Biomarkers associated with survival in patients with platinum-refractory urothelial carcinoma treated with paclitaxel

Abstract

Background: Taxane- based chemotherapy is widely used in patients with platinum- and immunotherapy refractory, metastatic urothelial carcinoma (mUC). Outcomes are poor and biomarkers associated with outcome are lacking. We aim to identify cancer hallmarks associated with survival in patients receiving paclitaxel. Methods: Whole-transcriptome profiles were generated for a subset of patients enrolled in a randomised phase II study investigating paclitaxel and pazopanib in platinum refractory mUC (PLUTO, EudraCT 2011-001841-34). Estimates of gene expression were calculated and input into the Almac proprietary analysis pipeline and signature scores were calculated using ClaraT V3.0.0. Ten key gene signatures were assessed: Immuno-Oncology, Epithelial to Mesenchymal Transition, Angiogenesis, Proliferation, Cell Death, Genome Instability, Energetics, Inflammation, Immortality and Evading Growth. Hazard ratios were calculated using Cox regression model and Kaplan-Meier methods were used to estimate progression free survival (PFS) and overall survival (OS). Results: 38 and 45 patients treated with paclitaxel or pazopanib were included. Patients with high genome instability expression treated with paclitaxel had significantly improved survival with a HR of 0.29 (95% CI: 0.14-0.61, p=0.001) and HR 0.34 (95% CI: 0.17-0.69, p=0.003) for PFS and OS, respectively. Similarly, patients with high evading growth suppressor expression treated with paclitaxel had improved PFS and OS with a HR of 0.35 (95% CI: 0.19-0.77, p=0.007) and HR 0.46 (95% CI: 0.23-0.91, p=0.026), respectively. No other gene signatures had significant impact on outcome. In both paclitaxel and pazopanib cohorts, angiogenesis activation was associated with worse PFS and OS, and VEGF targeted therapy did not improve outcomes. Conclusion: High Genome-instability and Evading-growth suppressor biologies are associated with improved survival in patients with platinum refractory mUC receiving paclitaxel. These may refine mUC risk stratification and guide treatment decision in the future.