BRCA 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 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 01, 2019
- Source ID
- 10.1158/2159-8290.cd-18-0715
Entities
People
- Amit M. Oza
- Ana Oaknin
- Anna V. Tinker
- Carmen Say
- Clare L. Scott
- David M. O'malley
- Elaina Mann
- Elena Helman
- Elizabeth M Swisher
- Gottfried E. Konecny
- Heidi Giordano
- Iain A McNeish
- Isabelle Ray-coquard
- James D Brenton
- James X. Sun
- Jeffrey D. Isaacson
- Kevin K. Lin
- Lan-thanh Vo
- Lara Maloney
- Marc R. Radke
- Maria I. Harrell
- Robert L Coleman
- Scott H Kaufmann
- Setsuko K. Chambers
- Thomas C. Harding
Organizations
- BC Cancer Agency
- Clovis Oncology
- Foundation Medicine
- Imperial College London
- Mayo Clinic
- Ohio State University
- United States Department of Defense
- University Health Network
- University of Arizona
- University of California, Los Angeles
- University of Cambridge
- University of Texas at Austin
- University of Washington
- Vall d'Hebron Hospital Universitari
- WEHI