Abstract 602: Deleterious alterations in DNA damage response genes are associated with improved outcome in muscle-invasive bladder cancer patients treated with radiation-based bladder preservation
Authors: Desai Neil B. , Iyer Gopa , Cha Eugene K. , Scott Sasinya N. , Hreiki Joseph , Sfakianos John P. , Kim Philip , Bagroida Aditya , Bochner Bernard H. , Rosenberg Jonathan E. , Bajorin Dean F. , Berger Michael F. , Kollmeier Marisa A. , Al-Ahmadie Hikmat , Solit David B. 
Published: August 2015

Abstract
Purpose: Radiotherapy (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 +/- perioperative chemotherapy. Improved understanding of the influence of DDR genetics on response to RT-based bladder preservation may aid patient selection.
Methods: 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 +/- 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.
Results: 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 TURBT 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%) patients 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 (HR 0.28, 95% CI 0.08-0.95; p = 0.041), as well as with a trend towards lower risk for metastasis (HR 0.32, 95% CI 0.10-1.11; p = 0.07) and any disease progression (HR 0.35, 95% CI 0.12-1.03; p = 0.06). 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 = 0.20) and disease-specific survival (p = 0.10).
Conclusion: 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 +/- 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.
Citation Format: Neil B. Desai, Gopa Iyer, Eugene K. Cha, Sasinya N. Scott, Joseph Hreiki, John P. Sfakianos, Philip Kim, Aditya Bagroida, Bernard H. Bochner, Jonathan E. Rosenberg, Dean F. Bajorin, Michael F. Berger, Marisa A. Kollmeier, Hikmat Al-Ahmadie, David B. Solit. Deleterious alterations in DNA damage response genes are associated with improved outcome in muscle-invasive bladder cancer patients treated with radiation-based bladder preservation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 602. doi:10.1158/1538-7445.AM2015-602