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

• Published in: Clinical cancer research Vol. 16; no. 19; pp. 4853 - 4863
• Main Authors: PENA, Carol, LATHIA, Chetan, MINGHUA SHAN, ESCUDIER, Bernard, BUKOWSKI, Ronald M
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.10.2010
• Subjects: Aged; Antigens, Neoplasm - blood; Antigens, Neoplasm - metabolism; Antineoplastic agents; Benzenesulfonates - administration & dosage; Benzenesulfonates - therapeutic use; Biological and medical sciences; Biomarkers, Tumor - blood; Carbonic Anhydrase IX; Carbonic Anhydrases - blood; Carbonic Anhydrases - metabolism; Carcinoma, Renal Cell - blood; Carcinoma, Renal Cell - diagnosis; Carcinoma, Renal Cell - drug therapy; Disease Progression; Drug Administration Schedule; Female; Humans; Kidney Neoplasms - blood; Kidney Neoplasms - diagnosis; Kidney Neoplasms - drug therapy; Kidneys; Male; Medical sciences; Nephrology. Urinary tract diseases; Niacinamide - analogs & derivatives; Pharmacology. Drug treatments; Phenylurea Compounds; Predictive Value of Tests; Prognosis; Proto-Oncogene Proteins p21(ras) - blood; Pyridines - administration & dosage; Pyridines - therapeutic use; Survival Analysis; Tissue Inhibitor of Metalloproteinase-1 - blood; Tissue Inhibitor of Metalloproteinase-1 - metabolism; Treatment Outcome; Tumors of the urinary system; Vascular Endothelial Growth Factor A - blood; Vascular Endothelial Growth Factor Receptor-2 - blood; Kidney disease; Antineoplastic agent; Human; Evaluation; Urinary system disease; Carcinoma; Prognosis; Tyrosine kinase inhibitor; Prediction; Enzyme inhibitor; Biological marker; Patient; Malignant tumor; Treatment; Sorafenib; Kidney cancer; Clinical trial; Grawitz tumor; Advanced stage; Multikinase inhibitor; Antiangiogenic agent; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-09-3343

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. 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. 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. 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.