Genomic analysis of circulating tumor DNA in 3,334 patients with advanced prostate cancer identifies targetable BRCA alterations and AR resistance mechanisms

Hanna Tukachinsky; Russell W. Madison; Jon H. Chung; Ole V. Gjoerup; Eric A. Severson; Lucas Dennis; Bernard J. Fendler; Samantha Morley; Lei Zhong; Ryon P. Graf; Jeffrey S. Ross; Brian M. Alexander; Wassim Abida; Simon Chowdhury; Charles J. Ryan; Karim Fizazi; Tony Golsorkhi; Simon P. Watkins; Andrew Simmons; Andrea Loehr; Jeffrey M. Venstrom; Geoffrey R. Oxnard

doi:10.1158/1078-0432.CCR-20-4805

Genomic analysis of circulating tumor DNA in 3,334 patients with advanced prostate cancer identifies targetable BRCA alterations and AR resistance mechanisms

Hanna Tukachinsky, Russell W. Madison, Jon H. Chung, Ole V. Gjoerup, Eric A. Severson, Lucas Dennis, Bernard J. Fendler, Samantha Morley, Lei Zhong, Ryon P. Graf, Jeffrey S. Ross, Brian M. Alexander, Wassim Abida, Simon Chowdhury, Charles J. Ryan, Karim Fizazi, Tony Golsorkhi, Simon P. Watkins, Andrew Simmons, Andrea LoehrJeffrey M. Venstrom, Geoffrey R. Oxnard

Medicine - Hematology, Oncology, Transplant

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

117 Scopus citations

Abstract

PURPOSE: Comprehensive genomic profiling (CGP) is of increasing value for patients with metastatic castration-resistant prostate cancer (mCRPC). mCRPC tends to metastasize to bone, making tissue biopsies challenging to obtain. We hypothesized CGP of cell-free circulating tumor DNA (ctDNA) could offer a minimally invasive alternative to detect targetable genomic alterations that inform clinical care.

EXPERIMENTAL DESIGN: Using plasma from 3,334 patients with mCRPC (including 1,674 screening samples from TRITON2/3), we evaluated the landscape of genomic alterations detected in ctDNA and assessed concordance with tissue based CGP.

RESULTS: 3,129 patients (94%) had detectable ctDNA with a median ctDNA fraction of 7.5%; BRCA1/2 were mutated in 295 (8.8%). In concordance analysis, 72/837 patients had BRCA1/2 mutations detected in tissue, 67 (93%) of which were also identified using ctDNA, including 100% of predicted germline variants. ctDNA harbored some BRCA1/2 alterations not identified by tissue testing, and ctDNA was enriched in therapy resistance alterations, as well as possible clonal hematopoiesis mutations (for example in ATM and CHEK2). Potential AR resistance alterations were detected in 940/2,213 patients (42%), including amplifications, polyclonal and compound mutations, rearrangements, and novel deletions in exon 8.

CONCLUSIONS: Genomic analysis of ctDNA from patients with mCRPC recapitulates the genomic landscape detected in tissue biopsies, with a high level of agreement in detection of BRCA1/2 mutations but more acquired resistance alterations detected in ctDNA. CGP of ctDNA is a compelling clinical complement to tissue CGP, with reflex to tissue CGP if negative for actionable variants.

Original language	English (US)
Pages (from-to)	3094-3105
Number of pages	12
Journal	Clinical cancer research : an official journal of the American Association for Cancer Research
Volume	27
Issue number	11
Early online date	Feb 8 2021
DOIs	https://doi.org/10.1158/1078-0432.CCR-20-4805 https://doi.org/10.1158/1078-0432.CCR-20-4805
State	Published - Jun 1 2021

Bibliographical note

Funding Information:
The TRITON2 and TRITON3 trials were funded by Clovis Oncology, Inc. We thank and acknowledge all patients and their families and caregivers who are participating in the trials, along with the investigators. We thank Brady Forcier and Jeff Lee for help with data analysis. We thank Neeru Bhardwaj for critical reading and helpful discussions of the article.

