Summary:

USPSTF released updated guidelines (2019) to help primary care professionals identify women who would benefit from further genetic counseling and testing for BRCA1 and BRCA2. Two major changes from previous USPSTF recommendations address the inclusion of two additional patient groups: (1) women with previous breast cancer or ovarian cancer who are considered cancer-free; (2) the explicit inclusion of ancestry.

The USPSTF recommends that primary care clinicians, using an “appropriate brief familial risk assessment tool” should screen women with  

• Personal or family history of breast, ovarian, tubal, or peritoneal cancer or
• Ancestry associated with BRCA1/2 gene mutation

The USPSTF document further states that

Women with a positive result on the risk assessment tool should receive genetic counseling and, if indicated after counseling, genetic testing. (Grade B – The USPSTF recommends the service. There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial)

Note: A patient with a family member with known BRCA1/2 pathogenic variant should also be referred to genetic counseling

For women whose personal or family history or ancestry is not associated with potential harmful BRCA1/2 gene mutations

The USPSTF recommends against routine risk assessment, genetic counseling, or genetic testing (Grade D – The USPSTF recommends against the service. There is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits)

Appropriate Familial Risk Assessment Tools

• USPSTF evaluated the following validated tools that can help estimate the likelihood of BRCA1/2 pathogenic variants and guide genetic referral
  • Ontario Family History Assessment Tool
  • Manchester Scoring System
  • Referral Screening Tool
  • Pedigree Assessment Tool
  • 7-Question Family History Screening Tool
  • International Breast Cancer Intervention Study instrument (Tyrer-Cuzick)
  • Brief versions of BRCAPRO (e.g., BRCAPROLYTE)

Note: NCCN and ACMG/ NSGC also have guidelines regarding when to refer women for genetic counseling (see ‘Learn More – Primary Sources’ below for links to these sites) | ACOG recommends that “Genetic counseling is recommended before initiation of genetic testing and can be performed by an obstetrician–gynecologist (or other gynecologic care provider) who has expertise in cancer genetics or by a genetic counselor”

KEY POINTS:

• BRCA1/2 pathogenic variants
  • Occur in an estimated 1/300 to 1/500 women and account for the following percent of cancer cases
    • Breast cancer: 5% to 10%
    • Ovarian cancer: 15%
  • Significantly increase cancer risk breast cancer: 45% to 65% (cumulative age 70)
  • Significantly increase ovarian, fallopian tube, or peritoneal cancer risk (cumulative age 70)
    • BRCA1: 39% 
    • BRCA2: 10% to 17%

Note: See ‘BRCA1 & BRCA2 Mutations: What Are the Risks for Developing Breast and Ovarian Cancer?’ in ‘Related ObG Topics’ below

• NCCN and other professional bodies recommend offering BRCA testing to any women with ovarian cancer
  • 15% of women with epithelial ovarian cancer will have a pathogenic variant in BRCA1/2
• NCCN also recommends that all individuals with pancreatic cancer be offered BRCA1/2 testing along with other related genes associated with this malignancy
• 2.5% (1/40) individuals of Ashkenazi Jewish heritage (unselected – i.e. do not need high risk family history) will have one of the 3 founder BRCA1/2 variants vs 0.1% in the general population
  • Founder pathogenic variants: BRCA1 185delAG | BRCA1 5382insC | BRCA2 6174delT
  • 90% of pathogenic BRCA1/2 pathogenic variants belong to one of the 3 founder mutations
  • NCCN updated its guidance (December 2019) and now states that testing for the 3 founder mutations can be ‘considered’ in an AJ individual without personal cancer history | Ideally testing should be offered within a longitudinal study, but if such a study is not readily available, the test may be provided if there is pre-test and education and post-test counseling available
• Multigene Panel Testing: USPSTF does not endorse the use of multigene panel testing beyond BRCA1/2, due to limited data regarding clinical utility
  • Benefit of multigene panels: Will detect variants associated with other cancers that are seen in conjunction with breast cancer, for example
    • Pancreatic cancer | Prostate cancer | Melanoma
  • Risks associated with multigene panels: While multigene panel testing offers more comprehensive coverage of other important genes there is additional risk for
    • Identifying variants of uncertain significance (VUS)
    • Clinical follow-up may not be well defined  
  • Pre and post genetic counseling may be especially beneficial for those offered multigene panel testing
  • Note: ACOG does address multigene panels and finds that “Genetic testing may be performed using a panel of multiple genes through next-generation sequencing technology” | Heritable cancer syndromes may overlap such that a strong family history for ovarian cancer may be the result of a pathogenic variant in BRCA1/2 or genes associated with Lynch Syndrome
• This USPSTF guidance specifically addresses women and not men
  • Metastatic prostate cancer
    • BRCA1/2 found in 6% of metastatic prostate | NCCN therefore considers this pathology an indication for genetic counseling and BRCA1/2 testing
• Population addressed in this current USPSTF guideline: Higher risk only and, therefore, may benefit from genetic counseling regarding BRCA1/2
  • USPSTF has another guideline specific to average risk population
    • All women at average risk (i.e., not at higher risk for BRCA1/2) should have a 5-year breast cancer risk assessment to determine if they may benefit from chemoprophylaxis (e.g., tamoxifen, raloxifene or aromatase inhibitor)
    • These risk assessment tools are different than those described above and focus on breast density, prior history of breast atypia etc. (See ‘Related ObG Topics below)
• New treatments (not addressed in this guidance)
  • Knowledge of BRCA status has implications for treatment
  • Poly (ADP-ribose) polymerase (PARP) inhibitors block an enzyme involved in DNA damage repair
  • FDA has approved PARP inhibitors for treatment of BRCA-associated metastatic breast and ovarian cancers, and other cancers in various pharmaceutical pipelines  

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Learn More – Primary Sources:

USPSTF Recommendation Statement: Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer

Editorial: Broadening Criteria for BRCA1/2 Evaluation: Placing the USPSTF Recommendation in Context

Editorial: USPSTF Recommendations for BRCA1 and BRCA2 Testing in the Context of a Transformative National Cancer Control Plan

PARP inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: current practice and future directions

Hereditary Cancer Evaluation in 2019—a Rapidly Evolving Landscape

BRCAPROLYTE: A Two-Stage Approach to Genetic Risk Assessment in Primary Care

NCCN GUIDELINES FOR DETECTION, PREVENTION, & RISK REDUCTION: Genetic/Familial High-Risk Assessment: Breast, Ovarian and Pancreatic (free but requires sign-up)

Addendum: A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment (see Table 1 in original article)

ACOG Practice Bulletin 182: Hereditary Breast and Ovarian Cancer Syndrome

ACOG Committee Opinion 793: Hereditary Cancer Syndromes and Risk Assessment

Locate a Genetic Counselor or Genetics services:

Genetic Services Locator-ACMG

Genetic Services Locator-NSGC

Genetic Services Locator-CAGC

Related ObG Topics: