Resistance to Platinum-Based Chemotherapy in Muscle-Invasive Bladder Cancer: Genetic and Immune Determinants and Implications for Treatment Sequencing — A Case Series

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Background/Objectives: Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy has been the standard of care for muscle-invasive bladder cancer (MIBC) for two decades, yet a substantial proportion of patients derive no benefit. With antibody–drug conjugates and immune checkpoint inhibitors now reshaping the treatment landscape, characterising the determinants of platinum resistance and the consequences for treatment sequencing has become clinically pressing. We aimed to describe, in a single-centre cohort with long follow-up, the patient trajectories, survival, immune microenvironment, tumour mutational burden (TMB) and genetic alterations associated with response to NAC. Methods: We retrospectively identified 54 consecutive patients with MIBC treated with neoadjuvant dose-dense MVAC (dd-MVAC) between November 2013 and November 2019. Pathologic response, recurrence, survival and subsequent therapy lines were recorded. Immunohistochemistry for CD3, CD8, FOXP3, PD-1, PD-L1, PD-L2 and NY-ESO-1, and paired genetic profiling (whole-exome sequencing and TSO-500) were performed on transurethral resection (TURBT) and cystectomy specimens. Marker changes after NAC were tested with Wilcoxon signed-rank tests; associations with pathologic complete response (pCR) with Fisher exact and Mann–Whitney tests; survival differences with the log-rank test. Results: pCR was achieved in 11/42 operated patients; 12 patients did not undergo cystectomy. Median follow-up was 87 months (IQR 24–104). Hydronephrosis (p = 0.016) was associated with absence of pCR. Overall and recurrence-free survival differed significantly by pathologic response (log-rank p = 0.040 and p = 0.026). NAC significantly reduced intratumoral FOXP3 (p < 0.001), NY-ESO-1 (p = 0.004), PD-L2 (p = 0.007) and CD3 (p = 0.029), whereas TMB was unchanged (TSO-500 p = 0.67; WES p = 0.86). No baseline immune marker, including PD-L1, predicted pCR. The mutational landscape was largely concordant before and after NAC. Conclusions: NAC remodels the bladder cancer immune microenvironment without altering the tumour genome or TMB. Baseline immune and genomic markers did not identify platinum-refractory patients, underscoring the need for better predictive biomarkers to guide patient selection and treatment sequencing in the antibody–drug conjugate era.

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