Genomic Analysis of Circulating Tumor DNA in 3,334 Patients with Advanced Prostate Cancer Identifies Targetable BRCA Alterations and AR Resistance Mechanisms.

Autor:	Tukachinsky H; Foundation Medicine Inc., Cambridge, Massachusetts., Madison RW; Foundation Medicine Inc., Cambridge, Massachusetts., Chung JH; Foundation Medicine Inc., Cambridge, Massachusetts., Gjoerup OV; Foundation Medicine Inc., Cambridge, Massachusetts., Severson EA; Foundation Medicine Inc., Cambridge, Massachusetts., Dennis L; Foundation Medicine Inc., Cambridge, Massachusetts., Fendler BJ; Foundation Medicine Inc., Cambridge, Massachusetts., Morley S; Foundation Medicine Inc., Cambridge, Massachusetts., Zhong L; Foundation Medicine Inc., Cambridge, Massachusetts., Graf RP; Foundation Medicine Inc., Cambridge, Massachusetts., Ross JS; Foundation Medicine Inc., Cambridge, Massachusetts.; Upstate Medical University, Syracuse, New York., Alexander BM; Foundation Medicine Inc., Cambridge, Massachusetts., Abida W; Memorial Sloan Kettering Cancer Center, New York, New York., Chowdhury S; Guy's, King's, and St. Thomas' Hospital, London, England, United Kingdom., Ryan CJ; University of Minnesota Medical School, Minneapolis, Minnesota., Fizazi K; Institut Gustave Roussy, Villejuif, France., Golsorkhi T; Clovis Oncology, Boulder, Colorado., Watkins SP; Clovis Oncology, Boulder, Colorado., Simmons A; Clovis Oncology, Boulder, Colorado., Loehr A; Clovis Oncology, Boulder, Colorado., Venstrom JM; Foundation Medicine Inc., Cambridge, Massachusetts., Oxnard GR; Foundation Medicine Inc., Cambridge, Massachusetts. goxnard@foundationmedicine.com.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2021 Jun 01; Vol. 27 (11), pp. 3094-3105. Date of Electronic Publication: 2021 Feb 08.
DOI:	10.1158/1078-0432.CCR-20-4805
Abstrakt:	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 (GA) 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 GAs detected in ctDNA and assessed concordance with tissue-based CGP. Results: A total of 3,129 patients (94%) had detectable ctDNA with a median ctDNA fraction of 7.5%; BRCA1/2 was mutated in 295 (8.8%). In concordance analysis, 72 of 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 (e.g., in ATM and CHEK2 ). Potential androgen receptor resistance alterations were detected in 940 of 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. See related commentary by Hawkey and Armstrong, p. 2961 . (©2021 American Association for Cancer Research.)
Databáze:	MEDLINE
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