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

Research output: Contribution to journalArticlepeer-review

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 languageEnglish (US)
Pages (from-to)3094-3105
Number of pages12
JournalClinical cancer research : an official journal of the American Association for Cancer Research
Volume27
Issue number11
Early online dateFeb 8 2021
DOIs
StatePublished - 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.

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