Association of Plasma Epigenetic Methylation Patterns with Resistance to Anti-PD-L1 Monotherapy in Advanced Urothelial Carcinoma

International Journal of Medical Advances and Discoveries | Vol. 17, No. 5, May 2026 | pp. 37–45

DOI: 10.46882/2026/IJMAD/000116

Original Research Article

Title: Association of Plasma Epigenetic Methylation Patterns with Resistance to Anti-PD-L1 Monotherapy in Advanced Urothelial Carcinoma

Names of Authors: Jean-Luc Moreau¹, Sofia I. Rodriguez², Chloe E. Sterling¹

Authors’ Affiliations: ¹Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France; ²Division of Urologic Oncology, Hospital Clínic de Barcelona, Barcelona, Spain

Abstract: Anti-PD-L1 immunotherapies yield durable clinical benefits in a subset of advanced urothelial carcinoma patients; however, primary and adaptive resistance mechanisms remain common and difficult to predict using traditional immunohistochemical biomarkers. This prospective translational study investigated whether baseline circulating cell-free DNA (cfDNA) epigenetic methylation signatures can predict resistance to anti-PD-L1 monotherapy (atezolizumab). Plasma samples from 145 patients with advanced urothelial carcinoma were collected prior to initiation of treatment. Genome-wide cfDNA methylation profiling was performed via bisulfite sequencing. A distinct 14-gene hypermethylation matrix, primarily involving promoter regions of T-cell homing and antigen-presentation pathways (including CXCL9 and HLA-A), was significantly enriched in non-responders compared to responders (p < 0.001). Patients presenting with a high hypermethylation index exhibited a significantly shorter median progression-free survival (2.1 months vs. 7.6 months; Hazard Ratio = 2.85, 95% Confidence Interval [1.92, 4.24], p < 0.0001) and an objective response rate of just 8.2%, compared to 42.5% in the low-methylation group. Multivariate Cox proportional hazards models confirmed that this plasma epigenetic signature serves as a strong, independent predictor of therapeutic resistance, outperforming tumor mutational burden and PD-L1 tissue expression metrics. Pre-treatment cfDNA methylation liquid biopsies represent a promising tool for refining patient selection in urothelial oncology workflows.

Keywords: Urothelial carcinoma, Immunotherapy resistance, Epigenetics, Cell-free DNA, DNA methylation, Liquid biopsy

Manuscript Timeline: Received: February 03, 2026; Revised: March 17, 2026; Accepted: April 09, 2026; Published: May 15, 2026

Citation: Moreau, J. L., Rodriguez, S. I., & Sterling, C. E. (2026). Association of Plasma Epigenetic Methylation Patterns with Resistance to Anti-PD-L1 Monotherapy in Advanced Urothelial Carcinoma. International Journal of Medical Advances and Discoveries, 17(5), 37–45. doi.org

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