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

Kevin K. Lin, Maria I. Harrell, Amit M. Oza, Ana Oaknin, Isabelle Ray-Coquard, Anna V. Tinker, Elena Helman, Marc R. Radke, Carmen Say, Lan Thanh Vo, Elaina Mann, Jeffrey D. Isaacson, Lara Maloney, David M. O'Malley, Setsuko K. Chambers, Scott H. Kaufmann, Clare L. Scott, Gottfried E. Konecny, Robert L. Coleman, James X. SunHeidi Giordano, James D. Brenton, Thomas C. Harding, Iain A. McNeish, Elizabeth M. Swisher

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

A key resistance mechanism to platinum-based chemotherapies and PARP inhibitors in BRCA-mutant cancers is the acquisition of BRCA reversion mutations that restore protein function. To estimate the prevalence of BRCA 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 BRCA mutations treated with the PARP inhibitor rucaparib. BRCA 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 (P = 0.049). Patients without BRCA 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; P < 0.0001). To study acquired resistance, we sequenced 78 postprogression cfDNA, identifying eight additional patients with BRCA reversion mutations not found in pretreatment cfDNA. SIGNIFICANCE: BRCA 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 BRCA reversion mutations, highlighting the ability to capture multiclonal heterogeneity.This article is highlighted in the In This Issue feature, p. 151.

Original languageEnglish (US)
Pages (from-to)210-219
Number of pages10
JournalCancer discovery
Volume9
Issue number2
DOIs
StatePublished - Feb 1 2019

ASJC Scopus subject areas

  • Oncology

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    Lin, K. K., Harrell, M. I., Oza, A. M., Oaknin, A., Ray-Coquard, I., Tinker, A. V., Helman, E., Radke, M. R., Say, C., Vo, L. T., Mann, E., Isaacson, J. D., Maloney, L., O'Malley, D. M., Chambers, S. K., Kaufmann, S. H., Scott, C. L., Konecny, G. E., Coleman, R. L., ... Swisher, E. M. (2019). BRCA Reversion Mutations in Circulating Tumor DNA Predict Primary and Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma. Cancer discovery, 9(2), 210-219. https://doi.org/10.1158/2159-8290.CD-18-0715