Integrative clinical, genomic, and transcriptomic characterization of circulating KIM-1 in metastatic RCC.

Abstract

4546 Background: Kidney injury molecule-1 (KIM-1) is a transmembrane protein that is overexpressed in renal cell carcinoma (RCC) and correlated with clinical outcomes in localized and metastatic disease. Nevertheless, association between circulating KIM-1 protein levels and the underlying tumor biology represented by genomic and transcriptomic correlates is not well understood. Methods: KIM-1 was measured in plasma at baseline (C1D1) and at C3D1 using an MSD electrochemiluminescence-based assay. Differential gene expression (DGE) and gene set enrichment analysis (GSEA) were performed using DESeq2, with KIM-1 treated as a continuous variable. Associations between circulating KIM-1 levels and clinical, genomic, and transcriptomic tissue data from the JAVELIN Renal 101 trial were evaluated using the Wilcoxon rank-sum test (for categorical groups) and Cox regression (for time-to-event outcomes). Results: Plasma for analysis was available from 612 patients (69% of the ITT population), including 323 treated with avelumab plus axitinib and 289 with sunitinib. Elevated baseline KIM-1 levels were correlated with higher tumor burden as assessed by the sum of tumor diameters (Spearman’s ρ = 0.55, p < 0.0001), decreased with tumor shrinkage (p < 0.0001), and were associated with poorer PFS (HR 1.32 per unit increase in log KIM-1, 95% confidence interval (CI) 1.16–1.49, p < 0.0001) and OS (HR 1.96 per unit increase in log KIM-1, 95% CI 1.61–2.37, p < 0.0001). Higher KIM-1 levels were found in IMDC poor–risk versus intermediate–risk (p < 0.0001) and in intermediate–risk versus favorable–risk groups (p < 0.001). Loss-of-function (LOF) BAP1 mutations, associated with more aggressive disease, were associated with higher KIM-1 RNA expression (p < 0.0001) and protein expression (p = 0.038) and remained significant after adjustment for tumor burden as assessed by linear regression residuals. Transcriptomic analysis showed that RNA expression levels of HAVCR1 , the gene coding KIM-1, were associated with circulating KIM-1 protein (Spearman’s ρ = 0.31, p < 0.0001), and that higher KIM-1 levels were associated with interferon gamma response whereas lower KIM-1 levels were associated with a hypoxia transcriptional program. Higher circulating KIM-1 was also associated with enrichment for proliferative versus angiogenic gene expression signatures (p = 0.013). The findings were independent of therapy arms. Conclusions: We present the first integrative clinical, transcriptomic, and genomic evaluation of circulating KIM-1. High KIM-1 is a biomarker of poor prognosis in RCC and correlates with specific LOF mutations and transcriptions programs. Prospective studies are needed for the clinical implementation of KIM-1 as a biomarker in RCC.