Expanded USPSTF BRCA1/2 testing recommendations may not go far enough

By Andrew D. Bowser

Recently updated guidelines from the U.S. Preventive Services Task Force (USPSTF) have substantially expanded the pool of individuals for whom breast cancer susceptibility gene (BRCA)-related cancer risk assessment is warranted. But does the update go far enough?

The USPSTF recommendations from 2013 had stated that genetic counseling and evaluation was warranted for women with a family history associated with an increased risk of potentially harmful BRCA1/2 gene mutations.

The latest statement from the expert panel expands the screening-eligible population to include those with personal history of breast cancer or ovarian, tubal, or peritoneal cancer and also calls out ancestry linked to BRCA1/2 mutations as a risk factor.

However, all that focus on BRCA-only testing, rather than panel testing, could have substantial adverse consequences in the identification of hereditary breast and ovarian cancer, some have argued.

Namely, directing the recommendations toward BRCA1/2 means potentially missing important genes linked to inherited breast cancer and missing actionable mutations that are potentially not suggested by family history and that could have important treatment implications, Marie E. Wood, MD, and colleagues said in an editorial in the Breast Journal.


Dr. Marie E. Wood
There are a number of highly penetrant genes tied to breast cancer, including PALB2, PTEN, and LFS, as well as genes linked to ovarian cancer that could be useful to evaluate; with that in mind, it may be time to “think beyond BRCA1 and BRCA2,” Dr. Wood said in an interview.

“There are now panels of genes that we test for, so it’s important to be thinking a little bit more broadly,” said Dr. Wood, director of the Familial Cancer Program in the hematology/oncology division of the department of medicine at the University of Vermont, Burlington.

Thinking beyond breast and ovarian cancer also could improve identification of hereditary cancers, Dr. Wood and colleagues said in the July editorial, which was written based on an earlier version of the USPSTF recommendations update that had been published for public comment.

“When you’re thinking about BRCA1 and BRCA2, it’s more than breast and ovarian cancer today,” explained Dr. Wood. “What we were advocating for is making sure that you include other populations that we know have cancer risk associated with BRCA1 and BRCA2, such as high-grade or hormone-refractory prostate cancer, pancreatic cancer, and male breast cancer.

The USPSTF did respond to public comment in the final version of their updated recommendation statement, published in JAMA on August 20.

“The USPSTF’s recommendation focuses on BRCA1/2 mutations because they are more prevalent and the findings are clinically actionable,” the expert panel authors said in their report.

They also acknowledged comments requesting the statement be expanded to discuss those other BRCA-associated cancers: “The scope of the recommendation is limited to the prevention of breast, ovarian, tubal, and peritoneal cancer because the net benefit demonstrated was in the prevention of these cancers,” wrote Douglas K. Owens, MD, of Stanford (Calif.) University and coauthors of the task force report.

Some commenters, including Dr. Wood and colleagues, had advocated for newer genetic testing options, including use of multigene panels that would include other gene mutations (e.g., PALB2). However, those newer panels and tests require further investigation, according to the expert panel, and evidence is “currently limited” on other genes that they say have a low incidence in the population.

Dr. Douglas K. Owens

Treatment Implications

While the USPSTF recommendations do not discuss systemic therapy, finding a BRCA mutation in a cancer patient today has important implications for treatment, said Rachel L. Yung, MD, of the University of Washington, Seattle, and Larissa A. Korde, MD, MPH, of the National Cancer Institute.

Specifically, poly (ADP-ribose) polymerase (PARP) inhibitors have proven effective in certain BRCA-related cancers, and the Food and Drug Administration has already approved several PARP inhibitors for treatment of BRCA-linked metastatic breast or ovarian cancers. Studies are underway for other tumor types, including prostate and pancreatic cancers that harbor a BRCA mutation.

“Increasing awareness of BRCA mutation as a target for treatment will likely lead to an increase in the identification of patients with cancer harboring germline BRCA mutations, which in turn will increase the need for cascade testing for relatives of affected probands,” said Dr. Yung and Dr. Korde in their editorial, which appears in JAMA Oncology.

Again, however, it’s not all about BRCA mutations, according to Dr. Wood.

For example, patients with mutations in other DNA repair genes may also respond to PARP inhibitors, while those with mismatch repair gene mutations could respond to immunotherapy, she said.


