Analysis of Circulating Cell-Free DNA Identifies Multiclonal Heterogeneity of BRCA2 Reversion Mutations Associated with Resistance to PARP Inhibitors.
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Date
2017-09-01ICR Author
Author
Quigley, D
Alumkal, JJ
Wyatt, AW
Kothari, V
Foye, A
Lloyd, P
Aggarwal, R
Kim, W
Lu, E
Schwartzman, J
Beja, K
Annala, M
Das, R
Diolaiti, M
Pritchard, C
Thomas, G
Tomlins, S
Knudsen, K
Lord, CJ
Ryan, C
Youngren, J
Beer, TM
Ashworth, A
Small, EJ
Feng, FY
Type
Journal Article
Metadata
Show full item recordAbstract
Approximately 20% of metastatic prostate cancers harbor mutations in genes required for DNA repair by homologous recombination repair (HRR) such as BRCA2 HRR defects confer synthetic lethality to PARP inhibitors (PARPi) such as olaparib and talazoparib. In ovarian or breast cancers, olaparib resistance has been associated with HRR restoration, including by BRCA2 mutation reversion. Whether similar mechanisms operate in prostate cancer, and could be detected in liquid biopsies, is unclear. Here, we identify BRCA2 reversion mutations associated with olaparib and talazoparib resistance in patients with prostate cancer. Analysis of circulating cell-free DNA (cfDNA) reveals reversion mutation heterogeneity not discernable from a single solid-tumor biopsy and potentially allows monitoring for the emergence of PARPi resistance.Significance: The mechanisms of clinical resistance to PARPi in DNA repair-deficient prostate cancer have not been described. Here, we show BRCA2 reversion mutations in patients with prostate cancer with metastatic disease who developed resistance to talazoparib and olaparib. Furthermore, we show that PARPi resistance is highly multiclonal and that cfDNA allows monitoring for PARPi resistance. Cancer Discov; 7(9); 999-1005. ©2017 AACR.See related commentary by Domchek, p. 937See related article by Kondrashova et al., p. 984See related article by Goodall et al., p. 1006This article is highlighted in the In This Issue feature, p. 920.
Collections
Subject
Humans
Prostatic Neoplasms
Piperazines
Phthalazines
BRCA2 Protein
Antineoplastic Agents
Drug Resistance, Neoplasm
Germ-Line Mutation
Male
DNA Copy Number Variations
Poly(ADP-ribose) Polymerase Inhibitors
Whole Exome Sequencing
Cell-Free Nucleic Acids
Research team
Gene Function
Language
eng
Date accepted
2017-04-26
License start date
2017-09
Citation
Cancer discovery, 2017, 7 (9), pp. 999 - 1005
Publisher
AMER ASSOC CANCER RESEARCH