Broader recommendations on screening for BRCA1/2 genetic mutations published by the U.S. Preventive Services Task Force (USPSTF) on August 20 represent a vote of confidence for more testing, which has been widely viewed as underused.
The USPSTF published new recommendations for BRCA1/2 mutations in the Journal of the American Medical Association (August 20, 2019, Vol. 322:7, pp. 652-665), as an update to its 2013 guidance on the topic. Additionally, four editorials putting the changes into context were published on the same day in JAMA, JAMA Oncology, JAMA Surgery, and JAMA Network Open.
BRCA mutations are associated with an increased risk for breast and ovarian cancers, as well as for other tumor types, such as cancers of the prostate and pancreas. The USPSTF made two key recommendation statements in its 2019 version of recommendations on risk assessment, counseling, and genetic testing for BRCA-related cancer:
- B recommendation -- high certainty that the net benefit is moderate: Primary care physicians should assess women with a personal or family history of breast, ovarian, tubal, or peritoneal cancer, or who have an ancestry associated with BRCA1/2 gene mutations, with an appropriate brief familial risk assessment tool. Those positive on screening should have counseling and then genetic testing.
- D recommendation -- moderate or high certainty that the service has no benefit or harms outweigh benefits: Routine risk assessment, genetic counseling, or genetic testing for women whose personal or family history or ancestry is not associated with potentially harmful BRCA1/2 gene mutations is not advised.
"Testing for BRCA1/2 mutations should be performed only when an individual has personal or family history that suggests an inherited cancer susceptibility, when an individual is willing to talk with a health professional who is suitably trained to provide genetic counseling and interpret test results, and when test results will aid in decision-making," wrote Dr. Douglas Owens, director of the Center for Health Policy and the Center for Primary Care and Outcomes Research at Stanford University, and colleagues in a statement about the new recommendations.
The USPSTF also noted that tests for BRCA1/2 mutations are "highly sensitive and specific for known mutations," and the number of options has increased since 2013, with multigene panels available for screening 80-plus genes, as well as direct-to-consumer tests.
Impact on the Ashkenazi Jewish debate
In the 2013 version of the recommendations for BRCA1/2 testing, the USPSTF recommended screening for women with a family history of cancer, but it did not recommend testing for women with a personal history (Moyer et al, Annals of Internal Medicine, February 18, 2014, Vol. 160:4, pp. 271-281).
"The addition of women with prior breast and ovarian cancer is an important step forward," wrote oncologists Dr. Susan Domchek of the University of Pennsylvania and Dr. Mark Robson of Memorial Sloan Kettering in an editorial in the current JAMA issue. "Patients with breast cancer and BRCA1/2 pathogenic variants have high risks for ovarian cancer, which is largely preventable."
Also, the recommendations now explicitly include ancestry associated with BRCA1/2 mutations -- that is, founder mutations -- as a risk factor.
"A group that has been the subject of particularly vigorous discussion regarding unselected population testing is the Ashkenazi Jewish population," the authors wrote.
Prevalence is higher for this demographic group and screening is more straightforward and less expensive than in the general population, Domchek and Robson suggested.
BRCA testing 'woefully underused'
A number of editorial authors noted that BRCA1/2 testing is vastly underused, despite the wide availability of testing. BRCA1/2 mutations are present in 15% of patients with epithelial ovarian cancer, and testing for these patients is recommended by the National Comprehensive Cancer Network -- yet only 30% get tested, according to Domchek and Robson.
"Testing appears even lower for underrepresented minorities and those of lower socioeconomic status," they wrote. "Even though failure to adequately test those at highest risk for having a BRCA1/2 pathogenic variant has been well documented, there have been calls to markedly lower the threshold for testing."
Similarly, University of Chicago oncologist Dr. Padma Rajagopal and colleagues wrote in a JAMA Network Open editorial that germline testing for BRCA1 and BRCA2 remains "woefully underused" in the U.S. Only 20% to 30% of patients eligible for testing based on a personal breast or ovarian cancer history discuss testing with a clinician, though this rate is likely to increase with a greater focus on mutations in targeted oncology care, the authors added.
"Among unaffected women with a positive family history screen, less than 10% of patients reported discussing genetic testing with a [healthcare] professional," Rajagopal and colleagues wrote. "Primary care practitioners face challenges such as infrequent experience, lack of updated knowledge, and lack of familiarity with advanced genetics services that can create discomfort with discussions about personalized medicine and genetic testing."
Editorial authors also flagged omissions in the latest USPSTF recommendations, including the usefulness of knowing BRCA1/2 status for patients with newly diagnosed early-stage breast cancer to guide surgeries. Nor do the USPSTF recommendations address screening for other tumor types, such as prostate and pancreatic cancers and melanoma. Increasingly, drugs are being used to target patients with BRCA mutations for cancer types aside from breast and ovarian.
"While further expansion of the USPSTF recommendation should be considered, the importance is clear: identification of individuals at risk of carrying a BRCA1/2 mutation can be lifesaving and should be a part of routine medical care," Domchek and Robson wrote.
Getting primary care docs up to speed
Questions remain about how testing will be performed going forward. Large multigene panels have replaced BRCA1/2 testing, Domchek and Robson noted, but the challenges with this trend include a large increase in the number of findings that may not be clinically meaningful.
"As consideration of criteria for testing for BRCA1/2 pathogenic variants is broadened, it is important to recognize the evolving complexities of testing options and increase education for physicians and other [healthcare] professionals to navigate the landscape," they wrote. "In addition, uptake of testing among individuals at the highest risk must improve, and persistent disparities in testing must be resolved."