What the Recommendations Say

The USPSTF statement, as published in JAMA, recommends that primary care clinicians “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.”

Positive results on the risk assessment tool should prompt genetic counseling and then genetic testing if indicated after counseling, the USPSTF adds.

By contrast, the task force recommends against routine assessment, counseling, and testing in women with no family history, personal history, or ancestry linked to possibly harmful BRCA1/2 gene mutations, consistent with their previous recommendation.

Mutations of BRCA1/2 genes occur in an estimated 1 in 300-500 women in the general population, and account for 15% of ovarian cancer and up to 10% of breast cancer cases, according to the USPSTF.

Breast cancer risk is increased up to 65% by age 70 years in those women with clinically significant BRCA1/2 mutations, while risk of ovarian, fallopian tube, or peritoneal cancer are increased by up to 39%, according to studies cited by the USPSTF.

Important Step Forward

Including women with prior breast and ovarian cancer in the screening-eligible population is an “important step forward,” said Susan Domchek, MD, of the Basser Center for BRCA, University of Pennsylvania, Philadelphia, and Mark Robson, MD, of Memorial Sloan Kettering Cancer Center, New York, in a related editorial.

“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,” Dr. Domchek and Dr. Robson wrote in their editorial, which also appears in JAMA.

While the updated recommendations explicitly call out ancestry as a risk factor, they stop short of endorsing testing for unaffected Ashkenazi Jewish women with no family history, the authors noted.

“However, the statement may be interpreted as a step toward supporting unselected testing in this group,” they added.

Among unselected individuals of Askhenazi Jewish descent, 1 in 40 have 1 of 3 specific BRCA1 or BRCA2 founder mutations, according to one study cited by Dr. Domchek and Dr. Robson.

More Research Needed

However, current research is still “limited or lacking” to address many key questions about the benefits and harms of risk assessment, genetic counseling, and genetic testing in women without BRCA1/2-related cancer, according to authors of a literature review used by the USPSTF.

Notably, the ability of risk assessment, testing, and counseling to reduce cancer incidence and mortality among such women has not been directly evaluated by studies to date, wrote review authors, led by Heidi D. Nelson, MD, MPH, of the Oregon Health & Science University in Portland.

“Without effectiveness trials of intensive screening, practice standards have preceded supporting evidence,” Dr. Nelson and coauthors wrote in a report on the review findings.

In observational studies, mastectomy and oophorectomy have been associated with substantial reductions in subsequent cancer incidence and mortality; however, they are invasive procedures with potential complications, the authors noted.

“To determine the appropriateness of risk assessment and genetic testing for BRCA1/2 mutations as a preventive service in primary care, more information is needed about mutation prevalence and the effect of testing in the general population,” they added.

Studies of BRCA1/2 assessment as preventive service in primary care have generally looked at highly selected patient populations in referral centers and have reported relatively short-term outcomes, they noted in the report.

Research is additionally needed on access to genetic testing and follow-up, effectiveness of risk stratification and multigene panels, and the impact of direct-to-consumer genetic testing, among other key questions, authors of the review added.

Dr. Heidi D. Nelson

Addressing Disparities in Care

The USPSTF recommendations for BRCA risk assessment do not address disparities in testing referral and variation in breast cancer phenotypes among women of African ancestry owing to lack of evidence, according to Lisa Newman, MD, MPH, of the Interdisciplinary Breast Program at New York-Presbyterian/Weill Cornell Medical Center in New York.

“Paradoxically, the data-driven basis for the USPSTF recommendation statement may magnify existing genetic testing disparities,” Dr. Newman wrote in an editorial that appears in JAMA Surgery.

Non-Hispanic black women in the United States have a twofold higher incidence of triple-negative breast cancer, which is a well-documented risk factor for BRCA1 mutation–carrier status, according to Dr. Newman.

Despite this, she added, genetic counseling and testing referrals remain “disproportionately low” among U.S. patients of African ancestry.

“It remains imperative for clinicians to exercise clinical judgment and to be mindful of patient subsets that do not necessarily fit into recommendations designed for the majority or general populations,” Dr. Newman concluded in her editorial.

The USPSTF is funded by the Agency for Healthcare Research and Quality (AHRQ). Members of the task force receive travel reimbursement and honoraria for participating in USPSTF meetings.

Dr. Lisa A. Newman