Publisher Copyright:
© 2021 American Association for Cancer Research.

PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Publisher link

Find It

Find It at U of M Libraries

Cite this

Tukachinsky, H., Madison, R. W., Chung, J. H., Gjoerup, O. V., Severson, E. A., Dennis, L., Fendler, B. J., Morley, S., Zhong, L., Graf, R. P., Ross, J. S., Alexander, B. M., Abida, W., Chowdhury, S., Ryan, C. J., Fizazi, K., Golsorkhi, T., Watkins, S. P., Simmons, A., ... Oxnard, G. R. (2021). Genomic analysis of circulating tumor DNA in 3,334 patients with advanced prostate cancer identifies targetable BRCA alterations and AR resistance mechanisms. Clinical cancer research : an official journal of the American Association for Cancer Research, 27(11), 3094-3105. https://doi.org/10.1158/1078-0432.CCR-20-4805, https://doi.org/10.1158/1078-0432.CCR-20-4805

Genomic analysis of circulating tumor DNA in 3,334 patients with advanced prostate cancer identifies targetable BRCA alterations and AR resistance mechanisms. / Tukachinsky, Hanna; Madison, Russell W.; Chung, Jon H. et al.
In: Clinical cancer research : an official journal of the American Association for Cancer Research, Vol. 27, No. 11, 01.06.2021, p. 3094-3105.

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

Tukachinsky, H, Madison, RW, Chung, JH, Gjoerup, OV, Severson, EA, Dennis, L, Fendler, BJ, Morley, S, Zhong, L, Graf, RP, Ross, JS, Alexander, BM, Abida, W, Chowdhury, S, Ryan, CJ, Fizazi, K, Golsorkhi, T, Watkins, SP, Simmons, A, Loehr, A, Venstrom, JM & Oxnard, GR 2021, 'Genomic analysis of circulating tumor DNA in 3,334 patients with advanced prostate cancer identifies targetable BRCA alterations and AR resistance mechanisms', Clinical cancer research : an official journal of the American Association for Cancer Research, vol. 27, no. 11, pp. 3094-3105. https://doi.org/10.1158/1078-0432.CCR-20-4805, https://doi.org/10.1158/1078-0432.CCR-20-4805

Tukachinsky H, Madison RW, Chung JH, Gjoerup OV, Severson EA, Dennis L et al. Genomic analysis of circulating tumor DNA in 3,334 patients with advanced prostate cancer identifies targetable BRCA alterations and AR resistance mechanisms. Clinical cancer research : an official journal of the American Association for Cancer Research. 2021 Jun 1;27(11):3094-3105. Epub 2021 Feb 8. doi: 10.1158/1078-0432.CCR-20-4805, 10.1158/1078-0432.CCR-20-4805

@article{63aa1f96dc21409ead619aaaeafae77f,

title = "Genomic analysis of circulating tumor DNA in 3,334 patients with advanced prostate cancer identifies targetable BRCA alterations and AR resistance mechanisms",

