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

David Quigley, Joshi 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 (Tom) Beer, Alan Ashworth, Eric J. Small, Felix Y. Feng

Research output: Contribution to journalArticle

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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 1 2017

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Prostatic Neoplasms
Recombinational DNA Repair
Mutation
DNA Repair
Biopsy
DNA
Ovarian Neoplasms
Poly(ADP-ribose) Polymerase Inhibitors
Breast Neoplasms
olaparib
Genes
talazoparib
Neoplasms

ASJC Scopus subject areas

  • Oncology

Cite this

Analysis of circulating cell-free DnA identifies multiclonal heterogeneity of BRCA2 reversion mutations associated with resistance to PARP inhibitors. / Quigley, David; Alumkal, Joshi; Wyatt, Alexander W.; Kothari, Vishal; Foye, Adam; Lloyd, Paul; Aggarwal, Rahul; Kim, Won; Lu, Eric; Schwartzman, Jacob; Beja, Kevin; Annala, Matti; Das, Rajdeep; Diolaiti, Morgan; Pritchard, Colin; Thomas, George; Tomlins, Scott; Knudsen, Karen; Lord, Christopher J.; Ryan, Charles; Youngren, Jack; Beer, Tomasz (Tom); Ashworth, Alan; Small, Eric J.; Feng, Felix Y.

In: Cancer Discovery, Vol. 7, No. 9, 01.09.2017, p. 999-1005.

Research output: Contribution to journalArticle

Quigley, D, Alumkal, J, 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, TT, Ashworth, A, Small, EJ & Feng, FY 2017, 'Analysis of circulating cell-free DnA identifies multiclonal heterogeneity of BRCA2 reversion mutations associated with resistance to PARP inhibitors', Cancer Discovery, vol. 7, no. 9, pp. 999-1005. https://doi.org/10.1158/2159-8290.CD-17-0146
Quigley, David ; Alumkal, Joshi ; Wyatt, Alexander W. ; Kothari, Vishal ; Foye, Adam ; Lloyd, Paul ; Aggarwal, Rahul ; Kim, Won ; Lu, Eric ; Schwartzman, Jacob ; Beja, Kevin ; Annala, Matti ; Das, Rajdeep ; Diolaiti, Morgan ; Pritchard, Colin ; Thomas, George ; Tomlins, Scott ; Knudsen, Karen ; Lord, Christopher J. ; Ryan, Charles ; Youngren, Jack ; Beer, Tomasz (Tom) ; Ashworth, Alan ; Small, Eric J. ; Feng, Felix Y. / Analysis of circulating cell-free DnA identifies multiclonal heterogeneity of BRCA2 reversion mutations associated with resistance to PARP inhibitors. In: Cancer Discovery. 2017 ; Vol. 7, No. 9. pp. 999-1005.
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AU - Quigley, David

AU - Alumkal, Joshi

AU - Wyatt, Alexander W.

AU - Kothari, Vishal

AU - Foye, Adam

AU - Lloyd, Paul

AU - Aggarwal, Rahul

AU - Kim, Won

AU - Lu, Eric

AU - Schwartzman, Jacob

AU - Beja, Kevin

AU - Annala, Matti

AU - Das, Rajdeep

AU - Diolaiti, Morgan

AU - Pritchard, Colin

AU - Thomas, George

AU - Tomlins, Scott

AU - Knudsen, Karen

AU - Lord, Christopher J.

AU - Ryan, Charles

AU - Youngren, Jack

AU - Beer, Tomasz (Tom)

AU - Ashworth, Alan

AU - Small, Eric J.

AU - Feng, Felix Y.

PY - 2017/9/1

Y1 - 2017/9/1

N2 - 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.

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