<i>BRCA</i> Reversion Mutations in Circulating Tumor DNA Predict Primary and Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma

Abstract

A key resistance mechanism to platinum-based chemotherapies and PARP inhibitors in <i>BRCA</i>-mutant cancers is the acquisition of <i>BRCA</i> reversion mutations that restore protein function. To estimate the prevalence of <i>BRCA</i> reversion mutations in high-grade ovarian carcinoma (HGOC), we performed targeted next-generation sequencing of circulating cell-free DNA (cfDNA) extracted from pretreatment and postprogression plasma in patients with deleterious germline or somatic <i>BRCA</i> mutations treated with the PARP inhibitor rucaparib. <i>BRCA</i> reversion mutations were identified in pretreatment cfDNA from 18% (2/11) of platinum-refractory and 13% (5/38) of platinum-resistant cancers, compared with 2% (1/48) of platinum-sensitive cancers (<i>P</i> = 0.049). Patients without <i>BRCA</i> reversion mutations detected in pretreatment cfDNA had significantly longer rucaparib progression-free survival than those with reversion mutations (median, 9.0 vs. 1.8 months; HR, 0.12; <i>P</i> < 0.0001). To study acquired resistance, we sequenced 78 postprogression cfDNA, identifying eight additional patients with <i>BRCA</i> reversion mutations not found in pretreatment cfDNA. SIGNIFICANCE: <i>BRCA</i> reversion mutations are detected in cfDNA from platinum-resistant or platinum-refractory HGOC and are associated with decreased clinical benefit from rucaparib treatment. Sequencing of cfDNA can detect multiple <i>BRCA</i> reversion mutations, highlighting the ability to capture multiclonal heterogeneity.<i>This article is highlighted in the In This Issue feature, p. 151</i>.