A Panel-Based Mutational Signature of Mismatch Repair Deficiency is Associated With Durable Response to Pembrolizumab in Metastatic Castration-Resistant Prostate Cancer.

Autor: Boiarsky D; Department of Medicine, Tufts Medical Center, Boston, MA., Gulhan DC; Department of Biomedical Informatics, Harvard Medical School, Boston, MA., Savignano H; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA., Lakshminarayanan G; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA., McClure HM; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA., Silver R; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA., Hirsch MS; Department of Pathology, Brigham and Women's Hospital, Boston, MA., Sholl LM; Department of Pathology, Brigham and Women's Hospital, Boston, MA., Choudhury AD; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA., Ananda G; Department of Data Science, Dana-Farber Cancer Institute, Boston, MA., Park PJ; Department of Biomedical Informatics, Harvard Medical School, Boston, MA., Tewari AK; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA., Berchuck JE; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA. Electronic address: jacob_berchuck@dfci.harvard.edu.
Jazyk: angličtina
Zdroj: Clinical genitourinary cancer [Clin Genitourin Cancer] 2024 Apr; Vol. 22 (2), pp. 558-568.e3. Date of Electronic Publication: 2024 Jan 20.
DOI: 10.1016/j.clgc.2024.01.011
Abstrakt: Introduction/background: 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.
Patients and Methods: 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.
Results: 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.
Conclusion: SigMA detects additional cases of MMRd as compared to MSI testing in PCa and identifies patients likely to experience durable response to pembrolizumab.
(Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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