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 Ryan; Jack Youngren; Tomasz M. Beer; Alan Ashworth; Eric J. Small; Felix Y. Feng

doi:10.1158/2159-8290.CD-17-0146

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

Pediatrics

Research output: Contribution to journal › Article › peer-review

213 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 language	English (US)
Pages (from-to)	999-1005
Number of pages	7
Journal	Cancer discovery
Volume	7
Issue number	9
DOIs	https://doi.org/10.1158/2159-8290.CD-17-0146
State	Published - Sep 2017

Bibliographical note

Funding Information:
This work was supported by a Stand Up To Cancer–Prostate Cancer Foundation–Prostate Dream Team Translational Cancer Research Grant (grant number: SU2C-AACR-DT0812). This research grant is made possible by the generous support of the Movember

Funding Information:
Foundation. Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. V. Kothari is supported by a Prostate Cancer Foundation Young Investigator Award. F.Y. Feng and E.J. Small acknowledge support from the Prostate Cancer Foundation. D. Quigley and A. Ashworth acknowledge support from the BRCA Foundation; A. Ashworth acknowledges support from the Breast Cancer Research Foundation and the Susan G Komen Foundation. K. Knudsen acknowledges funding from the Prostate Cancer Foundation.

Publisher Copyright:
© 2017 American Association for Cancer Research.

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10.1158/2159-8290.CD-17-0146

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581695

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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

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 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

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

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.",

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

note = "Funding Information: This work was supported by a Stand Up To Cancer–Prostate Cancer Foundation–Prostate Dream Team Translational Cancer Research Grant (grant number: SU2C-AACR-DT0812). This research grant is made possible by the generous support of the Movember Funding Information: Foundation. Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. V. Kothari is supported by a Prostate Cancer Foundation Young Investigator Award. F.Y. Feng and E.J. Small acknowledge support from the Prostate Cancer Foundation. D. Quigley and A. Ashworth acknowledge support from the BRCA Foundation; A. Ashworth acknowledges support from the Breast Cancer Research Foundation and the Susan G Komen Foundation. K. Knudsen acknowledges funding from the Prostate Cancer Foundation. Publisher Copyright: {\textcopyright} 2017 American Association for Cancer Research.",

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T1 - Analysis of circulating cell-free DnA identifies multiclonal heterogeneity of BRCA2 reversion mutations associated with resistance to PARP inhibitors

AU - Quigley, David

AU - Alumkal, Joshi J.

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 M.

AU - Ashworth, Alan

AU - Small, Eric J.

AU - Feng, Felix Y.

N1 - Funding Information: This work was supported by a Stand Up To Cancer–Prostate Cancer Foundation–Prostate Dream Team Translational Cancer Research Grant (grant number: SU2C-AACR-DT0812). This research grant is made possible by the generous support of the Movember Funding Information: Foundation. Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. V. Kothari is supported by a Prostate Cancer Foundation Young Investigator Award. F.Y. Feng and E.J. Small acknowledge support from the Prostate Cancer Foundation. D. Quigley and A. Ashworth acknowledge support from the BRCA Foundation; A. Ashworth acknowledges support from the Breast Cancer Research Foundation and the Susan G Komen Foundation. K. Knudsen acknowledges funding from the Prostate Cancer Foundation. Publisher Copyright: © 2017 American Association for Cancer Research.

PY - 2017/9

Y1 - 2017/9

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.

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

Abstract

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