Sex-based differences in genetic alterations and immune checkpoint inhibitor response in urothelial bladder cancer.

Abstract

Introduction: Bladder cancer exhibits significant sex-based disparities, with men showing higher incidence rates and women experiencing more aggressive disease and poorer survival outcomes. This study investigates sex-specific somatic genetic alterations (GAs) in urothelial bladder cancer and their effects on survival, immune cell infiltration, and immune checkpoint inhibitor (ICI) responses.

Methods: We analyzed 3,157 patients with urothelial bladder cancer using next-generation sequencing data from the American Association for Cancer Research (AACR) Project GENIE. Kaplan-Meier analysis assessed overall survival, while TIMER2.0 and ROC Plotter evaluated immune cell infiltration and ICI responses. Synthetic lethal interactions were identified through the SLOAD database, and co-occurrence patterns were examined (significance at P < 0.05).

Results: Among the 3,157 patients (median age: 70), 76% were male. Somatic gene alterations were identified in 35% of cases, more frequently in men (38% vs. 29%, P < 0.001). Men had more alterations in RB1, CDKN1A, and ERCC2 (all P < 0.001), while AR gene alterations were more common in women. Patients with CDKN1A, RB1, or ERCC2 alterations had significantly worse 5-year survival (18-27 vs. 35.4 months; P = 0.0219), with RB1 alterations linked to the lowest 10-year survival rates (21.3% vs. 28.3%, P = 0.0219). Immune profiling revealed increased CD8⁺ T cell and NK cell infiltration in RB1-altered tumors, while AR alterations correlated with decreased monocyte infiltration.

Conclusion: Somatic GAs contribute to sex-based survival disparities in bladder cancer. RB1 and AR alterations emerge as critical drivers of poor outcomes and potential therapeutic targets, underscoring the need for sex-tailored treatment strategies.