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23 August 2019

Earlier this week, the United States Preventative Services Task Force (USPSTF) released an updated recommendation for genetic testing for BRCA 1 and 2 mutations. Their previous guideline, released in 2013, recommended risk assessment and consideration of testing in women with a family history of breast and/or ovarian cancer. The current guidelines add consideration for ancestry and personal history of breast, ovarian, fallopian tube or peritoneal cancer (BRCA-associated cancers for the purpose of this post). Under the Affordable Care Act, private insurers follow USPSTF recommendations, often with no out-of-pocket cost to the patient.

The BRCA 1 and 2 genes are involved in DNA repair. Mutations in these genes may impact the ability of a cell to repair DNA damage resulting in an increased risk of certain cancers. In women, the most common BRCA-associated cancers are breast and ovarian cancer. In men, the most common BRCA-associated cancers are prostate, breast and pancreatic cancers as well as melanoma. The abnormal genes can be inherited from the mother or father.  Mutations in BRCA 1 and 2 genes have been identified in every racial and ethnic group with a prevalence ranging from 1 in 40 to 1 in 500. The Ashkenazi Jewish population has the highest mutation prevalence.  Not everyone that inherits an abnormal gene will develop the cancer – the risk and type of cancer depend on the specific mutation and many other factors. Mutations in the BRCA genes account for approximately 5-10% of breast cancers and approximately 15% of ovarian cancers.

The updated USPSTF recommendation applies only to women (they did not address genetic testing in men) and only applies to the BRCA 1 and 2 genes, which are the most common genes associated with hereditary breast and ovarian cancer. 

The current guideline recommends a 3-step process. In patients who have a personal or family history of BRCA-associated cancers or a hereditary susceptibility (Ashkenazi Jewish) the task force recommends:

  • Use of a validated tool to determine likelihood of a genetic mutation
  • Referral of patients with a high likelihood of carrying a genetic mutation for genetic counseling
  • Genetic testing if the results would impact medical decision making

It is important to note that they are not stating that all Ashkenazi Jewish women, or that all women with a personal or family history of breast or ovarian cancer be tested – but that they be evaluated and then considered for testing based on likelihood of having a deleterious (harmful) mutation. They recommend against risk assessment, genetic counseling and genetic testing in those with a personal or family history of cancer or ancestry not associated with a high likelihood of deleterious BRCA mutations. 

Identification of patients who carry mutations in these genes is important for several reasons. In those who do not have cancer, identification of a mutation carrier may lead to recommendations for more intensive screening (most commonly annual MRI in addition to annual mammography for breast cancer surveillance) or prophylactic surgery. Family members can also be appropriately counseled and tested. Tamoxifen may be considered for breast cancer risk reduction. However, in an accompanying editorial, Dr. Lisa Newman noted that breast cancers that develop in women with BRCA 1 mutations are more likely to be “triple negative”, which are not responsive to tamoxifen or other therapies that target the estrogen receptor. BRCA 2 related breast cancers are more often estrogen receptor positive, and tamoxifen may be an option in these patients for risk reduction.

In patients that have a history of a BRCA-associated cancer, knowledge of genetic status can inform surveillance recommendations for other associated cancers as well as counseling and testing of family members. 

The USPSTF specified that patients with a prior history of BRCA-associated cancers, who “have completed treatment are considered cancer-free but have not been previously tested” are included in this guideline. I believe it is unfortunate that they did not include newly diagnosed patients in this guideline as knowledge of mutation status can influence surgical recommendations and may influence systemic therapy (chemotherapy) recommendations, a point made in the editorial by Drs. Sharon Domchek and Mark Robson. There may also be value in testing patients who have metastatic disease as their family members can then make informed decisions regarding their own health. The most recent American Society of Breast Surgeons genetic testing guideline recommends that all breast cancer patients be considered for genetic testing.

The USPSTF recommendations did not touch on this, but It is important to note that if BRCA testing was performed prior to 2012-2014, consideration should be given to repeat testing. A large number of mutations have been identified since that time, and some who have previously testing negative may actually carry a deleterious mutation.

Genetic testing in men was not addressed in the current USPSTF statement. Drs. Rachel Yung and Larissa Korde, in an accompanying editorial, stated that lack of inclusion of men in the guideline was a “missed opportunity”. They noted that that metastatic prostate cancer is the most common BRCA-associated cancer in men and that the National Comprehensive Cancer Network (NCCN) guidelines list family history of metastatic prostate cancer is an indication for genetic counseling and BRCA testing. Many patients (and some physicians) are unaware that BRCA mutations can be inherited from male relatives and may lead to cancer development in men. For that reason, some have called for the renaming of “Hereditary Breast and Ovarian Cancer Syndrome” to “King Syndrome”, after Dr. Mary-Claire King, the scientist who discovered the location of the BRCA 1 gene and its relationship to hereditary breast and ovarian cancer.

In addition, not specifically covered in this statement, but discussed in editorials by Dr. Lisa Newman, Drs. Susan Domchek and Mark Robson, and Dr. Padma Sheila Rajagopal et al was racial and socioeconomic disparities in genetic testing and the importance of ongoing work in this area.

While (in my opinion) the current recommendations are incomplete, they are a step forward in helping to ensure patients with deleterious mutations, and their family members, are properly identified and counseled regarding their risk and their options. 

Men and women should be aware of their family history of all cancers (going back 3 generations), not just breast and ovarian cancer. Those who feel they fit the new guidelines based on family history, personal history, or ethnic background, even if previously tested (before 2012-2014) should speak with their physician about referral to a provider who specializes in cancer genetics for consideration of testing. 

If access to any of the references articles is desired, please email me: contact at drattai dot com and I will be happy to provide a copy.

References and Resources: