Genomic Features of Muscle-invasive Bladder Cancer Arising After Prostate Radiotherapy

Radiation-associated muscle-invasive bladder cancers arising after prostate cancer radiotherapy have mutational evidence of radiation exposure but share many driver alterations with non–radiation-associated muscle-invasive bladder cancers. Muscle-invasive bladder cancer (MIBC) is a rare but serious event following definitive radiation for prostate cancer. Radiation-associated MIBC (RA-MIBC) can be difficult to manage given the challenges of delivering definitive therapy to a previously irradiated pelvis. The genomic landscape of RA-MIBC and whether it is distinct from non–RA-MIBC are unknown. To define mutational features of RA-MIBC and compare the genomic landscape of RA-MIBC with that of non–RA-MIBC. We identified patients from our institution who received radiotherapy for prostate cancer and subsequently developed MIBC. We performed whole exome sequencing of bladder tumors from RA-MIBC patients. Tumor genetic alterations including mutations, copy number alterations, and mutational signatures were identified and were compared with genetic features of non–RA-MIBC. We used the Kaplan-Meier method to estimate recurrence-free (RFS) and overall (OS) survival. We identified 19 RA-MIBC patients with available tumor tissue ( n = 22 tumors) and clinical data. The median age was 76 yr, and the median time from prostate cancer radiation to RA-MIBC was 12 yr. The median RFS was 14.5 mo and the median OS was 22.0 mo. Compared with a cohort of non–RA-MIBC analyzed in parallel, there was no difference in tumor mutational burden, but RA-MIBCs had a significantly increased number of short insertions and deletions (indels) consistent with previous radiation exposure. We identified mutation signatures characteristic of APOBEC-mediated mutagenesis, aging, and homologous recombination deficiency. The frequency of mutations in many known bladder cancer genes, including TP53 , KDM6A , and RB1 , as well as copy number alterations such as CDKN2A loss was similar in RA-MIBC and non-RA-MIBC. We identified unique mutational properties that likely contribute to the distinct biological and clinical features of RA-MIBC. Bladder cancer is a rare but serious diagnosis following radiation for prostate cancer. We characterized genetic features of bladder tumors arising after prostate radiotherapy, and identify similarities with and differences from bladder tumors from patients without previous radiation.