| Abstract: |
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-1α) 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-1α percent of tumor expression groups 0-2 (HIF-1α low) versus 3-4 (HIF-1α 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-1α were identified as relevant baseline biomarkers of sunitinib activity in advanced RCC, warranting further research into their prognostic versus predictive value. |
| Keywords: |
vasculotropin receptor 3; adult; controlled study; treatment outcome; disease-free survival; vascular endothelial growth factor a; single nucleotide polymorphism; genetics; polymorphism, single nucleotide; clinical trial; angiogenesis inhibitor; sunitinib; disease free survival; metabolism; phase 2 clinical trial; randomized controlled trial; drug administration schedule; tumor markers, biological; drug screening; pathology; drug screening assays, antitumor; tumor antigen; tumor marker; kidney neoplasms; blood; antigens, neoplasm; carcinoma, renal cell; multicenter study; vasculotropin a; drug monitoring; drug administration; indoles; pyrroles; angiogenesis inhibitors; indole derivative; hypoxia inducible factor 1alpha; von hippel lindau protein; angiopoietin 2; hypoxia-inducible factor 1, alpha subunit; pyrrole derivative; gelatinase a; carbonate dehydratase; carbonic anhydrases; angiopoietin-2; procedures; matrix metalloproteinase 2; vascular endothelial growth factor receptor-3; von hippel-lindau tumor suppressor protein; humans; prognosis; human; male; female; ca9 protein, human
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