USPSTF Guidelines for Primary Care Clinicians: BRCA-Related Cancer Risk Assessment

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

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  

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

Mammography Guidelines for Average-Risk Women

SUMMARY:

Professional organizations continue to release evidence based guidance on mammography, with ACP the latest to provide updated recommendations. While required frequency and starting age may differ, they all emphasize shared decision making with patients, which entails counseling about uncertainty, risk/benefit and related patient values.

BENEFITS OF MAMMOGRAPHY

  • Appears to decreases breast cancer mortality by 15 to 20%
    • Studies demonstrate varying magnitude
    • ACS (RCT data): Relative risk 0.80-0.82
    • Recent data from the Canadian National Breast Screening Study did not show decrease when comparing mammography to controls perhaps due to more recent improvements in treatments but does not take in to account advances in imaging
  • Reduces advanced cancer (although no evidence regarding advanced cancer treatment)
    • USPSTF evidence review in women > 50 years of age: Relative risk 0.62 (95% CI, 0.46 – 0.83)
  • May increase life expectancy (ACS systematic review) but could not quantitate

HARMS OF MAMMOGRAPHY

False Positives (additional images and benign biopsies)

  • USPSTF review 10 yr cumulative false positive rate
    • Annual: 61% false positive / 7% require biopsy
    • Every 2 years: 42% false positive / 5% require biopsy
  • ACS review of the same data
    • Increased risk of false positive with dense breasts among women 40-49
    • Callbacks minimized if prior films available

Anxiety and Distress

  • May persist even if follow-up is normal
  • Financial concerns as patient may be responsible for paying for additional tests

Discomfort

  • USPSTF review identified mammography as being a painful procedure
  • Follow-up procedures may also result in pain

Overdiagnosis and Overtreatment

  • Overdiagnosis is defined as detecting a cancer that would have remained indolent and not become apparent without screening
  • Overtreatment is defined as treatment for an overdiagnosed cancer
  • Difficult to discern actual number of overdiagnosed cancers
    • USPSTF review suggests 10.7% – 22.7% based on RCT data
    • 1/8 cancers will be overdiagnosed and 2 to 3 women will be treated unnecessarily
  • Inclusion of Ductal Carcinoma in Situ may impact data
  • Other organizations such as ACS make the point that certain assumptions may not be verifiable in addition to bias in methodology and design

Radiation

  • USPSTF using modelling but not direct studies of radiation exposure estimates 2 per 100,000 deaths among women 50-59 yrs due to mammography screening
  • Other models in women 40-74 yrs suggest 125 cases of breast cancer and 25 cancer deaths due to radiation exposure, but 986 cancer deaths prevented

PROFESSIONAL GUIDELINES:

ACOG 2017

  • Start Age
    • Recommend at age 50
    • Offer from age 40 (shared decision making)
  • Screening Interval
    • Every 1 or 2 years (shared decision making)
  • Stop Age
    • Age 75
    • > 75 shared decision making including overall health and longevity

USPSTF 2016

  • Start Age
    • Recommend at age 50
  • Screening Interval
    • > age 50: every 2 years until age 74
  • Stop Age
    • ≥ age 75:  Insufficient evidence to recommend for/against

ACS 2015

  • Start Age
    • Recommend at age 45
  • Screening Interval
    • Age 45 – 50 age: annual
    • 55 yrs: Every 2 years or can choose annual
  • Stop Age
    • Continue if good health and life expectancy >10 years

ACR 2010

  • Start Age
    • Recommend at age 40
  • Screening Interval
    • Annual
  • Stop Age
    • Stop when life expectancy is less than 5 to 7 years because of age/comorbid conditions

ACP 2019

  • Start Age
      • Offer at age 50
    • Age 40 – 49: Discuss risks vs benefits and patient preference (“potential harms outweigh the benefits for most women” in this age bracket )
  • Screening Interval
    • Every 2 years
  • Stop Age
      • Screening not recommended for women ≥75
    • Life expectancy ≤10 years

AAFP 2016

  • Start Age
    • Recommend at age 50
  • Screening Interval
    • Every 2 years
  • Stop Age
    • ≥ age 75:  Insufficient evidence to recommend for/against

