms associated with surgical interventions, although most were small in size and had mixed outcomes. For mastectomy, complication rates ranged from 49% to 69%.¹⁴ Complications included numbness, pain, tingling, infection, swelling, breast hardness, bleeding, organizing hematoma, failed reconstruction, breathing problems, thrombosis, and pulmonary embolism.¹⁴ Postsurgical complications associated with oophorectomy/salpingo-oophorectomy include bleeding, pain, infection, and hematoma formation, with 1% to 3% of women in one study reporting such complications.¹³⁹ In another small study of women who were BRCA mutation carriers, most women reported worsening vasomotor symptoms and decreased sexual function.¹⁴³ Psychosocial distress was reported in women receiving risk-reducing mastectomy (five studies)^129-134,136 and risk-reducing oophorectomy/salpingo-oophorectomy (three studies).^140,141 Commonly reported symptoms included reductions in body image, sexual activity/satisfaction, and general mental health (anxiety/depression symptoms); however, many of these symptoms were transient.¹⁴

Estimate of Magnitude of Net Benefit

For women whose family or personal history is associated with an increased risk for harmful mutations in the BRCA1 or BRCA2 genes, there is adequate evidence that the benefits of screening, genetic counseling, genetic testing, and interventions are moderate. For women whose family history is not associated with an increased risk for harmful mutations in the BRCA 1 or BRCA 2 genes, there is adequate evidence that the benefits of screening, genetic counseling, genetic testing, and interventions are small to none.

The USPSTF found adequate evidence that the overall harms of screening, genetic counseling, genetic testing, and interventions are small to moderate.

For women whose family history is associated with an increased risk for harmful mutations in the BRCA1 or BRCA2 genes, the USPSTF concludes with moderate certainty that the net benefit of screening and referral to genetic counseling for consideration of testing, detection, and intervention is moderate. For women whose family history is not associated with an increased risk for harmful mutations in the BRCA1 or BRCA2 genes, the USPSTF concludes with moderate certainty that the harms of screening and referral to genetic counseling for consideration of testing, detection, and intervention outweigh the benefits.

How Does the Evidence Fit With Biological Understanding?

The BRCA1 and BRCA2 genes are tumor suppressor genes. Mutations of these genes have been linked to hereditary breast and ovarian cancer. Risks for breast, ovarian, and other types of BRCA-related cancer are greatly increased in patients who have inherited potentially harmful BRCA1 or BRCA2 mutations. Genetic testing may identify such mutations. Several options are available to manage cancer risk in patients who are found to be mutation carriers.

In 2005 and 2013, the USPSTF recommended that women whose family history is associated with an increased risk for potentially harmful mutations in the BRCA1 or BRCA2 genes be referred for genetic counseling and evaluation for BRCA testing. It also recommended against routine referral for genetic counseling or routine BRCA mutation testing for women whose family history is not associated with an increased risk for potentially harmful mutations in the BRCA1 or BRCA2 genes.^144,145 This recommendation statement is consistent with the USPSTF’s previous recommendation.

Since 2013, the validity of genetic testing for BRCA mutations has been established and the potential benefits and harms of previously reviewed interventions, such as risk-reducing medications and surgery, have been studied for longer followup periods. In addition, there have been more studies of newer imaging techniques (breast MRI), surgeries (salpingo-oophorectomy rather than oophorectomy alone), and medications (aromatase inhibitors).

The National Comprehensive Cancer Network provides specific criteria for genetic counseling and testing.¹⁵ The American College of Medical Genetics and the American Society of Clinical Oncology recommend testing for BRCA mutations only when an individual has personal or family cancer history suggestive of inherited cancer susceptibility, the test can be adequately interpreted, and the results will aid in management.^146,147 The American College of Obstetricians and Gynecologists recommends performing a hereditary cancer risk assessment and subsequent referral to a specialist in cancer genetics if necessary.¹⁴⁸ The Society for Gynecologic Oncology recommends that individuals with a likelihood of inherited predisposition to cancer based on personal or family history should be offered genetic counseling.¹⁴⁹ The National Institute for Health and Care Excellence recommends that health care professionals respond to a patient who presents with concerns but should not, in most instances, actively seek to identify persons with a family history of breast cancer.¹⁵⁰ It recommends that in some circumstances, including when a patient has concerns about relatives with breast cancer, a first- and second-degree family history be taken in primary care to assess risk. Referral to secondary care is recommended if risk factors are identified in family history taking.¹⁵⁰ The European Society for Medical Oncology follows the recommendations of the National Institute for Health and Care Excellence for initial risk assessment and the decision when to perform genetic counseling and testing.¹⁵¹

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