Prospective exploratory analysis of the association between genetic polymorphisms and sunitinib toxicity and efficacy in metastatic renal-cell carcinoma.

Abstract

4620 Background: Sunitinib (SU) is a multi-targeted receptor tyrosine kinase inhibitor treatment that is approved for metastatic renal cell carcinoma (mRCC). However, several patients either do not respond to treatment or they experience significant toxicity.Our study aims to find genetic markers of toxicity and efficacy using a commercially available DNA microarray genotyping system. Methods: 30 patients with newly diagnosed mRCC, from January 2010 to May 2011, were evaluated prospectively at Hospital 12 de Octubre (Madrid, Spain). Pts received SU 50 mg/day, 4 wks on / 2 wks off treatment schedule. A total of 92 of single nucleotide polymorphisms (SNPs) in 34 genes in the pharmacokinetic and pharmacodynamic pathways of drugs were analyzed using Drug inCode pharmacogenetic service. SNPs in candidate genes, together with clinical characteristics were tested univariately for association with the number of days of SU treatment until the first reduction of dose, PFS and OS. Results: Complete analysis was possible in 25 pts. Pts with CYP1A2*1/*1.a low metabolizing genotype, had an increased risk of dose reductions due to toxicity compare to allele *1F (Median time to dose reduction : 2.33 months vs NR; p<0.006). Pts with CYP2C19*1/*1 , wild type genotype, had an increased risk of dose reductions due to toxicity vs. other genotypes (Median time to dose reduction: 2.8 vs 9.73 months; p<0.021). Catechol-O-methyltransferase (COMT) V158M polymorphisms, was associated with PFS and OS (Met/Met carriers median PFS and OS NR; Met/Val pts PFS= 15 months; OS=17.2 months and Val/Val pts PFS=3.3 months; OS= 4.4 months ; p=0.005 for PFS and p=0.003 for OS). Conclusions: This preliminary analysis suggests that CYP1A2 and CYP2C19 SNPs may be associated with toxicity in patients with RCC treated with SU. As CYP1A2 and CYP2C19 activity could be affected by a variety of non-genetic factors, if these is confirmed, it could lead to the necessity of controlling toxic and dietary habits of pts treated with SU. SNPs associated with toxicity and survival in this preliminary analysis are being validated in an independent cohort of RCC treated with SU (García-Donas J, et al. Lancet Oncol 2011).