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

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Abstract
Pathologic complete response (pCR) after cisplatin-based neoadjuvant 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 patients with MIBC with high tumor mutational burden (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 mutations per megabase (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 relapse-free survival (RFS)/overall survival [OS; hazard ratio (HR), 0.456; P = 0.08 and 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%; odds ratio (OR), 0.39; P = 0.044] and improved RFS (HR, 0.330; P < 0.001) and OS (HR, 0.388; P = 0.013). Exploratory analyses showed a trend toward enrichment of mismatch repair alterations (OR, 3.57; P = 0.087) in TMB-high tumors. Baseline TMB ≥ 10 Mut/Mb was associated with improved pathologic response and survival in MIBC treated with cisplatin-based NAC and warrants prospective evaluation in contemporary perioperative regimens. Significance: In MIBC treated with cisplatin-based neoadjuvant chemotherapy, we found that baseline TMB ≥10 Mut/Mb was associated with higher pCR rates and improved RFS and OS. These findings support the prospective study of TMB as a prognostic biomarker in contemporary perioperative treatment regimens.
Funding Information
  • Atrium Health Foundation (P30CA012197)

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