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Biomarkers Predicting Outcome in Patients with Advanced Renal Cell Carcinoma: Results from Sorafenib Phase III Treatment Approaches in Renal Cancer Global Evaluation Trial.

Author(s): Pena C, Lathia C, Shan M, Escudier B, Bukowski RM

Affiliation(s): Authors' Affiliations: Bayer HealthCare Pharmaceuticals, Montville, New Jersey; Institut Gustave Roussy, Villejuif, France; and Cleveland Clinic Taussig Cancer Center, Cleveland, Ohio.

Publication date & source: 2010-10-01, Clin Cancer Res., 16(19):4853-4863. Epub 2010 Jul 22.

PURPOSE: Plasma proteins [vascular endothelial growth factor (VEGF), soluble VEGF receptor 2 (sVEGFR-2), carbonic anhydrase IX (CAIX), tissue inhibitor of metalloproteinase 1 (TIMP-1), and Ras p21] and one tumor gene (VHL) were analyzed to identify prognostic biomarkers or indicators of response to sorafenib in a subset of patients enrolled in the Treatment Approaches in Renal Cancer Global Evaluation Trial. EXPERIMENTAL DESIGN: Nine hundred three patients with advanced renal cell carcinoma (RCC) were randomized to 400 mg sorafenib twice a day or placebo. Samples collected at baseline and after 3 and 12 weeks were subjected to enzyme-linked immunosorbent assays. VHL exons were sequenced from tumor biopsies. RESULTS: Baseline biomarker data were available for VEGF (n = 712), sVEGFR-2 (n = 713), CAIX (n = 128), TIMP-1 (n = 123), Ras p21 (n = 125), and VHL mutational status (n = 134). Higher Eastern Cooperative Oncology Group performance status (ECOG PS) score correlated with elevated baseline VEGF (P < 0.0001) and a higher incidence of VHL mutations (P = 0.008), whereas higher Memorial Sloan-Kettering Cancer Center (MSKCC) score correlated with elevated VEGF (P < 0.0001), CAIX (P = 0.027), and TIMP-1 (P = 0.0001). Univariable analyses of baseline levels in the placebo cohort identified VEGF (P = 0.0024), CAIX (P = 0.034), TIMP-1 (P = 0.001), and Ras p21 (P = 0.016) as prognostic biomarkers for survival. TIMP-1 remained prognostic for survival in a multivariable analysis model (P = 0.002) that also included ECOG PS, MSKCC score, and the other biomarkers assayed. In the placebo cohort, TIMP-1 (P < 0.001) and Ras p21 (P = 0.048) levels increased at 12 weeks. In the sorafenib cohort, VEGF levels increased at 3 and 12 weeks of treatment (both weeks P < 0.0001), whereas sVEGFR-2 (both weeks P < 0.0001) and TIMP-1 levels (P = 0.002, week 3; P = 0.006, week 12) decreased. CONCLUSIONS: VEGF, CAIX, TIMP-1, and Ras p21 levels were prognostic for survival in RCC patients. Of these, TIMP-1 has emerged as being independently prognostic. Clin Cancer Res; 16(19); 4853-63. (c)2010 AACR.

Page last updated: 2010-10-05

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