NCCN 2019

  • Start Age
    • Recommend at age 40
  • Screening Interval
    • Annual
  • Stop Age
    • Upper age limit not yet established
  • Consider comorbidities that may impact life expectancy (≤10 years)

Canadian Task Force on Preventative Healthcare 2018

  • Start Age
    • Recommend not to screen women age 40 to 49 (conditional recommendation; low-certainty evidence)
  • Screening Interval
    • Every 2 to 3 years
    • 50-69 years: “Conditional on the relative value that a woman places on possible benefits and harms from screening (conditional recommendation; very low-certainty evidence)
    • Age 50-59: 1333 women is the number needed to screen (NSS) to prevent one death from breast cancer (95% CI, 909 to 2857)
    • Age 60-69: NSS is 1087 (95% CI, 741 to 2325)
    • Age 70-74: NSS is 645 (95% CI, 441 to 1389)
  • Stop Age
    • No evidence found regarding harms vs benefits of screening ≥75 years

Note: The Canadian Task Force did not make any significant change from the previous guideline, however certainty of evidence – now ‘very low- to low-certainty’ was downgraded based on serious concerns of previous study bias

American Society of Breast Surgeons 2019

  • Start Age
    • Non-dense breasts (A and B density): 3D preferred modality | Age 40 | No need for supplemental imaging
    • Dense breasts (C and D density): 3D preferred modality | Age 40 | Consider supplemental imaging
  • Screening Interval
    • Annual
  • Stop Age
    • When life expectancy is <10 years

ADDITIONAL KEY POINTS: 

  • Clinical Breast Examination (CBE)
    • ACOG & NCCN: Offer every 1 to 3 years for women ages 25-39 and annually for ≥ age 40
    • USPSTF & AAFP: Insufficient evidence to recommend for or against
    • ACS, ACP & Canadian Task Force on Preventative Healthcare: Not recommended
  • Most professional organizations find insufficient evidence to recommend adjunctive screening using breast ultrasonography, MRI, Digital Breast Tomosynthesis, or other method in the setting of a normal mammogram and no other risk factors

Learn More – Primary Sources:

ACOG Practice Bulletin 179: Breast Cancer Risk Assessment and Screening in Average-Risk Women

Screening for breast cancer: U.S. Preventive Services Task Force recommendation statement

Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial

Canadian Task Force: Recommendations on screening for breast cancer in women aged 40–74 years who are not at increased risk for breast cancer

Breast cancer screening with imaging: recommendations from the Society of Breast Imaging and the ACR on the use of mammography, breast MRI, breast ultrasound, and other technologies for the detection of clinically occult breast cancer

Breast Cancer Screening for Women at Average Risk: 2015 Guideline Update From the American Cancer Society

Screening for Breast Cancer in Average-Risk Women: A Guidance Statement From the American College of Physicians

AAFP: Summary of Recommendations for Clinical Preventative Services

NCCN Guidelines: Breast Cancer Screening and Diagnosis

ASBrS: Position Statement on Screening Mammography

USPSTF Guidance: When to Use Medication to Reduce Breast Cancer Risk

CLINICAL ACTIONS:

Both USPSTF and ASCO have released guidance on the use of medications to reduce breast cancer risk in women who meet a certain risk threshold. The USPSTF guidance (2019) is in alignment with ASCO in the recommendation of aromatase inhibitors, along with tamoxifen and raloxifene, as drugs suitable for use as risk-reducing medications for women at increased risk for breast cancer and at low risk for adverse medication effect (Grade B – offer or provide this service).

