Originally published as JCO Early Release 10.1200/JCO.2008.21.7679 on August 10 2009

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Pharmacogenetic Pathway Analysis for Determination of Sunitinib-Induced Toxicity

From the Departments of Clinical Pharmacy & Toxicology and Clinical Oncology, Leiden University Medical Center, Leiden; Department of Medical Oncology, Erasmus University Medical Center, Rotterdam; Department of Medical Oncology, Vrije Universiteit University Medical Center; Department of Medical Oncology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam; and the Department of Medical Oncology, University Medical Center Groningen, Groningen, the Netherlands.

Corresponding author: Henk-Jan Guchelaar, PhD, PharmD, Leiden University Medical Center, Department of Clinical Pharmacy & Toxicology, Room L0-042, Albinusdreef 2, 2333 ZA Leiden, the Netherlands; e-mail: h.j.guchelaar{at}lumc.nl.

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 FLT3 738T/C (OR, 2.8; P = .008) were present or CAG in the NR1I3 (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.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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