mRNA expression, tumor heterogeneity, and response to therapy in patients with advanced renal cell carcinoma treated with immune-based combinations (ARON-1α)

Background: Renal Cell Carcinoma (RCC) represents a spectrum of tumors, characterized by heterogeneous growth patterns, histology and response to immune-based combinations. Objectives: The aim of the present retrospective analysis was to investigate the mRNA expression of 32 genes associated with RCC carcinogenesis and their potential involvement in patients treated with first-line immune-based combination therapies. Additionally, we examined the role of tumor heterogeneity by comparing mRNA expression levels between primary renal tumors and metastatic sites in a group of patients included in the ARON-1 study. Patients and methods: The study included patients with advanced RCC treated with first-line immune-based therapies. Total RNA was extracted from fixed paraffin-embedded tissue slices using the RNeasy FFPE Mini Kit. Quantitative RT-PCR was performed using the IQ5 Multicolor real-time PCR detection system. Coefficient of variations were calculated for each gene and compared between primary and metastatic samples. Results: 17 patients were included in this analysis; 9 of them had both primary and metastatic samples available. Three of the 4 patients showing the highest mRNA expression levels of the 32 analyzed genes reported complete remissions, while 2 of the 3 patients with the lowest expression levels were primary refractory to first-line therapy. As for tumor heterogeneity, VEGFA was the only gene significantly deregulated in the paired comparison. Conclusions: We showed differences in mRNA expression between primary and metastatic sites, and proposed a possible link to the response to first-line immune combination therapies. Additional research is required to clarify their potential as prognostic or predictive biomarkers.