Mutation Rates in Cancer Susceptibility Genes in Patients With Breast Cancer With Multiple Primary Cancers.

Purpose: Women with breast cancer have a 4%-16% lifetime risk of a second primary cancer. Whether mutations in genes other than are enriched in patients with breast and another primary cancer over those with a single breast cancer (S-BC) is unknown.

Patients And Methods: We identified pathogenic germline mutations in 17 cancer susceptibility genes in patients with -negative breast cancer in 2 different cohorts: cohort 1, high-risk breast cancer program (multiple primary breast cancer [MP-BC], n = 551; S-BC, n = 449) and cohort 2, familial breast cancer research study (MP-BC, n = 340; S-BC, n = 1,464). Mutation rates in these 2 cohorts were compared with a control data set (Exome Aggregation Consortium [ExAC]).

Results: Overall, pathogenic mutation rates for autosomal, dominantly inherited genes were higher in patients with MP-BC versus S-BC in both cohorts (8.5% 4.9% [ = .02] and 7.1% 4.2% [ = .03]). There were differences in individual gene mutation rates between cohorts. In both cohorts, younger age at first breast cancer was associated with higher mutation rates; the age of non-breast cancers was unrelated to mutation rate. and mutations were significantly enriched in patients with MP-BC but not S-BC, whereas and mutations were significantly enriched in both groups compared with ExAC.

Conclusion: Mutation rates are at least 7% in all patients with mutation-negative MP-BC, regardless of age at diagnosis of breast cancer, with mutation rates up to 25% in patients with a first breast cancer diagnosed at age < 30 years. Our results suggest that all patients with breast cancer with a second primary cancer, regardless of age of onset, should undergo multigene panel testing.