Tumor Mutational Burden and Clinical Outcomes in Muscle-Invasive Bladder Cancer Patients Treated with Neoadjuvant Chemotherapy

Abstract

Pathological complete response (pCR) after neoadjuvant cisplatin-based chemotherapy (NAC) is associated with improved outcomes in muscle-invasive bladder cancer (MIBC), but genomic predictors of benefit remain unvalidated. Based on observations in lung cancer, we hypothesized that MIBC patients with high TMB would be unlikely to benefit from NAC, indicated by residual disease after cystectomy. Pretreatment tumor specimens from patients treated with cisplatin-based NAC were analyzed using Tempus xT/xR platforms. Sample size was prespecified by statistical design. High TMB was defined as the upper TMB quintile within the cohort. Correlation of TMB values and genomic variants with outcomes was performed using logistic regression, Cox proportional hazards models, and Kaplan-Meier techniques. Ninety-one patients were included with a median follow-up of 63.6 months. pCR occurred in 31.9%. Median TMB was 8.9 Mut/Mb. Contrary to the prespecified hypothesis, higher TMB was associated with more favorable outcomes. Patients in the upper TMB quintile had a numerically higher pCR rate (47.4% vs 27.8%; p=0.165) and improved RFS/OS (HR 0.456, p=0.08; HR 0.495, p=0.16). Using a clinically relevant cutoff, TMB ≥10 Mut/Mb was associated with higher pCR (43.6% vs 23.1%; OR 0.39, p=0.044), improved RFS (HR 0.330, p<0.001) and OS (HR 0.388, p=0.013). Exploratory analyses showed a trend toward enrichment of MMR alterations (OR 3.57, p=0.087) in TMB-high tumors. Baseline TMB ≥10 Mut/Mb was associated with improved pathological response and survival in MIBC treated with cisplatin-based NAC and warrants prospective evaluation in contemporary perioperative regimens.