Multiplex Genetic Assays Identify Mutations Beyond BRCA1/2 in 10% of Patients at Risk for Breast Cancer

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One of 10 patients referred for BRCA1/2 mutation testing have pathogenic mutations in other genes, and these often prompt a change in care, according to Stanford University researchers who used a novel cancer gene sequencing panel to fully assess germline mutations in patients at risk for breast cancer.

“Multiple-gene sequencing panels are entering clinical practice. We are reporting on research testing with a custom sequencing panel (InVitae Corporation, San Francisco) in patients referred for assessment of hereditary breast and ovarian cancer risk,� said Allison W. Kurian, MD, MSc, who presented the findings at the 2013 Breast Cancer Symposium.

Patients were referred to the Stanford Cancer Genetics Program for clinical BRCA1 and BRCA2 mutation testing between 2002 and 2012. In blood samples from these patients, the entire coding region, exon-intron boundaries, and all known pathogenic variants in other regions were sequenced for 43 genes that have published associations with a risk for breast, ovarian, and other cancers. An additional 32 cancer-associated variants were also sequenced. Ultimately, they derived a set of 41 fully sequenced genes and 23 single nucleotide polymorphisms.

The researchers disclosed the results to the participants, and if they were clinically actionable (ie, an approved or investigational targeted agent was available,) these patients were invited to counseling.

Of 198 patients, 141 women had breast cancer and 57 carried a known BRCA1/2 mutation. Interestingly, a pathogenic variant in a gene other than BRCA1/2 was found in 21 patients. These included mutations in ATM, BLM, CDH1, CDKN2A, MUTYH, MLH1, NBN, PRSS1, and SLX4, Kurian reported.

Of these, 15 were actionable and 6 were not. Of the 15 patients with actionable genes, 3 were lost to follow-up, yielding 12 patients to be contacted by the researchers for follow-up care.

Of these 12 patients, 10 warranted new screening or prevention recommendations. In the most notable case, she said, “One 53-year-old patient with a personal history of breast and endometrial cancers was found to carry a pathogenic MLH1 mutation. She underwent risk-reducing salpingo-oophorectomy and colonoscopy, with removal of a tubular adenoma.�

Six patients underwent discussions of more intensive breast surveillance, and 6 chose to have more intensive gastrointestinal surveillance.

Discussing the study, Lajos Pusztai, MD, PhD, professor of medicine, Yale University, and codirector of the Yale Cancer Genetics Research Program, commented on the value of this cancer gene sequencing panel for hereditary risk assessment.

“This is very exciting research,� he said. “More than 10% of patients had a pathogenic mutation beyond BRCA1/2, and up to 12% of them had a clinically actionable finding. But the test also detected many variants of uncertain significance, averaging 76 per patient across 41 genes, and these did not contribute to patient care.�

“The study also showed the feasibility of patient notification and intervention. Most patients could be reached up to 10 years postenrollment. To date, early colonoscopy has likely prevented 1 cancer. Larger population-based studies should follow.�

More broadly, Pusztai commented on where the field is moving. “We are entering a new era of cancer risk prediction. Next-generation sequencing of a large number of risk alleles or whole exome sequencing can cast a much broader net to find disease-predisposing variants,� he said.

“Most ‘high-risk genetic screening clinics’ have adopt­ed multiplexed assays, either in-house or commercially. Moving forward, we must acknowledge 3 important challenges,� he added. “We must be able to functionally characterize the variants of unknown significance, quantify hazards more accurately, and test the value of our preventive interventions.�

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