USPSTF Expands BRCA-Testing Recs in Women

The U.S. Preventive Services Task Force (USPSTF) has broadened its criteria for BRCA cancer susceptibility gene testing in women.

Citing moderate benefit and small-to-moderate risk, the USPSTF now recommends that primary care clinicians assess women with either a personal or family history of breast or ovarian cancers as well as women with Ashkenazi Jewish ancestry for their risk of BRCA1/2 mutations -- a "B" rating. They recommend a three-step process: a brief risk assessment with a validated tool, referral to genetic counseling if positive, and then BRCA1/2 mutation testing if indicated.

Their final recommendation statement and evidence report backing it were published in JAMA, and expand upon the Task Force's 2013 guidance, which had recommended risk assessment, genetic counseling, and BRCA testing only in women with a family history of breast or ovarian cancers.

USPSTF continues to recommend against routine risk assessment for women with nothing to suggest likelihood of a positive test result -- those with no personal or family history of BRCA-related cancers or ancestry associated with BRCA mutations -- giving it a "D" rating.

"When we have a preventive service that can lead to treatments that can save lives, we get very excited about those, and those are our most important recommendations in many respects," USPSTF member Carol Mangione, MD, MSPH, of the University of California Los Angeles, said in an audio interview that accompanied the publication. "BRCA1 and BRCA2 mutations are important to detect because they really significantly increase the risk for breast or ovarian cancer."

By the age of 70, these mutations are estimated to increase breast cancer risk by 45% to 65%. For ovarian, fallopian, or peritoneal cancers, BRCA1 mutations increase the risk by 39% while BRCA2 mutations increase the risk by 10% to 17%.

BRCA mutations are present in about 0.2% to 0.3% of the general population, but their prevalence in women of Ashkenazi Jewish descent is tenfold.

"Because that rate is higher in the population of Ashkenazi Jewish women, the recommendation is that they be referred for consideration of genetic testing," Mangione said.

Cancer-free women with a personal history of a BRCA-related cancer are also now eligible for risk assessment screening under the new guidance.

"This is a big change," said Mangione.

Notably, the Task Force did not recommend multigene panel testing, omitting other genes linked to increased cancer risk, and instead focused on BRCA1/2 mutations specifically, citing the available evidence on and prevalence of these mutations, and their clinical actionability.

"The lack of recommendation for the use of multigene panels will need to continue to be evaluated as studies have demonstrated the use of multigene panels results in identifying more clinically actionable mutations," Kristen D. Whitaker, MD, of the clinical genetics department at Fox Chase Cancer Center in Philadelphia, told MedPage Today via email. "In the case of breast cancer predisposition genes, their identification is important as the presence of such mutations could change the clinical management of the woman."

USPSTF also stopped short of endorsing any specific available risk assessment tools, and instead highlighted the evidence for various "accurate" options. With sensitivity estimates ranging from 77% to 100%, these include: the Ontario Family History Assessment Tool, Manchester Scoring System, Referral Screening Tool, Pedigree Assessment Tool, 7-Question Family History Screening Tool, and the International Breast Cancer Intervention Study instrument (or Tyrer-Cuzick).

"If a patient is positive on those ... we recommend genetic counseling, because patients need to have their family tree looked at and need to have a comprehensive discussion about the pros and cons of testing in their specific situation," explained Mangione.

Well-known breast cancer risk models without a focus on family history -- such as the Gail Model -- are not recommended by the USPSTF to inform on the risks of BRCA mutations.

In a series of accompanying editorials, experts across various specialties addressed the implications of the new Task Force recommendations.

"Although the USPSTF discusses ancestry as a potential risk factor, it does not specifically endorse testing unaffected Ashkenazi Jewish women with no family history," wrote Susan Domchek, MD, of the University of Pennsylvania in Philadelphia, and Mark Robson, MD, of Memorial Sloan Kettering Cancer Center in New York City, in a JAMA editorial. "However, the statement may be interpreted as a step toward supporting unselected testing in this group."

Others also voiced concerns.

Rachel Yung, MD, of the University of Washington in Seattle, and Larissa Korde, MD, MPH, of the National Cancer Institute in Rockville, Maryland, called it a "missed opportunity" that the guidelines apply only to women.

"Metastatic prostate cancer is the most common BRCA-associated cancer in men," wrote Yung and Korde in JAMA Oncology. "Notably, 6% of men with metastatic prostate cancer have a BRCA1 or BRCA2 mutation."

By comparison, from 5% to 10% of breast cancer cases and roughly 15% of ovarian cancer cases are due to BRCA1/2 mutations.

In their statement, the Task Force did not recommend specific treatments for women who test positive for BRCA mutations but suggested referral for a full discussion of the options, which might include intensive screening, risk-reducing medications (tamoxifen or aromatase inhibitors), mastectomy to reduce breast cancer risk, and salpingo-oophorectomy to reduce ovarian cancer risk.

Lisa Newman, MD, MPH, of NewYork-Presbyterian/Weill Cornell Medical Center in New York City, pointed out in JAMA Surgery that the effectiveness of chemoprevention aimed at hormone-positive disease is unclear in women with BRCA1-associated breast cancer, as these cancers are mostly hormone-receptor negative.

"Carriers of these mutations are therefore less likely to benefit from this type of risk-reducing intervention," she said.

Newman also noted that "owing to lack of evidence," the new Task Force recommendations do not address the variations in tumor phenotypes among women with African ancestry and disparities in genetic testing referrals for this population.

"Paradoxically, the data-driven basis for the USPSTF recommendation statement may magnify existing genetic testing disparities," she wrote.

USPSTF guidelines on lung cancer have recently come under fire, with suggestions that a large proportion of black Americans at high risk for lung cancer based on their smoking history and other factors are excluded from low-dose CT screening under the current criteria.

Finally, Olufunmilayo Olopade, MD, of the University of Chicago, and colleagues highlighted in JAMA Network Open that germline BRCA testing "remains woefully underused" in the U.S. -- only 20% to 30% of patients with a personal breast or ovarian cancer history ever discuss testing with their physician, they noted, and less than 10% of women with a family history receive genetic testing.

Olopade's group also pointed out that other populations with high rates of BRCA mutations are being discovered, citing a cohort of Nigerian patients where 11% had BRCA1/2 mutations and a study of breast and ovarian cancer patients in India where 25% were found to have such mutations.