The AR-ADAR2-PD-L1 Axis as a Prognostic Biomarker System in BCG-Treated High-Grade Papillary Urothelial Carcinoma: A Single-Center Retrospective Cohort Study

Abstract

: Background: High-grade papillary urothelial carcinoma (HG-PUC) represents a high-risk non-muscle-invasive bladder cancer with frequent recurrence after intravesical Bacillus Calmette-Guérin (BCG) therapy, and reliable prognostic biomarkers remain lacking. The aim of this study was to evaluate the prognostic significance of the androgen receptor (AR)-ADAR2-programmed death-ligand 1 (PD-L1) axis in BCG-treated HG-PUC. Methods: A single-center retrospective cohort of 146 patients with HG-PUC treated with transurethral resection followed by intravesical BCG was evaluated. AR, ADAR2, PD-L1, CD4, and CD8 expression were evaluated by immunohistochemistry. miR-200a-3p and interferon-γ (IFN-γ ) transcript expression were assessed by quantitative PCR in an exploratory subgroup of 40 patients. Associations between molecular markers, clinicopathological variables, and Recurrence-Free Survival were assessed. Results: High AR expression was significantly associated with reduced ADAR2 expression, increased PD-L1 expression, higher CD4/CD8 ratios, and shorter RFS (all p < 0.0001). AR, ADAR2, and PD-L1 remained independent prognostic factors for RFS in multivariable analysis, and their combined model showed good prognostic discrimination (Harrell’s C-index = 0.792, 95% CI 0.754–0.830). During a median follow-up of 10 months (95% CI, 9–12), 52 RFS events occurred. In the exploratory cohort, tumors with low AR and high ADAR2 expression exhibited significantly higher miR-200a-3p and IFN-γ transcript levels. Conclusions: The AR-ADAR2-PD-L1 molecular profile was independently associated with RFS in patients with BCG-treated HG-PUC. These findings support its potential role in prognostic risk stratification, although prospective external validation and functional studies are required before clinical implementation.