Microsatellite Instability, Tumor Mutational Burden, and Response to Immune Checkpoint Blockade in Patients with Prostate Cancer.

Autor:	Lenis AT; Urology Section, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York., Ravichandran V; Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York., Brown S; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York., Alam SM; Urology Section, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York., Katims A; Urology Section, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York., Truong H; Urology Section, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York., Reisz PA; Urology Section, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York., Vasselman S; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York., Nweji B; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York., Autio KA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York., Morris MJ; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York., Slovin SF; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York., Rathkopf D; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York., Danila D; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York., Woo S; Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York., Vargas HA; Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York., Laudone VP; Urology Section, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York., Ehdaie B; Urology Section, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York., Reuter V; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York., Arcila M; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York., Berger MF; Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York., Viale A; Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York., Scher HI; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York., Schultz N; Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York., Gopalan A; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York., Donoghue MTA; Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York., Ostrovnaya I; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York., Stopsack KH; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York., Solit DB; Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York., Abida W; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2024 Sep 03; Vol. 30 (17), pp. 3894-3903.
DOI:	10.1158/1078-0432.CCR-23-3403
Abstrakt:	Purpose: Patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) and high tumor mutational burden (TMB-H) prostate cancers are candidates for pembrolizumab. We define the genomic features, clinical course, and response to immune checkpoint blockade (ICB) in patients with MSI-H/dMMR and TMB-H prostate cancers without MSI [TMB-H/microsatellite stable (MSS)]. Experimental Design: We sequenced 3,244 tumors from 2,257 patients with prostate cancer. MSI-H/dMMR prostate cancer was defined as an MSIsensor score ≥10 or MSIsensor score ≥3 and <10 with a deleterious MMR alteration. TMB-H was defined as ≥10 mutations/megabase. PSA50 and RECIST responses were assigned. Overall survival and radiographic progression-free survival (rPFS) were compared using log-rank test. Results: Sixty-three (2.8%) men had MSI-H/dMMR, and 33 (1.5%) had TMB-H/MSS prostate cancers. Patients with MSI-H/dMMR and TMB-H/MSS tumors more commonly presented with grade group 5 and metastatic disease at diagnosis. MSI-H/dMMR tumors had higher TMB, indel, and neoantigen burden compared with TMB-H/MSS. Twenty-seven patients with MSI-H/dMMR and 8 patients with TMB-H/MSS tumors received ICB, none of whom harbored polymerase epsilon (polE) catalytic subunit mutations. About 45% of patients with MSI-H/dMMR had a RECIST response, and 65% had a PSA50 response. No patient with TMB-H/MSS had a RECIST response, and 50% had a PSA50 response. rPFS tended to be longer in patients with MSI-H/dMMR than in patients with TMB-H/MSS who received immunotherapy. Pronounced differences in genomics, TMB, or MSIsensor score were not detected between MSI-H/dMMR responders and nonresponders. Conclusions: MSI-H/dMMR prostate cancers have greater TMB, indel, and neoantigen burden than TMB-H/MSS prostate cancers, and these differences may contribute to profound and durable responses to ICB. (©2024 American Association for Cancer Research.)
Databáze:	MEDLINE
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