Article

Pharmacogenetic pathway analysis for determination of sunitinib-induced toxicity.

Leiden University Medical Center, Department of Clinical Pharmacy & Toxicology, Leiden, the Netherlands.
Journal of Clinical Oncology (impact factor: 18.37). 09/2009; 27(26):4406-12. DOI:10.1200/JCO.2008.21.7679 pp.4406-12
Source: PubMed

ABSTRACT 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.
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.
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.
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.

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Keywords

12 candidate genes
 
31 single nucleotide polymorphisms
 
ABCG2
 
CAG
 
drug targets
 
efflux transporters
 
exploratory study
 
grade 2
 
grade 2 prevalence
 
metabolizing enzymes
 
multicenter pharmacogenetic association study
 
National Cancer Institute Common Toxicity Criteria higher
 
nongenetic determinants
 
nongenetic variants
 
odds ratio [OR]
 
optimize drug treatment
 
possible association
 
single-agent sunitinib
 
specific genes encoding
 
sunitinib-related toxicities