abstract = "PURPOSE: Comprehensive genomic profiling (CGP) is of increasing value for patients with metastatic castration-resistant prostate cancer (mCRPC). mCRPC tends to metastasize to bone, making tissue biopsies challenging to obtain. We hypothesized CGP of cell-free circulating tumor DNA (ctDNA) could offer a minimally invasive alternative to detect targetable genomic alterations that inform clinical care.EXPERIMENTAL DESIGN: Using plasma from 3,334 patients with mCRPC (including 1,674 screening samples from TRITON2/3), we evaluated the landscape of genomic alterations detected in ctDNA and assessed concordance with tissue based CGP.RESULTS: 3,129 patients (94%) had detectable ctDNA with a median ctDNA fraction of 7.5%; BRCA1/2 were mutated in 295 (8.8%). In concordance analysis, 72/837 patients had BRCA1/2 mutations detected in tissue, 67 (93%) of which were also identified using ctDNA, including 100% of predicted germline variants. ctDNA harbored some BRCA1/2 alterations not identified by tissue testing, and ctDNA was enriched in therapy resistance alterations, as well as possible clonal hematopoiesis mutations (for example in ATM and CHEK2). Potential AR resistance alterations were detected in 940/2,213 patients (42%), including amplifications, polyclonal and compound mutations, rearrangements, and novel deletions in exon 8.CONCLUSIONS: Genomic analysis of ctDNA from patients with mCRPC recapitulates the genomic landscape detected in tissue biopsies, with a high level of agreement in detection of BRCA1/2 mutations but more acquired resistance alterations detected in ctDNA. CGP of ctDNA is a compelling clinical complement to tissue CGP, with reflex to tissue CGP if negative for actionable variants.",

author = "Hanna Tukachinsky and Madison, {Russell W.} and Chung, {Jon H.} and Gjoerup, {Ole V.} and Severson, {Eric A.} and Lucas Dennis and Fendler, {Bernard J.} and Samantha Morley and Lei Zhong and Graf, {Ryon P.} and Ross, {Jeffrey S.} and Alexander, {Brian M.} and Wassim Abida and Simon Chowdhury and Ryan, {Charles J.} and Karim Fizazi and Tony Golsorkhi and Watkins, {Simon P.} and Andrew Simmons and Andrea Loehr and Venstrom, {Jeffrey M.} and Oxnard, {Geoffrey R.}",

note = "Funding Information: The TRITON2 and TRITON3 trials were funded by Clovis Oncology, Inc. We thank and acknowledge all patients and their families and caregivers who are participating in the trials, along with the investigators. We thank Brady Forcier and Jeff Lee for help with data analysis. We thank Neeru Bhardwaj for critical reading and helpful discussions of the article. Publisher Copyright: {\textcopyright} 2021 American Association for Cancer Research.",

year = "2021",

month = jun,

day = "1",

doi = "10.1158/1078-0432.CCR-20-4805",

language = "English (US)",

volume = "27",

pages = "3094--3105",

journal = "Clinical cancer research : an official journal of the American Association for Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

number = "11",

}

TY - JOUR

T1 - Genomic analysis of circulating tumor DNA in 3,334 patients with advanced prostate cancer identifies targetable BRCA alterations and AR resistance mechanisms

AU - Tukachinsky, Hanna

AU - Madison, Russell W.

AU - Chung, Jon H.

AU - Gjoerup, Ole V.

AU - Severson, Eric A.

AU - Dennis, Lucas

AU - Fendler, Bernard J.

AU - Morley, Samantha

AU - Zhong, Lei

AU - Graf, Ryon P.

AU - Ross, Jeffrey S.

AU - Alexander, Brian M.

AU - Abida, Wassim

AU - Chowdhury, Simon

AU - Ryan, Charles J.

AU - Fizazi, Karim

AU - Golsorkhi, Tony

AU - Watkins, Simon P.

AU - Simmons, Andrew

AU - Loehr, Andrea

AU - Venstrom, Jeffrey M.

AU - Oxnard, Geoffrey R.

N1 - Funding Information: The TRITON2 and TRITON3 trials were funded by Clovis Oncology, Inc. We thank and acknowledge all patients and their families and caregivers who are participating in the trials, along with the investigators. We thank Brady Forcier and Jeff Lee for help with data analysis. We thank Neeru Bhardwaj for critical reading and helpful discussions of the article. Publisher Copyright: © 2021 American Association for Cancer Research.

