Women with a BRCA variant of uncertain significance (VUS) or a noninformative negative test result may still be at higher risk of developing breast cancer than the general population.

In a large population-based study, women with a noninformative negative BRCA result had about twice the estimated lifetime risk of developing breast cancer compared with the general population: about 26% vs 12%. For those with a VUS, the risk was about 31%.

“This is not surprising,” said Kathy Miller, MD, medical breast oncologist at Indiana University Health in Indianapolis, who wasn’t involved in the study.

Genetic testing is typically recommended because patients already have risk factors including age, disease phenotype, and family history. “In essence, those who are tested are already at higher risk than the general population,” Miller told Medscape Medical News.

The researchers said the elevated risk likely reflects the underlying family and clinical risk factors that prompted these women to undergo genetic testing in the first place.

By contrast, women who tested negative for a specific BRCA mutation known to run in their family had a risk similar to that of the general population. This is “reassuring,” said Judy Garber, MD, MPH, chief of the Division of Cancer Genetics and Prevention at Dana-Farber Cancer Institute in Boston, who also wasn’t part of the study. Testing negative is supposed to tell patients they don’t have this risk, and they didn’t, Garber added.

Filling a Gap

Up until now, “we haven’t had a good understanding of cancer risk in women who carry a VUS or a noninformative negative result,” lead author Fahima Dossa, MD, PhD, surgical oncologist at Cedars-Sinai Medical Center in Los Angeles, told Medscape Medical News.

To better understand breast and ovarian cancer risk in this patient population, Dossa and colleagues conducted a retrospective cohort study of nearly 16,000 women who underwent BRCA testing in Ontario, Canada, from 2007 to 2016. Genetic and family history information was linked with administrative health data, and participants were followed through September 2024. The researchers matched 6966 women eligible for breast cancer analyses with 34,830 control individuals and 13,276 women eligible for ovarian cancer analyses with 66,380 control individuals. A noninformative negative result indicated no risk-increasing variant was identified in the BRCA1/2 genes, but clinical suspicion for increased risk was still high given patients’ personal and family cancer history.

During a median follow-up of 11 years, the estimated cumulative breast cancer risk by age 80 was 62% among BRCA1 pathogenic variant carriers and 66% among BRCA2 pathogenic variant carriers vs 12% in the general population.

The estimated cumulative breast cancer risk by age 80 was 31.2% among women with a VUS, 26% among women with a noninformative negative result, and 13% among women with a predictive negative result.

Family history further stratified risk, especially among BRCA carriers. Among women with noninformative negative results, cumulative breast cancer incidence was 21% with no affected first-degree relatives, 28% with one, and 43% with at least two. Among BRCA1/2 pathogenic variant carriers, risks were substantially higher at 56% with no affected first-degree relatives, 68% with one, and 86% with two or more.

The investigators did not observe increased ovarian cancer risk among women with a VUS or noninformative negative result.

What Should Clinicians Tell Patients?

Women whose overall breast cancer risk meets accepted high-risk screening thresholds may benefit from intensified surveillance, including annual breast MRI, the authors wrote. However, overall cancer event rates were too low to determine whether other risk-reducing strategies, including surgery, are beneficial, they said.

The absence of an observed increase in ovarian cancer risk suggests that ovarian risk-reducing strategies should generally remain reserved for women with confirmed pathogenic variants or other established indications, they added.

Overall, “our study provides quantitative data to inform counseling discussions between clinicians and patients about risk reduction across all BRCA test result groups and highlights the importance of considering family history of cancer in decisions around risk-reduction strategies,” Dossa told Medscape Medical News. “These decisions should necessarily be individualized.”

The study was supported by ICES, the Canadian Cancer Society, and the Canadian Institutes of Health Research. Author disclosures are available with the original publication. Miller disclosed relationships with Pfizer, Astex Pharmaceuticals, Genentech, Merck, AstraZeneca, Roche, and Celcuity Inc. Garber reported no relevant disclosures.