Background New biomarkers are needed to improve treatment selection in patients with metastatic clear cell renal cell carcinoma (CCRCC). This study aims to identify predictive biomarkers through the investigation of serum proteins related to angiogenesis and tumor immune escape, alongside metabolic patterns associated with clinical outcomes. Methods We conducted a prospective, multicenter study in patients with locally advanced or metastatic CCRCC receiving first-line sunitinib. Serum protein levels, including those related to angiogenesis and immune escape, were measured. Additionally, untargeted lipidomic and targeted metabolic analyses focused on tryptophan metabolism and amino acid profiles were performed. Routine blood test results were recorded, and correlations among all parameters were analyzed. Results Thirty-eight patients from ten Spanish hospitals were included. Median progression-free survival (PFS) was 9.87 months, and median overall survival (OS) was 21.10 months. Multivariate analysis identified higher interleukin-6 (IL-6), arginase-1, and S100 calcium binding protein A9 (S100A9) concentrations as significant predictors of shorter OS. We defined three distinct risk groups based on the combined levels of S100A9 and IL-6: high levels of both proteins, high levels of either one protein, or low levels of both proteins confer a poor, intermediate and favorable prognosis, respectively. Metabolomic analysis revealed significant differences in the tryptophan-kynurenine pathway between patients with extreme PFS and OS phenotypes. Elevated levels of tryptophan metabolites were associated with poorer PFS, while alterations in amino acids and tryptophan metabolites correlated with OS extremes. Notably, significant correlations were observed between IL-6 levels and increased tryptophan metabolism. Conclusions This study underscores the prognostic value of specific proteins and metabolites in metastatic CCRCC, proposing potential biomarkers for patient stratification and treatment response prediction.
Quintás et al. (2026) studied this question.