Heterogeneous Drug Target Expression As Possible Basis for Different Clinical and Radiological Response to the Treatment of Primary and Metastatic Renal Cell Carcinoma: Suggestions from Bench to Bedside

Metastatic disease occurs in a significant percentage of patients with renal cell carcinoma (RCC) and is usually associated with an overall poor prognosis. However, not all of the sites of metastases seem to have the same prognostic significance in patients receiving targeted agents. Indeed, patients with lung-only metastases seem to present a better survival than patients with other sites, whereas liver and bone metastases are associated with a worst prognosis. Some clinical studies suggest that metastatic sites are more responsive than primary tumors. This event may be due to intratumor heterogeneity in terms of somatic mutations, chromosome aberrations, and tumor gene expression, primarily centered around Von Hippel-Lindau (VHL) pathway, such as VHL mutations, HIF levels, vascular endothelial growth factor (VEGF) isoforms, and VEGF receptor levels. Nevertheless, these data do not completely explain the discordant biological behavior between primary tumor and metastatic sites. Understanding the causes of this discordance will have profound consequences on translational research and clinical trials in RCC. In this review, we overview current data on the differences between primary RCC and metastases in terms of drug target expression and clinical/radiological response to targeted agents, thus describing the prognostic role of different metastatic sites in RCC patients.