Data from Identification of a Variant in <i>KDR</i> Associated with Serum VEGFR2 and Pharmacodynamics of Pazopanib

Abstract

<div>Abstract<p><b>Purpose:</b> VEGF receptor (VEGFR) kinases are important drug targets in oncology that affect function of systemic endothelial cells. To discover genetic markers that affect VEGFR inhibitor pharmacodynamics, we performed a genome-wide association study of serum soluble vascular VEGFR2 concentrations [sVEGFR2], a pharmacodynamic biomarker for VEGFR2 inhibitors.</p><p><b>Experimental Design:</b> We conducted a genome-wide association study (GWAS) of [sVEGFR2] in 736 healthy Old Order Amish volunteers. Gene variants identified from the GWAS were genotyped serially in a cohort of 128 patients with advanced solid tumor with baseline [sVEGFR2] measurements, and in 121 patients with renal carcinoma with [sVEGFR2] measured before and during pazopanib therapy.</p><p><b>Results:</b> rs34231037 (C482R) in <i>KDR</i>, the gene encoding sVEGFR2 was found to be highly associated with [sVEGFR2], explaining 23% of the variance (<i>P</i> = 2.7 × 10<sup>−37</sup>). Association of rs34231037 with [sVEGFR2] was replicated in 128 patients with cancer with comparable effect size (<i>P</i> = 0.025). Furthermore, rs34231037 was a significant predictor of changes in [sVEGFR2] in response to pazopanib (<i>P</i> = 0.01).</p><p><b>Conclusion:</b> Our findings suggest that genome-wide analysis of phenotypes in healthy populations can expedite identification of candidate pharmacogenetic markers. Genotyping for germline variants in <i>KDR</i> may have clinical utility in identifying patients with cancer with unusual sensitivity to effects of VEGFR2 kinase inhibitors. <i>Clin Cancer Res; 21(2); 365–72. ©2014 AACR</i>.</p></div>