Differential expression of c-Met between primary and metastatic sites in clear-cell renal cell carcinoma (ccRCC) and its association with PD-L1 expression.

4573 Background: Preclinical models show that c-Met promotes survival of renal cancer cells through the regulation of programmed death-ligand 1 (PD-L1). The relationship between c-Met and PD-L1 in human ccRCC is not well characterized. We compared c-Met expression between primary and metastatic sites in ccRCC tissues and evaluated the association with PD-L1 expression. Methods: Pairedprimary and metastatic samples from 45 ccRCC patients were included. Areas with predominant and highest Fuhrman nuclear grade (FNG) were selected. c-Met expression was evaluated by IHC using an anti-Met monoclonal antibody (MET4 Ab, VARI) and calculated by a combined score (CS, 0-300) as: intensity of c-Met staining (0-3) x % of positive cells (0-100). PD-L1 expression was previously assessed by IHC (PMID: 26014095). c-Met expression (average c-Met CS) between paired primary and metastatic samples were compared using Wilcoxon signed-rank test. Associations of c-Met expression with PD-L1 expression (+/-) and other clinical features were assessed with Wilcoxon rank-sum tests. Results: Our cohort included 45 primary ccRCCs and 54 corresponding metastases. c-Met expression was higher in metastatic sites compared to primary (c-Met CS: 55 vs. 28, p=0.0003) and was numerically-greater in PD-L1+ vs. PD-L1- tumors. Higher c-Met expression was associated with higher FNG and T-stage in both primary and metastatic sites (Table). Conclusions: Higher c-Met expression in metastases compared to paired primary tumors in our cohort of ccRCC suggests that testing for biomarkers of response to c-Met inhibitors should be conducted in metastases. Although the observation of higher c-Met expression in PD-L1+ tumors requires further investigation, it supports exploring these targets in combination trials. [Table: see text]