Systems Biology and Multi-Omics Determinants of Response to Bladder-Preserving Trimodality Therapy in Muscle-Invasive Bladder Cancer

Trimodality therapy (TMT)—maximal transurethral resection of bladder tumor (TURBT) followed by concurrent chemoradiotherapy—can offer oncologic outcomes comparable to radical cystectomy (RC) in carefully selected muscle-invasive bladder cancer (MIBC) patients while preserving the bladder and, possibly, the quality of life. Systematic reviews and long-term series support durable bladder-intact survival in responders, yet there is still a significant percentage of patients who exhibit incomplete response or invasive intravesical recurrence requiring salvage RC. This review covers computational genomics, transcriptomics, immune contexture, radiogenomics, and digital pathology approaches for predicting response in order to avoid preventable TMT failures. We discuss clinically relevant endpoints (complete response, invasive recurrence, bladder-intact survival, and salvage RC), patient selection (carcinoma in situ, hydronephrosis, debulking feasibility, and histology), and DNA damage response (DDR) biology—highlighting ERCC2 and related pathways as determinants of chemo-radiation sensitivity. We then review reproducible transcriptomic subtype classifiers and immune deconvolution methods, emphasizing translational constraints and reporting standards. Finally, we propose an integrated hypothetical modeling framework (calibration, external validation, and decision-curve thresholds) to guide recommendations for upfront RC versus bladder preservation with intensified surveillance and timely salvage RC.