Germline single-nucleotide polymorphisms (SNPs) associated with response of urothelial carcinoma (UC) to platinum-based therapy: The role of the host.

Abstract

236 Background: Platinum-based therapy improves outcome in neoadjuvant and metastatic UC. Since cell-line and human subject studies in other cancers show germline associations with platinum response, we hypothesized that germline variation also identifies genes that determine UC response to platinum-based therapy. Methods: Saliva or blood was prospectively collected from 651 UC patients (pts) diagnosed between 1984 and 2010. SNPs (n=80) were selected based on previously reported associations with UC and/or platinum response and genotyped using Sequenom MassArray iPLEX system. Samples and SNPs were filtered for genotyping rate (<0.8), minor allele frequency (<0.05) and departures from Hardy-Weinberg equilibrium (<1E-03). Clinical data were ascertained and linked with the genomic data in an anonymized manner. This analysis focused on 199 pts who received cisplatin or carboplatin and were eligible for response assessment (RES=partial response or complete response, n=90). Associations between SNPs and RES were tested using one and two degree of freedom tests. Results: Sixty-nine pts received neoadjuvant therapy (RES=54%), 126 chemo-naive pts received first-line metastatic treatment (RES=37%) and 4 received systemic treatment after prior chemoradiotherapy (RES=25%). We expected 4 associations due to chance alone at p < 0.05. However, on univariate analysis using a 2 degree of freedom test, 9 SNPs were associated (p < 0.05) with RES. Individual odds ratios (ORs) ranged from 0.32 to 3.29 with p-values ranging from 0.006 to 0.05. In analysis of rs9344 (CCND1) in all treated pts, 75/148 (51%) responded with AG/GG compared to 12/44 (27%) with AA [p=0.005312, OR 2.74 (CI 1.34, 5.92)]. In neoadjuvant pts treated with cisplatin, rs9344 analysis showed 29/48 (60%) responses in AG/GG pts compared to 5/17 (29%) with AA [p=0.026, OR 3.66 (CI 1.16, 13.1)]. Conclusions: We identified associations between 9 SNPs and response of UC to platinum-based therapy that are biologically and clinically relevant. A larger study will be required to independently validate these findings. Additional investigation of associations with time to metastasis and overall survival is ongoing. [Table: see text]