Introduction:

Radiation-associated muscle-invasive bladder cancer (RA-MIBC) is a rare but serious event following definitive radiation for prostate cancer. 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-radiation-associated MIBC is unknown. Our goal is to define the genomic landscape of RA-MIBC and compare to primary (non radiation-associated) MIBC.

Methods:

We identified patients from our institution who received radiotherapy for prostate cancer and subsequently developed MIBC. We performed whole exome sequencing (WES) of bladder tumors from RA-MIBC patients. Tumor genetic alterations including mutations, copy-number alterations, and mutational signatures were identified and were compared to genetic features of primary MIBC. We used the Kaplan-Meier method to estimate recurrence-free survival (RFS) and overall survival (OS).

Results:

We identified 19 RA-MIBC patients with available tumor tissue (n=22 tumors) and clinical data (Table 1). The median age was 76.4 years and the median time from prostate cancer radiation to RA-MIBC was 11.5 years. Median RFS was 14.5 months and median OS was 22.0 months. We identified unique mutational features of RA-MIBCs (Figure 1), including a high frequency of short deletions compared to primary MIBC as well as mutation signatures characteristic of APOBEC-mediated mutagenesis and homologous recombination deficiency. When compared to primary MIBCs, RA-MIBCs had high frequency of alterations in several DNA repair genes, but similar frequency of mutations in many known bladder cancer genes including TP53, KDM6A, and RB1 as well as copy-number alterations such as CDKN2A loss.

Conclusion:

We identified unique mutational properties that may contribute to the distinct biological and clinical features of RA-MIBC. We also observed an increased frequency of mutations in several DNA damage and repair (DDR) genes in the RA-MIBC cohort, including FANCA, BRCA1, MSH6, and CHEK2. Additional work is necessary to determine the biological impact of DDR gene alterations in RA-MIBC and whether therapies designed to target tumor DDR deficiency may be active in this setting.

Funding: N/A