  • All patients should initially be assessed to determine if they are at high risk for breast cancer and if so, appropriate referral should be considered in the following circumstances
    • Personal history of breast cancer, LCIS or DCIS
    • Personal history of mantle radiation for Hodgkin’s lymphoma
    • Personal or family history suggestive of high risk for pathogenic variants in  BRCA1, BRCA2 and other high or intermediate risk genes that may cause heritable cancer syndromes
  • If patients do not meet the above high risk criteria,  an absolute 5 year risk score can be calculated using a validated assessment tool (see ‘Learn More – Primary Sources’ below; both publicly available)
    • Gail or Breast Cancer Surveillance Consortium (BCSC) Risk Calculator for women who are ≥ 35 years of age are validated 5-year risk assessment tools
    • BCSC Risk Calculator includes field for breast density
  • Alternatives to the above as per the USPSTF, clinicians may consider a combination of risk factors including (but not limited to)

Age 65 years or older with 1 first-degree relative with breast cancer

45 years or older with more than 1 first-degree relative with breast cancer or 1 first-degree relative who developed breast cancer before age 50 years

40 years or older with a first-degree relative with bilateral breast cancer

Presence of atypical ductal or lobular hyperplasia or lobular carcinoma in situ on a prior biopsy.

SYNOPSIS:

Based on data review, the USPSTF and ASCO determined that certain medications have the potential to reduce the risk of estrogen receptor positive breast cancer by almost 50% in women above a certain 5-year risk threshold cut-off (see thresholds below).  An individualized approach which integrates personal and family medical history is used to determine the best risk reduction approach.

KEY POINTS:

  • 5-year risk threshold cut-offs:
    • USPSTF recommends 3% (1/33) risk of breast cancer in next 5 years
    • ASCO recommends 1.66% (1/60) risk of breast cancer in the next 5 years
  • Medication options recommended by the USPSTF include

Tamoxifen, raloxifene, and aromatase inhibitors all reduce primary breast cancer risk in postmenopausal women

Use of raloxifene and aromatase inhibitors is indicated only in postmenopausal women

Only tamoxifen is indicated for risk-reduction of primary breast cancer in premenopausal women

  • SERMs such as Tamoxifen and Raloxifene can significantly reduce risk of ‘estrogen receptor positive’ breast cancer
  • Aromatase inhibitors are also appropriate
    • NCCN: Risk-reduction agents for women age ≥35 years and older
      • Tamoxifen for premenopausal women only
      • Tamoxifen, raloxifene, anastrozole, or exemestane may be used in postmenopausal women
    • ACOG: Tamoxifen and raloxifene may be considered for risk reduction of breast cancer in women with BRCA genetic mutations
      • Raloxifene only in postmenopausal women
      • Aromatase an alternative in women who cannot use tamoxifen
      • Monitor women on tamoxifen for endometrial hyperplasia (see ‘Related ObG Topics’ below)
    • AAFP: Supports the USPSTF recommendation
  • 5-year risk assessment is not appropriate as an initial assessment in high risk families
    • Referral to genetic counseling should be made if there is a significant family history of cancers including non-breast malignancies, such as colon, ovarian and uterine
    • Paternal family history of breast and other cancers is critical in this setting and requires a multiple generation pedigree analysis
    • See “USPSTF Guidelines for Primary Care Clinicians: BRCA-Related Cancer Risk Assessment” in Related ObG Topics below
  • USPSTF recommends against the use of medications to reduce breast cancer risk in women ≥ 35 who are not at increased risk (Grade D – discourage the use of this service)

Harms Associated with Risk Reduction Medications

  • Tamoxifen and raloxifene are associated with small to moderate harms
    • Increased risk for VTE
      • Tamoxifen > raloxifene | Greater risk in older women
    • Tamoxifen increases risk for endometrial cancer (not raloxifene)
    • Hot flashes common with both
  • Aromatase inhibitors are associated with small to moderate harms including
    • Hot flashes | GI symptoms | MSK pain | Possible cardiovascular events (e.g., stroke)
    • May increase risk of fractures

Learn More – Primary Sources:

USPSTF: Breast Cancer Medications for Risk Reduction

Use of pharmacologic interventions for breast cancer risk reduction: American Society of Clinical Oncology clinical practice guideline

Breast Cancer Risk Assessment Tool (Gail)

Breast Cancer Surveillance Consortium Risk Calculator

Locate a Genetic Counselor or Genetics services:

Genetic Services Locator-ACMG

Genetic Services Locator-NSGC

Genetic Services Locator-CAGC