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Geisinger Exome Study IDs Breast Cancer Risk Variants That May Not Have Been Detected in Routine Care

NEW YORK (GenomeWeb) – Geisinger Health System researchers found that sequencing the exomes of patients can identify breast cancer risk variants, even in patients without a family history of cancer or who otherwise would not be considered to be at an elevated risk.

The researchers, who reported the results of their study today in JAMA Network Open, sequenced the exomes of more than 50,000 individuals. The work was born out of Geisinger's MyCode Community Health Initiative, a research study that began returning actionable results to patients for 76 genes in 2015. The project — a partnership with Regeneron Pharmaceutical, which conducts the sequencing — has enrolled around 200,000 individuals thus far.

In the JAMA Network Open study, the researchers found that the vast majority — 99.5 percent — of the 50,726 individuals who had their exomes sequenced did not have pathogenic or likely pathogenic variants in the BRCA1 or BRCA2 genes. However, 267 participants did have pathogenic BRCA variants, a number that the researchers said was around five times greater when compared with previous clinical care.

Just over half of the carriers — or 148 — were women, while 119 — or 44.6 percent — were men, and carriers ranged in age from 23 to 90. About 82 percent of the individuals had no prior clinical testing.

"The prevalence of BRCA1/2 variants in the general population may be substantially higher than previously estimated," Geisinger CSO and executive vice president David Ledbetter said in a statement. "Current screening methods and family history don't provide an adequate assessment of risk, and that needs to change." Ledbetter also noted that routine healthcare should include genomic screening as a component.

Among the 89 carriers who had not previously been tested but who had comprehensive personal and family history data, 44 did not meet published guidelines for clinical testing, the authors reported.

The individuals who participated in the study enrolled between 2014 and 2016, and in some cases individuals had passed away before results were returned. The researchers reviewed those cases and found that of the 23 individuals who died, nine deaths were due to BRCA-associated cancer.

In three cases, sequencing enabled detection of early cancer, including a woman in her 40s for whom subclinical disease was detected when she went for screening after being told of her carrier status.

At a conference earlier this year, Ledbetter described another case where he said the genomic results were likely life saving. Sequencing identified a BRCA1 variant in a 57-year-old woman without a known family history and after discussing the finding with the woman, who was raising grandchildren, she opted for prophylactic surgery to remove both her breasts and ovaries. At the time of surgery, the doctors discovered and removed a tumor in her fallopian tube and she started chemotherapy.

The researchers also reported that some individuals found to have pathogenic BRCA mutations either currently had or had previously had cancer, but not had BRCA testing. In those cases, the individual's management was changed as a result of the finding and testing for at-risk family members was offered.

Overall, the authors concluded that "the prevalence of BRCA1/2variants in the general population may be substantially higher than was previously estimated, and reliance on personal and family history may be an inadequate measure to ascertain risk for BRCA1/2variants."

The Geisinger team's study adds to a growing body of evidence suggesting that current guidelines for hereditary cancer screening may miss a large number of individuals who are at risk. In this study, for instance, half of the individuals with either a personal or family history who were found to have BRCA variants did not meet the National Comprehensive Cancer Network's criteria for testing.

A project led by the Women's College Hospital in Toronto found that population screening for cancer risk mutations found a significantly higher number of mutations than would have been expected. And, of eight individuals with BRCA mutations, only half met guidelines for testing. Similarly, genetic testing firm Counsyl found that during a three-month program where it offered free hereditary cancer screening to women, about half of the 108 women who had positive results did not meet NCCN testing guidelines.

Such findings have prompted discussions about the merits of population-based screening for some hereditary cancer mutations.

The Geisinger researchers noted that their study, along with others "should prompt prioritization of further research into genomic sequencing-based population screening."

Indeed, the health system itself has already taken a step in that direction with a 1,000-person pilot program it launched earlier this year to offer clinical exome sequencing that returns limited medically actionable results to patients as part of routine health care.