Deleterious Alterations In Dna Damage Response Genes Are Associated With Improved Outcome In Muscle-Invasive Bladder Cancer Patients Treated With Radiation-Based Bladder Preservation

Radiation therapy (RT)-based bladder preservation is an alternative to perioperative chemotherapy and radical cystectomy (RC) for selected patients with muscle-invasive bladder cancer (MIBC). Recent data suggest that somatic DNA damage response (DDR) alterations are associated with improved outcome in MIBC patients receiving RC with or without perioperative chemotherapy. Improved understanding of the influence of DDR genetics on response to RT-based bladder preservation may aid patient selection. We performed deep, targeted capture sequencing of primary bladder tumors and paired/pooled normal specimens from 48 RT-treated MIBC patients with a DDR gene-enriched panel. To test whether correlations of DDR alterations with outcomes were specific to a RT cohort, we also assessed a subset of these DDR genes that were sequenced in a previously published series of 89 patients who received RC with or without neoadjuvant platinum-based chemotherapy. Specimens were re-reviewed to confirm urothelial histology. Deleterious alterations were defined as somatic nonsense, frameshift, or splice site mutations, or missense mutations at or near functionally significant residues validated in the literature. In the RT cohort, median RT dose was 66 Gy, and chemotherapy use was neoadjuvant and concurrent (46%), concurrent only (48%), or none (6%). Visibly complete transurethral resection of bladder tumor was achieved in 71% of patients. Median surviving follow-up was 28 months. There were 30 progression events (crude rate, 63%), comprised of 22 metastases (crude, 46%) and 24 local in-bladder recurrences (crude, 50%). While 30 (63%) patients had alterations in DDR genes, only 13 (27%) had deleterious DDR alterations, specifically in ATM (2), BRCA1 (1), BRIP1 (1), ERCC2 (6), FANCD2 (1), and PALB2 (1). On multivariable Cox proportional hazards analysis, the presence of a deleterious DDR alteration was associated significantly with lower relapse risk (hazard ratio [HR] 0.28, 95% confidence interval [CI] 0.08-0.95; P=.041), as well as with a trend toward lower risk for metastasis (HR 0.32, 95% CI 0.10-1.11; P=.07) and any disease progression (HR 0.35, 95% CI 0.12-1.03; P=.06). In the RC cohort, neoadjuvant chemotherapy was given in 39% of patients, and deleterious DDR gene alterations were noted only in 8% of the patients. On 2-sided log-rank testing, such alterations conferred a non-significant trend for improved recurrence-free survival (P=.20) and disease-specific survival (P=.10). Deleterious somatic alterations in DDR genes were associated with significantly improved outcomes in bladder cancer patients undergoing RT-based therapy and with a trend for improved outcomes in those treated with RC with or without platinum chemotherapy. Further research is warranted to validate these findings on an independent RT-treated dataset and to clarify the relationship in a larger chemotherapy-treated RC cohort.