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

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.

Trial registration: ClinicalTrials.gov NCT00267748.

Figures

Fig. 1

Kaplan–Meier curves of a TTP, b PFS, and c OS after stratification by level of HIF-1α percent of tumor expression in patients from both treatment arms combined (intent-to-treat population). HIF-1α percent of tumor expression (individual variable score) was stratified in groups (0, 1, 2, 3, 4) and the cutoff point was set at 3. Groups 0–2 correspond to 0–50 % (i.e., low HIF-1α expression) and groups 3–4 correspond to 51–100 % (i.e., high HIF-1α expression). An HR >1 indicates a reduction in hazard rate in favor of groups 0–2, whereas an HR <1 indicates a reduction in hazard rate in favor of groups 3–4. HIF-1α hypoxia-inducible factor 1-alpha, HR hazard ratio, NR not reached, OS overall survival, PFS progression-free survival, TTP time to tumor progression