Information for Health Care Providers

What is Hereditary Breast and Ovarian Cancer Syndrome (HBOC)?

Hereditary breast and ovarian cancer syndrome (HBOC) is associated with germline mutations in the BRCA1 and BRCA2 (BRCA1/2) genes. It is estimated that 2-7% of breast cancers, and 10-15% of ovarian cancers are the result of an inherited mutation in one of these two genes.

It is estimated that 1/300 individuals in the general population carry a mutation in BRCA1/2. Among individuals of Ashkenazi Jewish descent, this number is as high as 1/40. Women who carry a BRCA1/2 mutation have a lifetime risk for breast cancer of 50-80% and a lifetime risk for ovarian cancer of 10-40%. Unfortunately, the vast majority of individuals who carry BRCA1/2 mutations have not yet been identified, and when they are, it is often because of a diagnosis of breast and ovarian cancer.

What are the red flags for HBOC?

  • Two or more cases of breast and/or ovarian cancer on the same side of family
  • Breast cancer before age 50
  • Ovarian cancer at any age
  • Breast and ovarian cancer in same person
  • Two primary (different) breast cancers in same person
  • Male relative with breast cancer
  • Pancreatic cancer
  • Ashkenazi Jewish ancestry
  • Triple negative breast cancer (estrogen, progesterone, and HER2 negative) diagnosed prior to age 60
  • Blood relative with known BRCA gene mutation

How will this knowledge benefit my patient?

  • Early screening and prevention options for BRCA1/2 mutation carriers have been demonstrated to substantially reduce cancer risk and mortality and include:
    • Bilateral prophylactic mastectomy
    • Bilateral salpingoophorectomy
    • Breast MRI
    • Chemoprevention (i.e. Tamoxifen)
  • Identification of a BRCA1/2 mutation also allows for accurate testing of family members to identify who is and is not at increased risk for cancer.

Should I refer my patient for cancer genetic counseling?

In 2005 and 2014 the United States Preventive Services Task Force (USPSTF) published grade B recommendations endorsing screening women for possible HBOC risk, emphasizing those identified at increased risk should receive genetic counseling and, if indicated after counseling, BRCA testing. Please click the following link to learn more about genetic counseling services.

Why use the B-RST tool for risk assessment?

The B-RST has been endorsed by the USPSTF as one of several validated screening tools that are clinically useful predictors for determining which women need to be referred for cancer genetic counseling. B-RST is simple, quick and provides accurate results in identifying individuals at potential risk for HBOC.

Tool Validation

The B-RST tool was originally validated in a population of 2,464 unselected women undergoing screening mammography. When compared to complex models requiring detailed four-generation family history information, BRST demonstrated an overall discriminative accuracy of 0.90 (95% CI 0.86-0.95) in identifying women with a ? 10% probability of carrying aBRCA1/2 mutation (sensitivity 89%, specificity 92%). Based on changing data,the B-RST algorithm was recently revised (B-RST 3.0) and re-evaluated in a large cohort tested for BRCA1/2 mutations. B-RST 3.0 was found to have an sensitivity of 93% to identify individuals with a BRCA1/2 mutation, while maintaining a specificity significantly higher than that of the NCCN guidelines. Women who screen positive on B-RST, but are not appropriate candidates for genetic testing, typically are at moderate increased risk for breast cancer based on their family history, and may benefit from consideration of enhanced screening or chemoprevention.

B-RSTTM Score Interpretation

  • POSITIVE: Person has a 5-10% or greater chance of carrying a mutation in BRCA1 or BRCA2. Referral for Cancer Genetic Counseling is indicated
    • Note: Individuals who screen positive on the B-RSTTM may not be found to be appropriate candidates for BRCA1/2 testing when a comprehensive cancer risk assessment is performed. In many cases, testing an affected family member first is warranted.
  • NEGATIVE: Person is unlikely to carry a BRCA1/2 mutation.
    • LOW Risk = Based on family history, person's risks for breast/ovarian cancer expected to be at or below that of the general population.
    • MODERATE Risk = Persons who do not have a family history suggestive of hereditary cancer, but may have a risk for breast cancer that is somewhat increased (~2-4 fold) above that of the general population. Further risk assessment and/or enhanced screening or prevention strategies may be appropriate for some of these individuals.

NOTES:

  • B-RST is NOT designed to determine who should be offered BRCA1/2 genetic testing, but to identify who should be referred for a comprehensive cancer genetic counseling. Suitably trained healthcare providers in cancer genetics can be found through links under resources.
  • This screening tool does not assess non-familial risk factors for breast or ovarian cancer.
  • Changes in family history could result in a change in the risk score. B-RSTTM should be re-run if additional cases of breast and/or ovarian cancer occur.
  • In families with few females, single cases of breast cancer ages 40-50 may be related to a BRCA1/2 mutation.
  • There are other, less common hereditary causes of breast and ovarian cancer. A cancer genetics consultation should be pursued if:
    • There are multiple individuals with cancer in multiple generations
    • Cancers are of an usually early age of onset
    • Rare or unusual cancers or tumors have occurred (examples: cancer of adrenal glands, medullary thyroid cancer, hamartomatous polyps, paragangliomas)

Gene Panels:

Recently, genetic testing trends for individuals at-risk for hereditary breast and/or ovarian cancer have included the use of panels, which evaluate other hereditary cancer genes beyond BRCA1/2. Though not designed to screen for these other syndromes, a positive B-RST screen would be expected to also identify a portion of individuals with other hereditary cancer syndromes. Note that many of the genes on these panels are associated with moderate or uncertain risks, and data is limited regarding best management strategies.

Selected References

Bellcross CA, Lemke AA, Pape LS, et al. Evaluation of a breast/ovarian cancer genetics referral screening tool in a mammography population. Genet Med. 2009;11:783-789.

Bellcross CA. Further development and evaluation of a breast/ovarian cancer genetics referral screening tool. Genet Med. 2010;12:240.

Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. J ClinOncol. 2007;25:1329-1333.

Domchek SM, Weber BL. Clinical management of BRCA1 and BRCA2 mutation carriers. Oncogene. 2006;25:5825-5831.

Domcheck SM, Friebel TM, Singer CF et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA. 2010;304:967-975.

Genetic/Familial High-Risk Assessment: Breast and Ovarian. NCCN Clinical Practice Guidelines in Oncology. Available at: http://www.nccn.org/professionals/physician_gls/f_guidelines_nojava.asp#detection

Meaney-Delman D and Bellcross CA. Hereditary Breast/Ovarian Cancer Syndrome: A Primer for OB/GYNs. ObstetGynecolClin N Am. 2013; 40:475–512

Moyer VA, on behalf of the U.S. Preventive Services Task Force. Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer in Women: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2014;160:271-281.

Petrucelli N, Daly MB, Feldman GL. Hereditary breast and ovarian cancer due to mutations in BRCA1 and BRCA2. Genet Med. 2010;12(5):245-59.

Rebbeck TR, Kauff ND, Domcheck SM. Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-opoophorectomy in BRCA1 or BRCA2 mutation carriers. J Natl Cancer Inst. 2009;101:80-87.

United States Preventive Services Task Force. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility: recommendation statement. Ann Intern Med. 2005;143:355-361.

Warner E, Hill K, CauserP. et al. Prospective study of breast cancer incidence in women with a BRCA1 or BRCA2 mutation under surveillance with and without magnetic resonance imaging. JClinOncol. 2011; 29:664-1669