Reversion Mutations in Circulating Tumor DNA Predict Primary and Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma.

: A key resistance mechanism to platinum-based chemotherapies and PARP inhibitors in -mutant cancers is the acquisition of reversion mutations that restore protein function. To estimate the prevalence of 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 mutations treated with the PARP inhibitor rucaparib. 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 ( = 0.049). Patients without 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; < 0.0001). To study acquired resistance, we sequenced 78 postprogression cfDNA, identifying eight additional patients with reversion mutations not found in pretreatment cfDNA. SIGNIFICANCE: 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 reversion mutations, highlighting the ability to capture multiclonal heterogeneity..