Multigene testing for hereditary breast and ovarian cancer has increased the detection predisposition genes beyond BRCA1 and BRCA2, according to study findings presented at the San Antonio Breast Cancer Symposium on December 7, 2018. 

Researchers retrospectively sequenced the following mutations in 2,806 individuals undergoing hereditary breast and ovarian cancer testing at their institution between March 2016 and August 2017: BARD1, BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, TP53, MRE11A, RAD50, NBN, FAM175A, ATM, PALB2, STK11, MEN1, PTEN, CDH1, MUTYH, CHEK2, BLM, XRCC2, EPCAM, MLH1, MSH6, PMS2, and MSH2.

Among the cohort, 11.9% had a detectable germline pathogenic alteration. BRCA1 and BRCA2 were the most common detections (3.35% and 2.92%, respectively). Other common germline alterations included CHEK2 (2.5%), ATM (1.1%), PALB2 (0.5%), and TP53 (0.1%); 1% of patients had germline alterations that contribute to ovarian cancer risk (BRIP, RAD51C, or RAD51D). 

The median age at onset of breast cancer in patients with CHEK2, ATM, or PALB2 mutations was 47, 53, and 39 years, respectively; however, the age of breast cancer diagnosis in those with germline TP53 alterations was significantly younger (33 years) than patients with CHEK2, ATM, or PALB2 mutations. 

Among patients with CHEK2, PALB2, or TP53 mutations, researchers detected in situ carcinomas in 9%, 11%, and 11% of patients, respectively. Researchers observed T3 or higher tumors among 33% of patients with PALB2, 22% with TP53, 13% with CHEK2, and 12% with ATM mutations.  

Forty to 60% of patients with those four mutations had negative nodal status. More than half of patients with CHEK2, ATM, or PALB2 mutations had luminal tumors compared to 22% of patients with TP53 alterations. 

“Almost half of the pathogenic mutations detected are alterations in genes other than BRCA1 and BRCA2,” the researchers concluded. “CHEK2 mutations are by far the most prevalent, followed by ATM, PALB2, and TP53.”