Molecular Biomarkers of Response to Trimodal Therapy in Bladder Cancer - Expert Commentary

Radiation therapy can be an effective way to eliminate the need for radical surgery in bladder cancer patients. Trimodality therapy (TMT) is a bladder-preserving treatment that consists of maximal transurethral resection of bladder tumor (TURBT) followed by chemoradiation. Identifying biomarkers predicting tumor response to different treatments can enable selecting patients likely to benefit from radiotherapy. An important study by Kamran et al. characterized molecular biomarkers in patients with muscle-invasive bladder cancer (MIBC) treated with TMT to elucidate molecular biomarkers associated with patient outcomes.

The investigators performed whole exome sequencing (WES) in 76 eligible patients. The median age was 72.3 years, and 24% of the patients were female. Most patients were treated with cisplatin-based chemotherapy (66%) concurrent with radiation. The most frequently mutated gene was TP53, which was present in 52.6% of samples, followed by KMT2D in 40.8% of samples. Mutational signature analysis identified four dominant signatures across samples. Signature 1, found in 81.6% of samples, was characterized by age-associated spontaneous or enzymatic deamination of 5-methylcytosine to thymine. Signature 5, which had previously been associated with ERCC2 mutations in urothelial tumors and with smoking history, was present in 89.5% of samples. Signatures 2 and 13 resulting from APOBEC-induced mutations and previously described in MIBC were found in 57.9% and 51.3% of cases

The median follow-up duration was 74.6 months. Approximately half of the patients had favorable long-term outcomes for modified bladder-intact event-free survival (mBI-EFS). The 5-year overall survival rate was 48.6%. Interestingly, there was no significant difference in tumor mutational burden (TMB) between patients with favorable or unfavorable mBI-EFS. Mutations in DNA damage response (DDR) genes were associated with improved mBI-EFS (HR, 0.51; 95% CI, 0.27–0.97; p = 0.040). Of the DDR gene alterations, ERCC2 mutations were significantly associated with better mBI-EFS (p = 0.027). To correlate this finding with treatment sensitivity, the investigators tested radiation and cisplatin on bladder cancer cell lines with or without ERCC2 mutations. ERCC2-mutant cell lines were significantly more sensitive to cisplatin monotherapy and the combination of cisplatin and radiation than wild-type lines.

The findings from this study highlight alterations in DDR genes as potential predictive markers for response to bladder-sparing treatment in MIBC. Prospective validation of this promising biomarker in randomized trials is warranted.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine


  1. Kamran SC, Zhou Y, Otani K, et al. Genomic Tumor Correlates of Clinical Outcomes Following Organ-Sparing Chemoradiation Therapy for Bladder Cancer [published online ahead of print, 2023 Oct 19]. Clin Cancer Res. 2023;10.1158/1078-0432.CCR-23-0792. doi:10.1158/1078-0432.CCR-23-0792
Read the Abstract