Molecular Subtypes and Gene Expression Signatures as Prognostic Features in Fully Resected Clear Cell Renal Cell Carcinoma: A Tailored Approach to Adjuvant Trials

Trials with adjuvant vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) failed to demonstrate meaningful benefit in clinically high-risk, fully resected clear cell renal cell carcinoma (ccRCC). We evaluated whether the ccrcc1-4 molecular subtypes and gene expression signatures (GES) are associated with outcomes in this setting.We determined molecular subtypes as well as angiogenesis- and immune-related GES through RNA sequencing of 75 fresh frozen (FF) and 62 formalin-fixed, paraffin-embedded (FFPE) tumor samples. We studied disease-free (DFS) and overall survival (OS) and determined correlations among GES and Leibovich score.Angiogenesis-related GES and molecular subtypes were associated with longer DFS and OS across both cohorts, whereas immune-related GES were not. In the FF cohort, molecular subtypes (ccrcc2 & 3 vs. ccrcc1 & 4) were associated with DFS and OS, on bivariable analysis with Leibovich score (HR 0.62, 95%CI 0.39-0.98, P = .04 and HR 0.35, 95%CI 0.19-0.64, P < .001). In the FFPE cohort, molecular subtypes (ccrcc2 & 3 vs. ccrcc1&4) were also associated with DFS (HR 0.53, 95%CI 0.31-0.93, P = .03), but not OS (HR 0.59, 95%CI 0.31-1.13, P = .11) on bivariable analysis with Leibovich score. Leibovich score was significantly inversely correlated with all angiogenesis-related GES (all P < .01), but not correlated with immune-related GES.Molecular subtypes and angiogenesis-related GES are prognostic for DFS and OS in fully resected, localized ccRCC. Favorable ccrcc2 & 3 molecular subtypes with high angiogenesis-related GES, which respond best to VEGFR-TKIs, are at lower risk of relapse but were probably underrepresented in the adjuvant VEGFR-TKI trials since they inversely correlate with Leibovich score. Conversely, immune-related GES are not correlated with Leibovich score and clinically high-risk tumors can display both high and low immune-related GES. Therefore, molecular characterization could guide patient selection for adjuvant treatment.