More women at risk for breast, ovarian and other cancers should be assessed for their chance of having cancer-causing gene variants (mutations) in the BRCA1 and BRCA2 genes by their primary care health practitioners, the U.S. Preventive Service Task Force (USPSTF) recently recommended.
The new recommendations state that women from specific ancestries, or who have family or personal history of cancers associated with harmful variants in the BRCA genes, should get risk assessments from their primary care providers. Such risk assessments might involve, for example, talking to a healthcare practitioner about close relatives with breast cancer (family history) and going through a woman's medical history. If the assessment indicates a woman might be at high risk, the next step is genetic counseling and possibly testing for disease-causing (pathogenic) variants in the BRCA genes, say recommendations published August 20 in the Journal of the American Medical Association (JAMA).
The BRCA genes produce proteins that repair damage to DNA. Inheriting certain variants in BRCA genes from just one parent can diminish the DNA repair activity of these proteins and lead to development of breast, ovarian, fallopian tube, and peritoneal cancers, among others. There is particular concern about increased risk of breast cancer, which is the second most common cancer and the second leading cause of cancer death in women in the United States, according to the USPSTF.
Only about 0.2% of the U.S. population carries a BRCA1 or BRCA2 pathogenic variant. However, it is important to identify women who have inherited harmful variants because they have up to a 60% lifetime risk of developing breast cancer and a 15-40% lifetime risk of developing ovarian cancer, compared to the average population risk of 12% for breast cancer and 1.3% for ovarian cancer.
For BRCA gene testing, a blood sample is collected and the DNA is analyzed to detect variants that may be present. If a pathogenic variant (mutation that increases risk of cancer) is detected, options include more frequent cancer screenings and screening starting earlier in life (e.g., mammography, breast MRI), medications that could reduce risk (e.g., tamoxifen), or surgical removal of the ovaries or breasts. In addition, other family members who may be at increased risk can be informed and consider testing for themselves.
The new recommendations update a 2013 USPSTF statement that did not recommend risk assessment for women with previous diagnoses of cancer but focused on women with a family history of cancer. In contrast, the 2019 recommendations apply to women who completed treatment for breast, ovarian, fallopian tube, and peritoneal cancer and are now considered cancer-free. The recommendations are based on research that established the validity of genetic testing for BRCA variants and longer studies of risk-reducing medications and surgery. Additionally, the authors noted more evidence on the effectiveness of newer breast imaging techniques and surgical procedures that remove ovaries.
The USPSTF also recommends risk assessment—and possibly BRCA gene testing—for people from ancestry groups in which certain genetic variants are more common. The statement does not specifically recommend any group get BRCA testing but gives as an example testing for pathogenic variants common among people of Ashkenazi Jewish ancestry.
For women who fall into one of these high-risk groups, a positive risk assessment establishes the medical necessity of genetic counseling and testing for insurance providers.
The USPSTF continues to recommend against routine genetic counseling or BRCA testing for women whose personal or family history or ancestry do not suggest increased risk for potentially harmful variants in the BRCA genes (i.e., for those who have a negative risk assessment survey).
Not far enough?
A JAMA editorial accompanying the updated recommendations point outs that they do not include BRCA risk assessments for patients with newly diagnosed or advanced-stage breast cancer. Susan Domchek, MD and Mark Robson, MD write that knowing BRCA-related risk could help with decisions about surgery and it also could help determine appropriate treatment of certain advanced cancer.
Other editorials say that the updated guidelines would be better if they discussed risk among people of African and Hispanic ancestry. One author references studies showing that women of African ancestry have increased risk of triple-negative breast cancer, which is associated with BRCA1 variants. Additionally, non-Hispanic black women have BRCA variants with uncertain significance at higher rates than white women. Another editorial discusses reports of higher frequencies of BRCA1 and BRCA2 variants than previously recognized among African American breast cancer patients and Hispanic women with personal or family histories of breast or ovarian cancer.
Meanwhile, USPSTF-recommended screening tools ask different questions about family history and ancestry and are not uniformly useful in all groups, says another editorial. For example, one screening tool asks about ovarian cancer, breast cancer in both men and women, and Ashkenazi Jewish ancestry, while another considers early onset prostate and colon cancer, but not Ashkenazi Jewish heritage.
Increased use of BRCA genetic testing may complicate risk assessment, the editorials say. Panels that test 80 or more genes have largely replaced tests of just the two BRCA genes. These large panels detect more cancer-causing variants in more genes but can also identify variants with unknown meaning for disease risk in these genes as well. On the other hand, the authors point out that some direct-to-consumer genetic testing—such as a 23andMe service that tests for a few common BRCA variants—may provide false reassurance. Women who test negative for BRCA variants on the 23andMe panel should not assume they do not need further BRCA evaluation, they emphasize.