Synapse - Microsatellite instability, tumor mutational burden, and response to immune checkpoint blockade in patients with prostate cancer

Microsatellite instability, tumor mutational burden, and response to immune checkpoint blockade in patients with prostate cancer Journal Article

Authors:	Lenis, A. T.; Ravichandran, V.; Brown, S.; Alam, S. M.; Katims, A.; Truong, H.; Reisz, P. A.; Vasselman, S.; Nweji, B.; Autio, K. A.; Morris, M. J.; Slovin, S. F.; Rathkopf, D.; Danila, D.; Woo, S.; Vargas, H. A.; Laudone, V. P.; Ehdaie, B.; Reuter, V.; Arcila, M.; Berger, M. F.; Viale, A.; Scher, H. I.; Schultz, N.; Gopalan, A.; Donoghue, M. T. A.; Ostrovnaya, I.; Stopsack, K. H.; Solit, D. B.; Abida, W.
Article Title:	Microsatellite instability, tumor mutational burden, and response to immune checkpoint blockade in patients with prostate cancer
Abstract:	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.
Keywords:	adult; clinical article; human tissue; treatment response; aged; aged, 80 and over; middle aged; gene mutation; major clinical study; overall survival; sequence analysis; genetics; mutation; mortality; case report; cancer patient; nuclear magnetic resonance imaging; genetic analysis; dna repair; progression free survival; tumor volume; cohort analysis; cytogenetics; pathology; mutational analysis; tumor marker; monoclonal antibody; prostate cancer; gleason score; prostatic neoplasms; immunology; prostatectomy; mismatch repair; microsatellite instability; dna mismatch repair; prostate tumor; external beam radiotherapy; drug therapy; androgen deprivation therapy; dna extraction; transrectal ultrasonography; protein msh6; mismatch repair protein pms2; hereditary nonpolyposis colorectal cancer; non small cell lung cancer; dna directed dna polymerase epsilon; nucleic acid base substitution; immune checkpoint inhibitor; antibodies, monoclonal, humanized; high throughput sequencing; very elderly; sanger sequencing; humans; human; male; article; pembrolizumab; whole exome sequencing; immune checkpoint inhibitors; biomarkers, tumor; mutl protein homolog 1; robot-assisted prostatectomy; dna mismatch repair protein msh2; tumor mutational burden; checkpoint inhibitor therapy
Journal Title:	Clinical Cancer Research
Volume:	30
Issue:	17
ISSN:	1078-0432
Publisher:	American Association for Cancer Research
Date Published:	2024-09-01
Start Page:	3894
End Page:	3903
Language:	English
DOI:	10.1158/1078-0432.Ccr-23-3403
PUBMED:	38949888
PROVIDER:	scopus
PMCID:	PMC11371520
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85203205506&doi=10.1158%2f1078-0432.CCR-23-3403&partnerID=40&md5=f175784090dfbea9c0751c9989ec1bdd
Notes:	Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author are Wassim Abida and David Solit -- Source: Scopus