Genomic Features of Radiation-Associated Muscle-Invasive Bladder Cancer.

PURPOSE/OBJECTIVE(S) Radiation associated muscle-invasive bladder cancer (RA-MIBC) is a rare but potentially lethal late toxicity following definitive radiation therapy for prostate cancer. RA-MIBC is associated with worse prognosis compared to primary MIBC, but it remains unknown whether worse outcomes are driven primarily by difficulty with delivering definitive treatment in a previously irradiated pelvis or whether RA-MIBCs harbor specific aggressive biological features. We sought to characterize the genomic features of RA-MIBC to assess whether the underlying genetic alterations differ from primary (non-radiation associated) MIBC. MATERIALS/METHODS We performed whole-exome sequencing of 27 bladder tumors in patients previously treated with definitive radiation therapy for prostate cancer, and we correlated genomic with clinical data. We compared the mutation profile of RA-MIBC with primary MIBC from The Cancer Genome Atlas (TCGA). We used the Kaplan-Meier method to estimate progression-free survival (PFS) and overall survival (OS). RESULTS The median age of included patients was 79.2 years, and the median time from prostate radiation to MIBC diagnosis was 11.5 years. Median PFS was 12.4 months and median OS was 20.2 months. Among RA-MIBCs, we found mutation signatures characteristic of BRCA1/2 mutations, impaired DNA mismatch repair, and microsatellite instability. When compared to de novo MIBC from TCGA, RA-MIBCs also had significantly higher mutation rates of DNA repair genes, such as FANCA (38.1% vs 5.1%, P < 0.001), CHEK2 (26.1% vs 2.5%, P < 0.001) and MSH6 (26.1% vs 2.5%, P < 0.001). The most commonly mutated genes were TP53 (50%) and KDM6A (36%), which harbored mutations at similar rates as de novo MIBC samples from TCGA. CONCLUSION In this study, we characterize the mutational profiles and clinical outcomes of radiation-associated bladder cancer. These patients exhibited significantly worse PFS and OS compared to prior series of de novo MIBC. Genomically, these tumors exhibited higher rates of mutation signatures characteristic of impaired DNA damage repair compared to previously unirradiated tumors. These genomic differences suggest that some RA-MIBCs may represent a biologically distinct entity compared to de novo MIBC and may indicate an opportunity for the use and development of novel therapeutic strategies.