Clinical and prognostic implications of delta-like ligand 4 and hypoxia-inducible factors in metastatic renal cell carcinoma (mRCC) patients treated with sunitinib as first-line therapy.

Abstract

e15567 Background: Sunitinib is recommended as the first line treatment of patients with metastatic renal cell carcinoma (mRCC). Delta-like ligand 4 (DLL4) is a Notch ligand that is upregulated by hypoxia and has a role in tumor angiogenesis. The aim of this study was to evaluate clinical and prognostic implications of DLL4 and markers of hypoxia in mRCC patients treated with sunitinib as first-line therapy. Methods: Treated-naïve, clear cell mRCC patients were received sunitinib 50 mg/d for 4 weeks followed by 2 weeks off treatment (schedule 4/2). We prospectively collected plasma samples before treatment and the expressions of DLL4, Notch1, HIF-1α, HIF-2α were measured using enzyme-linked immunosorbent (ELISA). Progression-free survival (PFS) and overall survival (OS) were determined by Kaplan-Meier method. The log-rank test was used to assess the significance of univariate survival analysis. Multivariate analysis using Cox Regression model was performed to identify independent prognostic factors. Results: Between Aug 2008 and Sep 2010, consecutive 86 patients with mRCC were enrolled. Median follow up period was 35 months. The objective response rate (ORR) was 29.3% (95% confidence interval [CI], 13.5% to 37.7%), median PFS was 10.1 months (95% CI, 8.7 to 12.1 months), and median OS was 23.6 months (95% CI, 16.8 to 26.5 months). Most treatment-related side effect were mild to moderate, including hypertension, fatigue, thrombocytopenia and hand-foot syndrome. Both high DLL4 and low HIF-1α levels significantly correlated with lower ORR (DLL4: 19.8% versus 31.7%, P < 0.001; HIF-1α: 16.8% versus 33.5%, P = 0.002) and shorter PFS (DLL4: 8.6 versus 12.1 months, P = 0.01; HIF-1α: 8.3 versus 11.9 months, P = 0.01), but this was not predictive of OS. Neither survival nor ORR was associated with expressions of Notch1 and HIF-2α. Conclusions: Sunitinib has shown effective anti-tumor activity in treatment-naïve mRCC patients. High expression of DLL4 and low expression of HIF-1α may mediate resistance to sunitinib. Baseline levels of DLL4 and HIF-1α have prognostic impact on PFS for patients treated with sunitinib.