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Motzer RJ , Hutson TE , Hudes GR , Figlin RA , Martini JF , English PA , Huang X , Valota O , Williams JA
Investigation of novel circulating proteins, germ line single-nucleotide polymorphisms, and molecular tumor markers as potential efficacy biomarkers of first-line sunitinib therapy for advanced renal cell carcinoma
Cancer Chemother Pharmacol. 2014 Oct;74(4) :739-50
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PURPOSE: Sunitinib is a first-line advanced renal cell carcinoma (RCC) standard of care. In a randomized phase II trial comparing sunitinib treatment schedules, separate exploratory biomarker analyses investigated the correlations of efficacy with selected serum, germ line single-nucleotide polymorphism (SNP), or tumor markers. METHODS: Advanced RCC patients received first-line sunitinib 50 mg/day on the approved 4-week-on-2-week-off schedule (n = 146) or 37.5 mg/day continuous dosing (n = 146). The following correlation analyses were performed: (1) response evaluation criteria in solid tumors-defined tumor response with serum soluble protein levels via two distinct multiplex (n < 1,000) platforms; (2) response and time-to-event outcomes with germ line SNPs in vascular endothelial growth factor (VEGF)-A and VEGF receptor (VEGFR)3 genes; and (3) response and time-to-event outcomes with tumor immunohistochemistry status for hypoxia-inducible factor 1-alpha (HIF-1alpha) and carbonic anhydrase-IX or tumor Von Hippel-Lindau (VHL) gene inactivation status. RESULTS: Lower baseline angiopoietin-2 (Ang-2) and higher baseline matrix metalloproteinase-2 (MMP-2) levels were identified by both platforms as statistically significantly associated with tumor response. There were no significant correlations between VEGF-A or VEGFR3 SNPs and outcomes. Progression-free survival was longer for HIF-1alpha percent of tumor expression groups 0-2 (HIF-1alpha low) versus 3-4 (HIF-1alpha high; p = 0.034). There were no significant correlations between outcomes and each VHL inactivation mechanism [mutation (86% of VHL-inactive patients), methylation (14%), and large deletion (7%)] or mechanisms combined. CONCLUSIONS: Serum Ang-2 and MMP-2 and tumor HIF-1alpha were identified as relevant baseline biomarkers of sunitinib activity in advanced RCC, warranting further research into their prognostic versus predictive value.
Motzer, Robert J Hutson, Thomas E Hudes, Gary R Figlin, Robert A Martini, Jean-Francois English, Patricia A Huang, Xin Valota, Olga Williams, J Andrew ENG Clinical Trial, Phase II Multicenter Study Randomized Controlled Trial Research Support, Non-U.S. Gov't Germany 2014/08/08 06:00 Cancer Chemother Pharmacol. 2014 Oct;74(4):739-50. doi: 10.1007/s00280-014-2539-0. Epub 2014 Aug 7.