{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Boiarsky D"],"funding":["Department of Defense Prostate Cancer Research Program","U.S. Department of Defense","NCI NIH HHS","National Institutes of Health"],"pagination":["558-568.e3"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10939759"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["22(2)"],"pubmed_abstract":["<h4>Introduction/background</h4>Immune checkpoint inhibitors (ICIs) have limited efficacy in prostate cancer (PCa). Better biomarkers are needed to predict responses to ICIs. We sought to demonstrate that a panel-based mutational signature identifies mismatch repair (MMR) deficient (MMRd) PCa and is a biomarker of response to pembrolizumab.<h4>Patients and methods</h4>Clinico-genomic data was obtained for 2664 patients with PCa sequenced at Dana-Farber Cancer Institute (DFCI) and Memorial Sloan Kettering (MSK). Clinical outcomes were collected for patients with metastatic castration-resistant PCa (mCRPC) treated with pembrolizumab at DFCI. SigMA was used to characterize tumors as MMRd or MMR proficient (MMRp). The concordance between MMRd with microsatellite instability (MSI-H) was assessed. Radiographic progression-free survival (rPFS) and overall survival (OS) were collected for patients treated with pembrolizumab. Event-time distributions were estimated using Kaplan-Meier methodology.<h4>Results</h4>Across both cohorts, 100% (DFCI: 12/12; MSK: 43/43) of MSI-H tumors were MMRd. However, 14% (2/14) and 9.1% (6/66) of MMRd tumors in the DFCI and MSK cohorts respectively were microsatellite stable (MSS), and 26% (17/66) were MSI-indeterminate in the MSK cohort. Among patients treated with pembrolizumab, those with MMRd (n = 5) versus MMRp (n = 14) mCRPC experienced markedly improved rPFS (HR = 0.088, 95% CI: 0.011-0.70; P = .0064) and OS (HR = 0.11, 95% CI: 0.014-0.80; P = .010) from start of treatment. Four patients with MMRd experienced remissions of >= 2.5 years.<h4>Conclusion</h4>SigMA detects additional cases of MMRd as compared to MSI testing in PCa and identifies patients likely to experience durable response to pembrolizumab."],"journal":["Clinical genitourinary cancer"],"pubmed_title":["A Panel-Based Mutational Signature of Mismatch Repair Deficiency is Associated With Durable Response to Pembrolizumab in Metastatic Castration-Resistant Prostate Cancer."],"pmcid":["PMC10939759"],"funding_grant_id":["W81XWH-20-1-0118","R01 CA269805","1R01CA269805-01"],"pubmed_authors":["Park PJ","Ananda G","Berchuck JE","Savignano H","McClure HM","Gulhan DC","Sholl LM","Tewari AK","Silver R","Boiarsky D","Lakshminarayanan G","Hirsch MS","Choudhury AD"],"additional_accession":[]},"is_claimable":false,"name":"A Panel-Based Mutational Signature of Mismatch Repair Deficiency is Associated With Durable Response to Pembrolizumab in Metastatic Castration-Resistant Prostate Cancer.","description":"<h4>Introduction/background</h4>Immune checkpoint inhibitors (ICIs) have limited efficacy in prostate cancer (PCa). Better biomarkers are needed to predict responses to ICIs. We sought to demonstrate that a panel-based mutational signature identifies mismatch repair (MMR) deficient (MMRd) PCa and is a biomarker of response to pembrolizumab.<h4>Patients and methods</h4>Clinico-genomic data was obtained for 2664 patients with PCa sequenced at Dana-Farber Cancer Institute (DFCI) and Memorial Sloan Kettering (MSK). Clinical outcomes were collected for patients with metastatic castration-resistant PCa (mCRPC) treated with pembrolizumab at DFCI. SigMA was used to characterize tumors as MMRd or MMR proficient (MMRp). The concordance between MMRd with microsatellite instability (MSI-H) was assessed. Radiographic progression-free survival (rPFS) and overall survival (OS) were collected for patients treated with pembrolizumab. Event-time distributions were estimated using Kaplan-Meier methodology.<h4>Results</h4>Across both cohorts, 100% (DFCI: 12/12; MSK: 43/43) of MSI-H tumors were MMRd. However, 14% (2/14) and 9.1% (6/66) of MMRd tumors in the DFCI and MSK cohorts respectively were microsatellite stable (MSS), and 26% (17/66) were MSI-indeterminate in the MSK cohort. Among patients treated with pembrolizumab, those with MMRd (n = 5) versus MMRp (n = 14) mCRPC experienced markedly improved rPFS (HR = 0.088, 95% CI: 0.011-0.70; P = .0064) and OS (HR = 0.11, 95% CI: 0.014-0.80; P = .010) from start of treatment. Four patients with MMRd experienced remissions of >= 2.5 years.<h4>Conclusion</h4>SigMA detects additional cases of MMRd as compared to MSI testing in PCa and identifies patients likely to experience durable response to pembrolizumab.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Apr","modification":"2026-06-01T06:09:46.384Z","creation":"2026-04-08T09:46:06.839Z"},"accession":"S-EPMC10939759","cross_references":{"pubmed":["38342659"],"doi":["10.1016/j.clgc.2024.01.011"]}}