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

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.

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.

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.

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.

Clinical cancer research : an official journal of the American Association for Cancer Research. 2021 Feb 08 [Epub ahead of print]

Hanna Tukachinsky, Russell W Madison, Jon H Chung, Ole 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 D Simmons, Andrea Loehr, Jeffrey M Venstrom, Geoffrey R Oxnard

Clinical Development, Foundation Medicine Inc., Clinical Development, Foundation Medicine, Inc., Clinical Development, Foundation Medicine., Foundation Medicine., Pathology, Foundation Medicine., Foundation Medicine Inc., Biomedical Informatics, Foundation Medicine, Inc., Pathology, Foundation Medicine, Inc., Medical, Foundation Medicine, Inc., Medicine, Memorial Sloan Kettering Cancer Center., Medical Oncology, Guy’s and St Thomas’., University of Minnesota Medical School., Department of Medical Oncology, Institut Gustave Roussy, University of Paris Sud., Clinical Development, Clovis Oncology, Inc., Clovis Oncology (United States)., Translational Medicine, Clovis Oncology, Inc., Foundation Medicine, Inc., Clinical Development, Foundation Medicine .

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