Background: Trimodality therapy (TMT) offers comparable survival to radical cystectomy for bladder cancer patients with better life quality, but limited evidence exists to guide treatment modality selection. One key factor is radiosensitivity. Advances in molecular understanding have allowed us to use predictive biomarkers to evaluate this, particularly DNA Damage Response (DDR) genes, which regulate DNA damage. Hence, they could serve as potential predictors. While prior narrative reviews have explored molecular biomarkers in TMT, evidence linking DDR alterations to radiotherapy outcomes is scattered across numerous studies with different biomarkers, assays, and outcomes. This review synthesizes and evaluates existing evidence to identify promising DDR biomarkers to guide treatment decisions.
Methods: PubMed and Embase were systemically searched from 2002 through 2026 for studies that looked at the pre-treatment DDR gene status in bladder cancer patients receiving radiotherapy. Inclusion criteria required original data, a sample size of ≥10 patients, and reported response outcomes.
Results: Ten studies met inclusion criteria. DDR genes alterations were associated with better radiotherapy outcomes, although effect sizes and evidence of strength varied. One study of MRE11 emphasized assay standardization challenges, while four studies with high MRE11 expression demonstrated improved responses with radiotherapy (HR range 0.42-0.64). Additionally, ERCC2 mutations showed the largest individual effect: one cohort reporting significantly improved survival (HR 0.15) and another showing zero metastatic recurrences in mutant patients. Various other DDR genes were also linked to improved recurrence-free survival (HR range 0.32-0.51), and germline RAD51 and XPD/XRCC1 polymorphisms also showed associations with improved outcomes. Certainty of evidence was moderate due to limitations by retrospective designs, small sample sizes for some markers, assay variability, and potential publication bias.
Conclusion: In conclusion, both MRE11 and ERCC2 are consistently linked to better radiotherapy results, with MRE11 being proposed as the most reliable biomarker and ERCC2 mutations having the most impact. These markers, with germline SNPs, hold promise to guide treatment decisions in bladder cancer.
Methods: PubMed and Embase were systemically searched from 2002 through 2026 for studies that looked at the pre-treatment DDR gene status in bladder cancer patients receiving radiotherapy. Inclusion criteria required original data, a sample size of ≥10 patients, and reported response outcomes.
Results: Ten studies met inclusion criteria. DDR genes alterations were associated with better radiotherapy outcomes, although effect sizes and evidence of strength varied. One study of MRE11 emphasized assay standardization challenges, while four studies with high MRE11 expression demonstrated improved responses with radiotherapy (HR range 0.42-0.64). Additionally, ERCC2 mutations showed the largest individual effect: one cohort reporting significantly improved survival (HR 0.15) and another showing zero metastatic recurrences in mutant patients. Various other DDR genes were also linked to improved recurrence-free survival (HR range 0.32-0.51), and germline RAD51 and XPD/XRCC1 polymorphisms also showed associations with improved outcomes. Certainty of evidence was moderate due to limitations by retrospective designs, small sample sizes for some markers, assay variability, and potential publication bias.
Conclusion: In conclusion, both MRE11 and ERCC2 are consistently linked to better radiotherapy results, with MRE11 being proposed as the most reliable biomarker and ERCC2 mutations having the most impact. These markers, with germline SNPs, hold promise to guide treatment decisions in bladder cancer.