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Cancer Discov. 2017 Sep;7(9):999-1005. doi: 10.1158/2159-8290.CD-17-0146. Epub 2017 Apr 27.

Analysis of Circulating Cell-Free DNA Identifies Multiclonal Heterogeneity of BRCA2 Reversion Mutations Associated with Resistance to PARP Inhibitors.

Author information

1
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, California.
2
Department of Epidemiology and Biostatistics, UCSF, San Francisco, California.
3
Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon.
4
Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon.
5
Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada.
6
Department of Radiation Oncology, UCSF, San Francisco, California.
7
Division of Hematology and Oncology, UCSF, San Francisco, California.
8
Institute of Biosciences and Medical Technology, University of Tampere, Tampere, Finland.
9
Department of Laboratory Medicine, University of Washington, Seattle, Washington.
10
Department of Pathology, Oregon Health & Science University, Portland, Oregon.
11
Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan.
12
Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
13
The CRUK Gene Function Laboratory and Breast Cancer Now Research Centre, The Institute of Cancer Research, London, United Kingdom.
14
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, California. Felix.Feng@ucsf.edu Eric.Small@ucsf.edu Alan.Ashworth@ucsf.edu.
15
Department of Medicine, UCSF, San Francisco, California.

Abstract

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.

PMID:
28450426
PMCID:
PMC5581695
DOI:
10.1158/2159-8290.CD-17-0146
[Indexed for MEDLINE]
Free PMC Article

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