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
References:
- 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