Identification of Somatically Acquired Mutations by cfDNA Analysis in Patients with Metastatic Breast Cancer.

Purpose: Plasma genotyping may identify mutations in potentially "actionable" cancer genes, such as , but their clinical significance is not well-defined. We evaluated the characteristics of somatically acquired mutations in patients with metastatic breast cancer (MBC).

Experimental Design: Patients with MBC undergoing routine cell-free DNA (cfDNA) next-generation sequencing (73-gene panel) before starting a new therapy were included. Somatic mutations were classified as known germline pathogenic mutations or novel variants, and linked to clinicopathologic characteristics. The effect of the PARP inhibitor, olaparib, was assessed , using cultured circulating tumor cells (CTCs) from a patient with a somatically acquired mutation and a second patient with an acquired mutation.

Results: Among 215 patients with MBC, 29 (13.5%) had somatic cfDNA mutations [nine (4%) known germline pathogenic and rest (9%) novel variants]. Known germline pathogenic mutations were common in younger patients ( = 0.008), those with triple-negative disease ( = 0.022), and they were more likely to be protein-truncating alterations and be associated with mutations. Functional analysis of a CTC culture harboring a somatic mutation demonstrated high sensitivity to PARP inhibition, while another CTC culture harboring a somatic 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 mutant and wild-type cases, demonstrating the high mutational burden associated with advanced MBC.

Conclusions: Somatic mutations are readily detectable in MBC by cfDNA analysis, and may be present as both known germline pathogenic and novel variants.