By Kate O'Rourke

San Antonio—In a cohort of 2,000 patients, next-generation sequencing using a panel of 25 cancer susceptibility genes identified 4.8% more patients with mutations than the 9.3% identified by testing the BRCA1/2 genes alone. The results were presented at the San Antonio Breast Cancer Symposium.

“Identifying individuals with a hereditary cancer risk provides opportunities for early detection, through more intensive screening, and cancer prevention, through the use of prevention medications or prophylactic surgery,” said Nadine Tung, MD, director of the Cancer Risk and Prevention Program at Beth Israel Deaconess Medical Center in Boston.

The 25-gene panel is a precursor to the MyRisk Hereditary Cancer Test, which was launched in September 2013. The 25 genes are associated with eight major hereditary cancers including breast, colon, ovarian, endometrial, pancreatic, prostate, gastric and melanoma. The average price of the test is $3,700.

The new study included two patient cohorts. Cohort 1 included 1,951 prospective cases referred for BRCA1 and BRCA2 testing to Myriad Genetics. There were no Ashkenazi Jews in this cohort. Cohort 2 included 390 patients with hereditary breast and ovarian cancer history at Beth Israel Deaconess Medical Center who previously tested negative for BRCA1 or BRCA2. Some patients in this latter cohort had Ashkenazi ancestry.

Ninety-one percent of patients in cohort 1 and 97% of patients in cohort 2 had breast cancer. Of the patients in cohort 1, 9.3% had a mutation in BRCA1 or BRCA 2 and 4.8% of patients had a mutation in a gene other than BRCA1/2. In cohort 2, 4.4% had a mutation in at least one of 23 genes other than BRCA1/2. The most common mutations in genes other than BRCA1/2 were CHEK2 (31.8%), NBN (14.5%), ATM (12.7%) and PALB2 (12.7%). At least one variant of unknown significance was found in 44% of cohort 1 and 45.4% in cohort 2.

The typical predictors of BRCA1/2 mutations, such as age at breast cancer diagnosis and family history of breast and ovarian cancer, did not appear to predict for mutations in genes other than BRCA1/2. There was a trend toward increased prevalence of mutations in genes other than BRCA1/2 in patients with multiple breast cancers (P=0.061). “Factors that predict for BRCA1/2 mutations do not seem to predict for mutations in other genes,” said Dr. Tung. “It may well be that the cancer spectrum and phenotype are different for mutations in each gene.”

Matthew Ellis, MB, PhD, the director of the Breast Cancer Program at the Washington University School of Medicine in St. Louis, said the study shows that BRCA1 and 2 remain the dominant causes of hereditary breast cancer and that testing the other 23 genes unearthed only a few percent of patients who wouldn’t have been identified with BRCA1/2 testing.

“What that says is that all of these other causes are relatively rare, and because they are rare, we actually don’t have very good information on key issues that are used in clinical decision making like penetrance. Penetrance is the likelihood that you will develop cancer if you have inherited the allele,” said Dr. Ellis. “We know the penetrance is high for BRCA1/2, but it is not really clear how penetrant PALB2 or RAD51C mutations or any of these other genes really are.”

Dr. Ellis had several concerns as the test begins to be used in clinical practice. “We don’t really have good data to base practice guidelines yet, so a call for a lot more research is needed,” he said. Great care needs to be taken so patients are not misinformed as to the strength of the evidence, especially when the information is used to guide decisions about prophylactic therapy, particularly surgery, he added.