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

Abstract

Purpose: 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.Experimental Design: Patients with diagnosis of locally advanced and metastatic urothelial carcinoma treated with platinum-based chemotherapy who had exon sequencing with the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay were identified. Patients were dichotomized based on the presence/absence of alterations in a panel of 34 DDR genes. DDR alteration status was correlated with clinical outcomes and disease features.Results: 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 toward 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.Conclusions: 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. Clin Cancer Res; 23(14); 3610-8. ©2017 AACR.

Conflict of interest statement

Conflict of interest disclosures: Jonathan E. Rosenberg has a patent issued for ERCC2 chemotherapy sensitivity. The remaining authors made no disclosures.

©2017 American Association for Cancer Research.

Figures

Figure 1

The association between DDR (DNA damage response and repair) gene alteration status and (A) progression-free (PFS) and (B) overall survival (OS). DDRalt: altered DDR; DDRwt: wild type DDR.

Figure 2

Frequency of metastasis by site based on number of DDR alterations: (A) visceral metastasis, (B) nodal metastasis only (no visceral involvement), (C) any hepatic involvement, (D) any pulmonary involvement, (E) any osseous involvement and (F) any nodal involvement.

Figure 3

Influence of alterations in individual DDR pathways or components on (A) Progression-free survival and (B) overall survival.