Identification of somatically acquired BRCA1/2 mutations by cfDNA analysis in patients with metastatic breast cancer

PURPOSE: Plasma genotyping may identify mutations in potentially "actionable" cancer genes, such as BRCA1/2, but their clinical significance is not well defined. We evaluated the characteristics of somatically acquired BRCA1/2 mutations in patients with MBC. METHODS: Patients with MBC undergoing routine cell-free DNA (cfDNA) next generation sequencing (73 gene panel) before starting a new therapy were included. Somatic BRCA1/2 mutations were classified as known germline-pathogenic mutations or novel variants, and linked to clinicopathological characteristics. The effect of the PARP inhibitor olaparib was assessed in vitro, using cultured circulating tumor cells (CTCs) from a patient with a somatically acquired BRCA1 mutation and a second patient with an acquired BRCA2 mutation. RESULTS: Among 215 MBC patients, 29 (13.5%) had somatic cfDNA BRCA1/2 mutations (nine (4%) known germline-pathogenic and rest (9%) novel variants). Known germline-pathogenic BRCA1/2 mutations were common in younger patients (p=0.008), those with triple-negative disease (p=0.022), and they were more likely to be protein-truncating alterations and be associated with TP53 mutations. Functional analysis of a CTC culture harboring a somatic BRCA1-mutation demonstrated high sensitivity to PARP inhibition, while another CTC culture harboring a somatic BRCA2 mutation showed no differential sensitivity. Across the entire cohort, APOBEC mutational signatures (COSMIC Signatures 2 and 13) and the "BRCA" mutational signature (COSMIC Signature 3) were present in BRCA1/2 mutant and wild-type cases, demonstrating the high mutational burden associated with advanced MBC. CONCLUSION: Somatic BRCA1/2 mutations are readily detectable in MBC by cfDNA analysis, and may be present as both known germline-pathogenic and novel variants.