title: Genetic polymorphisms as predictive biomarker of survival in patients with gastrointestinal stromal tumors treated with sunitinib.
abstract: This study aimed to identify single-nucleotide polymorphisms (SNPs) that are associated with outcome to treatment with sunitinib in patients with advanced gastrointestinal stromal tumors (GIST). Forty-nine SNPS involved in the pharmacokinetic and pharmacodynamic pathway of sunitinib were associated with progression-free survival (PFS) and overall survival (OS) in 127 patients with advanced GIST who have been treated with sunitinib. PFS was significantly longer in carriers of the TT genotype in POR rs1056878 (hazards ratio (HR) 4.310, 95% confidence interval (CI):1.457-12.746, P=0.008). The presence of the T-allele in SLCO1B3 rs4149117 (HR 2.024, 95% CI:1.013-4.044, P=0.046), the CCC-CCC alleles in SLC22A5 haplotype (HR 2.603, 95% CI: 1.216-5.573, P=0.014), and the GC-GC alleles in the IL4 R haplotype (HR 7.131, 95% CI:1.518-33.496, P=0.013) were predictive for OS. This shows that polymorphisms in the pharmacokinetic and pharmacodynamic pathways of sunitinib are associated with survival in GIST. This may help to identify patients that benefit more from treatment with sunitinib.
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
authors.forename: J S L
authors.initials: JSL
authors.lastname: Kloth
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: M C
authors.initials: MC
authors.lastname: Verboom
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: J J
authors.initials: JJ
authors.lastname: Swen
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: van der Straaten
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.|Cancer Genomics Netherlands, Rotterdam, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Sleijfer
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: A K L
authors.initials: AKL
authors.lastname: Reyners
authors.affiliation: Department of Medical Oncology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
authors.forename: N
authors.initials: N
authors.lastname: Steeghs
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Gelderblom
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: H J
authors.initials: HJ
authors.lastname: Guchelaar
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
authors.forename: R H J
authors.initials: RHJ
authors.lastname: Mathijssen
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000209:etiology* / Q000235:genetics* / Q000401:mortality; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D000077982:Progression-Free Survival; D000077210:Sunitinib / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D000077210:Sunitinib