Background Sunitinib (SU) is an oral, small-molecule, multi-targeted tyrosine kinase receptor inhibitor that is approved for the treatment of renal cell carcinoma (RCC). However, several patients either do not respond to treatment, or they do, but they experience significant toxicity.
Purpose To find genetic markers of toxicity and efficacy using a commercially available DNA microarray genotyping system.
Materials and Methods 25 patients with newly-diagnosed metastatic RCC were evaluated prospectively from January 2010 to May 2011. Patients received SU in repeated 6-week cycles of 50 mg/day orally for 4 weeks, followed by 2 weeks off treatment. A total of 92 single nucleotide polymorphisms (SNPs) in 34 genes in the pharmacokinetic and pharmacodynamic pathways of drugs were analysed using the Drug inCode pharmacogenetic service. This test is performed from a saliva sample and uses a DNA microarray system. Polymorphisms in candidate genes, together with clinical characteristics, were tested by univariate analysis for association with the number of days of sunitinib treatment until the first reduction of dose, progression free survival (PFS) and overall survival (OS).
Results Patients with CYP1A2*1/*1, a low-metabolising genotype, needed dose reduction due to an increased risk of toxicity vs. *1F/*1F or 1F/1F*(Median time to dose reduction: 2.33 months vs. not reached during study period; p < 0.006). Patients with CYP2C19*1/*1, wild type genotype, had an increased risk of dose reductions due to toxicity versus other genotypes (Median time to dose reduction: 2.8 months vs. 9.73 months; P < 0.021). No statistically significant associations were observed among drug metabolising genes and PFS or OS.
Val(158)Met Catechol-O-methyltransferase (COMT) gene polymorphisms have been associated with PFS and OS. We found that Met/Met carriers, low metabolising allele, had longer PFS and OS compared to those with Met/Val (PFS not reached vs. 15 months; OS not reached Vs17.2 months) and Val/Val (PFS = 3.3 months; OS = 4.4 months) phenotypes (P = 0.005 for PFS and P = 0.003 for OS).
Conclusions This preliminary analysis suggests that CYP1A2 and CYP2C19 polymorphisms may be associated with toxicity in patients with RCC treated with sunitinib. Polymorphisms associated with toxicity and survival in this preliminary analysis are being validated in an independent cohort of 95 RCC patients treated with sunitinib.
No conflict of interest.
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