Markers of sunitinib-resistance in clear cell renal cell carcinoma: A gene expression analysis.

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Abstract
533 Background: Sunitinib is a standard first line treatment of metastatic renal cell carcinoma (ccRCC). Approximately 20% of patients experience primary resistance to therapy and no predictive biomarkers are available. The aim of our study is to discover novel biomarkers to predict response to sunitinib and to generate hypothesis about mechanisms of intrinsic resistance. Methods: Gene expression analysis was performed in formalin-fixed paraffin embedded (FFPE) samples from 44 patients with metastatic ccRCC treated with sunitinib in our institution. Affymetrix Human Gene 2.0 ST array was performed in primary tumors from 6 extremely sensitive (progression free survival (PFS) > 24 months) and 8 refractory (progression disease as best response) ccRCC. Technical validation with qPCR (Fluidigm Dynamic 96.96 Array) was performed in the whole cohort. The ΔΔCt method was used to quantify the relative amount of mRNA. Clinical and pathological data were correlated with gene expression. Results: 330 genes were differentially expressed between refractory and sensitive patients (p≤0.05). Network analysis showed 16 significant networks represented. Gene expression of 96 selected markers was tested in 47 primary tumors and 24 metastases. We found IL8, VEGF and NOTCH pathways upregulated on refractory patients. Survival analysis showed that the overexpression of IL8 correlated with a worse PFS (HR: 2.42, 95%CI1.27 – 4.63, p=0.0075) and overall survival (OS) (HR: 3.42, 95%CI 1.50 – 7.79, p=0.0034). Overexpression of VEGFBcorrelated with a prolonged PFS (HR 0.52, 95% CI 0.28 – 0.98, p=0.0415). Conclusions: Our results confirm the predictive value of IL8 expression in a cohort of ccRCC patients treated with sunitinib and suggests novel biomarkers of response to sunitinib. These data will be further validated in an independent cohort of patients.