Pharmacogenetic Pathway Analysis for Determination of Sunitinib-Induced Toxicity

NP van Erp, Karel Eechoute, AA van der Veldt, JB Haanen, AKL Reyners, RHJ Mathijssen, Eva Boven, T Straaten, RF Baak-Pablo, JAM Wessels, HJ Guchelaar, H Gelderblom

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Abstract

Purpose To identify genetic markers in the pharmacokinetic and pharmacodynamic pathways of sunitinib that predispose for development of toxicities: thrombocytopenia, leukopenia, mucosal inflammation, hand-foot syndrome, and any toxicity according to National Cancer Institute Common Toxicity Criteria higher than grade 2. Patients and Methods A multicenter pharmacogenetic association study was performed in 219 patients treated with single-agent sunitinib. A total of 31 single nucleotide polymorphisms in 12 candidate genes, together with several nongenetic variants, were analyzed for a possible association with toxicity. In addition, genetic haplotypes were developed and related to toxicity. Results The risk for leukopenia was increased when the G allele in CYP1A1 2455A/G (odds ratio [ OR], 6.24; P = .029) or the T allele in FLT37 38T/C (OR, 2.8; P = .008) were present or CAG in the NR1/3 (5719C/T, 7738A/C, 7837T/G) haplotype (OR, 1.74; P = .041) was absent. Any toxicity higher than grade 2 prevalence was increased when the T allele of vascular endothelial growth factor receptor 2 1191C/T (OR, 2.39; P = .046) or a copy of TT in the ABCG2 (-15622C/T, 1143C/T) haplotype (OR, 2.63; P = .016) were present. The risk for mucosal inflammation was increased in the presence of the G allele in CYP1A1 2455A/G (OR, 4.03; P = .021) and the prevalence of hand-foot syndrome was increased when a copy of TTT in the ABCB1 (3435C/T, 1236C/T, 2677G/T) haplotype (OR, 2.56; P = .035) was present. Conclusion This exploratory study suggests that polymorphisms in specific genes encoding for metabolizing enzymes, efflux transporters, and drug targets are associated with sunitinib-related toxicities. A better understanding of genetic and nongenetic determinants of sunitinib toxicity should help to optimize drug treatment in individual patients.
Original languageUndefined/Unknown
Pages (from-to)4406-4412
Number of pages7
JournalJournal of Clinical Oncology
Volume27
Issue number26
Publication statusPublished - 2009

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