Abstract
<div>AbstractPurpose:<p>Plasma genotyping may identify mutations in potentially “actionable” cancer genes, such as <i>BRCA1/2</i>, but their clinical significance is not well-defined. We evaluated the characteristics of somatically acquired <i>BRCA1/2</i> mutations in patients with metastatic breast cancer (MBC).</p>Experimental Design:<p>Patients with MBC undergoing routine cell-free DNA (cfDNA) next-generation sequencing (73-gene panel) before starting a new therapy were included. Somatic <i>BRCA1/2</i> 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 <i>in vitro</i>, using cultured circulating tumor cells (CTCs) from a patient with a somatically acquired <i>BRCA1</i> mutation and a second patient with an acquired <i>BRCA2</i> mutation.</p>Results:<p>Among 215 patients with MBC, 29 (13.5%) had somatic cfDNA <i>BRCA1/2</i> mutations [nine (4%) known germline pathogenic and rest (9%) novel variants]. Known germline pathogenic <i>BRCA1/2</i> mutations were common in younger patients (<i>P</i> = 0.008), those with triple-negative disease (<i>P</i> = 0.022), and they were more likely to be protein-truncating alterations and be associated with <i>TP53</i> mutations. Functional analysis of a CTC culture harboring a somatic <i>BRCA1</i> mutation demonstrated high sensitivity to PARP inhibition, while another CTC culture harboring a somatic <i>BRCA2</i> 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 <i>BRCA1/2-</i>mutant and wild-type cases, demonstrating the high mutational burden associated with advanced MBC.</p>Conclusions:<p>Somatic <i>BRCA1/2</i> mutations are readily detectable in MBC by cfDNA analysis, and may be present as both known germline pathogenic and novel variants.</p></div>
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