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

Area of Science:

• Oncology
• Genomics
• Cancer Research

Background:

• Pathological complete response (pCR) after neoadjuvant cisplatin-based chemotherapy (NAC) improves outcomes in muscle-invasive bladder cancer (MIBC).
• Genomic predictors of NAC benefit in MIBC are not well-validated.
• Previous research in lung cancer suggested high tumor mutational burden (TMB) might indicate poor response to chemotherapy.

Purpose of the Study:

• To investigate the association between TMB and response to NAC in MIBC patients.
• To determine if high TMB predicts residual disease after NAC and cystectomy.
• To validate genomic predictors of NAC benefit in MIBC.

Main Methods:

• Pretreatment tumor specimens from 91 MIBC patients treated with cisplatin-based NAC were analyzed.
• Tempus xT/xR platforms were used for genomic analysis.
• TMB was correlated with pathological complete response (pCR), recurrence-free survival (RFS), and overall survival (OS) using logistic regression, Cox models, and Kaplan-Meier analysis.

Main Results:

• Contrary to the hypothesis, higher TMB was associated with more favorable outcomes.
• Patients in the upper TMB quintile showed a numerically higher pCR rate (47.4% vs 27.8%) and improved RFS/OS.
• A TMB cutoff of ≥10 Mut/Mb was significantly associated with higher pCR (OR 0.39, p=0.044), improved RFS (HR 0.330, p<0.001), and OS (HR 0.388, p=0.013).
• Exploratory analyses indicated a trend towards MMR alterations in TMB-high tumors (OR 3.57, p=0.087).

Conclusions:

• Baseline TMB ≥10 Mut/Mb is associated with improved pathological response and survival in MIBC patients receiving cisplatin-based NAC.
• High TMB may serve as a positive predictive biomarker for NAC response in MIBC.
• Prospective evaluation of TMB in contemporary perioperative regimens is warranted.