DNA Damage Response and Repair Gene Alterations Are Associated with Improved Survival in Patients with Platinum-Treated Advanced Urothelial Carcinoma

Min Yuen Teo, Richard M. Bambury, Emily C. Zabor, Emmet Jordan, Hikmat Al-Ahmadie, Mariel E. Boyd, Nancy Bouvier, Stephanie A. Mullane, Eugene K. Cha, Nitin Roper, Irina Ostrovnaya, David M. Hyman, Bernard H. Bochner, Maria E. Arcila, David B. Solit, Michael F. Berger, Dean F. Bajorin, Joaquim Bellmunt, Gopakumar Iyer, Jonathan E. Rosenberg

Platinum-based chemotherapy remains the standard treatment for advanced urothelial carcinoma by inducing DNA damage. We hypothesize that somatic alterations in DNA damage response and repair (DDR) genes are associated with improved sensitivity to platinum-based chemotherapy. Patients with diagnosis of locally advanced and metastatic urothelial carcinoma treated with platinum-based chemotherapy who had exon sequencing with MSK-IMPACT assay were identified. Patients were dichotomized based on presence/absence of alterations in a panel of 34 DDR genes. DDR alteration status was correlated with clinical outcomes and disease features. One hundred patients were identified, of which 47 harbored alterations in DDR genes. Patients with DDR alterations had improved progression-free survival (9.3 vs. 6.0 months, log rank p=0.007) and overall survival (23.7 vs. 13.0 months, log rank p=0.006). DDR alterations were also associated with higher number mutations and copy number alterations. A trend towards positive correlation between DDR status and nodal metastases and inverse correlation with visceral metastases were observed. Different DDR pathways also suggested variable impact on clinical outcomes. Somatic DDR alteration is associated with improved clinical outcomes in platinum-treated patients with advanced urothelial carcinoma. Once validated, it can improve patient selection for clinical practice and future study enrollment.