Analysis of Circulating Cell-Free DNA Identifies Multiclonal Heterogeneity of <i>BRCA2</i> Reversion Mutations Associated with Resistance to PARP Inhibitors.
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Approximately 20% of metastatic prostate cancers harbor mutations in genes required for DNA repair by homologous recombination repair (HRR) such as <i>BRCA2</i> 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 <i>BRCA2</i> mutation reversion. Whether similar mechanisms operate in prostate cancer, and could be detected in liquid biopsies, is unclear. Here, we identify <i>BRCA2</i> 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.<b>Significance:</b> The mechanisms of clinical resistance to PARPi in DNA repair-deficient prostate cancer have not been described. Here, we show <i>BRCA2</i> 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. <i>Cancer Discov; 7(9); 999-1005. ©2017 AACR.</i><i>See related commentary by Domchek, p. 937</i><i>See related article by Kondrashova et al., p. 984</i><i>See related article by Goodall et al., p. 1006</i><i>This article is highlighted in the In This Issue feature, p. 920</i>.
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Drug Resistance, Neoplasm
DNA Copy Number Variations
Poly(ADP-ribose) Polymerase Inhibitors
Whole Exome Sequencing
Cell-Free Nucleic Acids
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Cancer discovery, 2017, 7 (9), pp. 999 - 1005