Pharmacogenetic pathway analysis for determination of sunitinib-induced toxicity.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
van Erp
Nielka P
NP
Leiden University Medical Center, Department of Clinical Pharmacy & Toxicology, Leiden, the Netherlands.
Eechoute
Karel
K
van der Veldt
Astrid A
AA
Haanen
John B
JB
Reyners
An K L
AK
Mathijssen
Ron H J
RH
Boven
Epie
E
van der Straaten
Tahar
T
Baak-Pablo
Renée F
RF
Wessels
Judith A M
JA
Guchelaar
Henk-Jan
HJ
Gelderblom
Hans
H
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects; D000090702:Constitutive Androstane Receptor; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D064420:Drug-Related Side Effects and Adverse Reactions / Q000139:chemically induced / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D007211:Indoles / Q000009:adverse effects* / Q000493:pharmacokinetics; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D052016:Mucositis / Q000139:chemically induced; D010597:Pharmacogenetics / Q000379:methods*; D020641:Polymorphism, Single Nucleotide; D011758:Pyrroles / Q000009:adverse effects* / Q000493:pharmacokinetics; D012307:Risk Factors; D000077210:Sunitinib; D055815:Young Adult
D000970:Antineoplastic Agents; D000090702:Constitutive Androstane Receptor; D007211:Indoles; C000716327:NR1I3 protein, human; D011758:Pyrroles; D019363:Cytochrome P-450 CYP1A1; D000077210:Sunitinib