PY - 2021/6/1

Y1 - 2021/6/1

N2 - PURPOSE: Comprehensive genomic profiling (CGP) is of increasing value for patients with metastatic castration-resistant prostate cancer (mCRPC). mCRPC tends to metastasize to bone, making tissue biopsies challenging to obtain. We hypothesized CGP of cell-free circulating tumor DNA (ctDNA) could offer a minimally invasive alternative to detect targetable genomic alterations that inform clinical care.EXPERIMENTAL DESIGN: Using plasma from 3,334 patients with mCRPC (including 1,674 screening samples from TRITON2/3), we evaluated the landscape of genomic alterations detected in ctDNA and assessed concordance with tissue based CGP.RESULTS: 3,129 patients (94%) had detectable ctDNA with a median ctDNA fraction of 7.5%; BRCA1/2 were mutated in 295 (8.8%). In concordance analysis, 72/837 patients had BRCA1/2 mutations detected in tissue, 67 (93%) of which were also identified using ctDNA, including 100% of predicted germline variants. ctDNA harbored some BRCA1/2 alterations not identified by tissue testing, and ctDNA was enriched in therapy resistance alterations, as well as possible clonal hematopoiesis mutations (for example in ATM and CHEK2). Potential AR resistance alterations were detected in 940/2,213 patients (42%), including amplifications, polyclonal and compound mutations, rearrangements, and novel deletions in exon 8.CONCLUSIONS: Genomic analysis of ctDNA from patients with mCRPC recapitulates the genomic landscape detected in tissue biopsies, with a high level of agreement in detection of BRCA1/2 mutations but more acquired resistance alterations detected in ctDNA. CGP of ctDNA is a compelling clinical complement to tissue CGP, with reflex to tissue CGP if negative for actionable variants.

AB - PURPOSE: Comprehensive genomic profiling (CGP) is of increasing value for patients with metastatic castration-resistant prostate cancer (mCRPC). mCRPC tends to metastasize to bone, making tissue biopsies challenging to obtain. We hypothesized CGP of cell-free circulating tumor DNA (ctDNA) could offer a minimally invasive alternative to detect targetable genomic alterations that inform clinical care.EXPERIMENTAL DESIGN: Using plasma from 3,334 patients with mCRPC (including 1,674 screening samples from TRITON2/3), we evaluated the landscape of genomic alterations detected in ctDNA and assessed concordance with tissue based CGP.RESULTS: 3,129 patients (94%) had detectable ctDNA with a median ctDNA fraction of 7.5%; BRCA1/2 were mutated in 295 (8.8%). In concordance analysis, 72/837 patients had BRCA1/2 mutations detected in tissue, 67 (93%) of which were also identified using ctDNA, including 100% of predicted germline variants. ctDNA harbored some BRCA1/2 alterations not identified by tissue testing, and ctDNA was enriched in therapy resistance alterations, as well as possible clonal hematopoiesis mutations (for example in ATM and CHEK2). Potential AR resistance alterations were detected in 940/2,213 patients (42%), including amplifications, polyclonal and compound mutations, rearrangements, and novel deletions in exon 8.CONCLUSIONS: Genomic analysis of ctDNA from patients with mCRPC recapitulates the genomic landscape detected in tissue biopsies, with a high level of agreement in detection of BRCA1/2 mutations but more acquired resistance alterations detected in ctDNA. CGP of ctDNA is a compelling clinical complement to tissue CGP, with reflex to tissue CGP if negative for actionable variants.

UR - http://www.scopus.com/inward/record.url?scp=85102840887&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85102840887&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-20-4805

DO - 10.1158/1078-0432.CCR-20-4805

M3 - Article

C2 - 33558422

SN - 1078-0432

VL - 27

SP - 3094

EP - 3105

JO - Clinical cancer research : an official journal of the American Association for Cancer Research

JF - Clinical cancer research : an official journal of the American Association for Cancer Research

IS - 11

ER -

Genomic analysis of circulating tumor DNA in 3,334 patients with advanced prostate cancer identifies targetable BRCA alterations and AR resistance mechanisms

Abstract

Bibliographical note

PubMed: MeSH publication types

UN SDGs

Publisher link

Find It

Other files and links

Fingerprint

Cite this