Background: Impaired DDR is associated with response to platinum-based chemotherapy. Several genomically directed trials have been proposed using DDR alteration status for enrolment. In this study, we characterized the deleterious DDR alteration (DDRa) landscape of UCB across various clinical states. Methods: Targeted exon capture and sequencing of at least 341 cancer-associated genes was performed prospectively on 451 UCB specimens (MSK-IMPACT assay). We assessed sequencing data for deleterious alterations in 34 genes representing canonical DDR pathways. Deleterious alterations included truncating mutations, homozygous deletions, and functionally validated missense mutations. Results: Table 1. In NMIBC, deleterious DDRa were enriched in high-grade disease ([39/136, 28.7%] high grade vs. low-grade [2/28, 7.1%]; p=0.02). The frequency of deleterious DDRa in chemo-naïve MIBC was enriched relative to unmatched post-neoadjuvant chemotherapy (NAC) residual MIBC ([33/112, 29.5%] vs. [8/55, 14.5%]; p=0.01). Patients with metastatic disease had similar rates of deleterious DDRa to MIBC ([31/116, 26.7%] vs. [33/112, 29.5%]). The percentage of patients having any type of DDR alteration was similar across states. The proportion of patients with a deleterious DDRa relative to any DDRa was 41/77 (53.2%) in NMIBC, 33/65 (50.8%) in chemo-naïve MIBC, 8/27(29.6%) in post-NAC residual MIBC, and 31/68 (45.6%) in metastatic disease. Conclusions: DDRa are found across the UCB disease spectrum. ERCC2 and ATM are the most common DDRa although alterations were seen in most other DDR genes. Many alterations are of unknown significance and further characterization is needed to develop genomically directed treatment.

TCGA = The Cancer Genome Atlas, MSK=Memorial Sloan Kettering, NMIBC = non-muscle invasive bladder cancer, MIBC = muscle invasive bladder cancer, NER = Nucleotide excision and repair, CP=checkpoint, FA = Fanconi Anemia