Analysis of circulating cell-free DnA identifies multiclonal heterogeneity of BRCA2 reversion mutations associated with resistance to PARP inhibitors

David Quigley, Joshi J. Alumkal, Alexander W. Wyatt, Vishal Kothari, Adam Foye, Paul Lloyd, Rahul Aggarwal, Won Kim, Eric Lu, Jacob Schwartzman, Kevin Beja, Matti Annala, Rajdeep Das, Morgan Diolaiti, Colin Pritchard, George Thomas, Scott Tomlins, Karen Knudsen, Christopher J. Lord, Charles RyanJack Youngren, Tomasz M. Beer, Alan Ashworth, Eric J. Small, Felix Y. Feng

Research output: Contribution to journalArticle

78 Scopus citations

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-defi cient 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.

Original languageEnglish (US)
Pages (from-to)999-1005
Number of pages7
JournalCancer discovery
Volume7
Issue number9
DOIs
StatePublished - Sep 2017

ASJC Scopus subject areas

  • Oncology

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    Quigley, D., Alumkal, J. J., Wyatt, A. W., 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, C. J., ... Feng, F. Y. (2017). Analysis of circulating cell-free DnA identifies multiclonal heterogeneity of BRCA2 reversion mutations associated with resistance to PARP inhibitors. Cancer discovery, 7(9), 999-1005. https://doi.org/10.1158/2159-8290.CD-17-0146