ABSTRACT: Cisplatin-based combination chemotherapy (CHT) is standard of care in locally advanced and metastatic urothelial cancer (mUC). No predictive biological biomarkers are available for clinical use. Here, we investigate the impact of molecular subtypes in relation to response and survival in mUC patients treated with first-line CHT. Molecular subtype classification according to Lund taxonomy was performed by tumour transcriptomic profiling and immunostaining in a retrospective cohort with mUC patients treated with CHT. We analyze overall response rate (ORR) and secondary endpoint overall survival (OS) in comparison to prespecified molecular subtypes. Differential gene expression and association to treatment response was explored. Ninety-five patients with mUC were classified into urothelial (Uro, 43%), genomically unstable (GU, 26%), basal/squamous (Ba/Sq, 20%), mesenchymal like (Mes-like, 8%) and small-cell/neuroendocrine-like (Sc/NE, 3%) subtypes. Gene expression data is available for 86 patients. Patients with Mes-like tumours had significantly lower ORR (14%), compared to Uro (70%), GU (77%), Ba/Sq (75%) and Sc/NE, 67%), p = 0.020. Further, patients with the Mes-like subtype had significantly shorter mOS (HR 3.13, 95% CI: 1.37-7.13, p = 0.007), with Uro as reference. An enrichment of down-regulated stromal- and immune-related genes was seen in responders. Down-regulation of interferon-induced transmembrane protein 2 (IFITM2), an inflammation related gene, was associated with increased ORR and improved OS. In patients treated with CHT for mUC, the Mes-like subtype showed significantly lower response rate and shorter overall survival. Down-regulation of IFITM2 was associated with clinical benefit, suggesting the presence of IFITM2 to be a possible unfavourable prognostic marker in mUC.
