Background Imatinib 400 mg per day is first-line therapy for patients with gastrointestinal stromal tumours (GISTs). Although clinical benefit is high, progression-free survival (PFS) is variable. This study explores the relationship of single nucleotide polymorphisms (SNPs) in genes related to imatinib pharmacokinetics and pharmacodynamics and PFS in imatinib-treated patients with advanced GIST.
Methods In 227 patients a pharmacogenetic pathway analysis was performed. Genotype data from 36 SNPs in 18 genes were tested in univariate analyses to investigate their relationship with PFS. Genetic variables which showed a trend (p < 0.1) were tested in a multivariate model, in which each singular SNP was added to clinicopathological factors.
Results In univariate analyses, PFS was associated with synchronous metastases (p = 0.0008) and the mutational status (p = 0.004). Associations with rs1870377 in KDR (additive model, p = 0.0009), rs1570360 in VEGFA (additive model, p = 0.053) and rs4149117 in SLCO1B3 (mutant dominant model, 0.027) were also found. In the multivariate model, significant associations and trends with shorter PFS were found for synchronous metastases (HR 1.94, p = 0.002), KIT exon 9 mutation (HR 2.45, p = 0.002) and the SNPs rs1870377 (AA genotype, HR 2.61, p = 0.015), rs1570360 (AA genotype, HR 2.02, p = 0.037) and rs4149117 (T allele, HR 0.62, p = 0.083).
Conclusion In addition to KIT exon 9 mutation and synchronous metastases, SNPs in KDR, VEGFA and SLCO1B3 appear to be associated with PFS in patients with advanced GIST receiving 400-mg imatinib. If validated, specific SNPs may serve as predictive biomarkers to identify patients with an increased risk for progressive disease during imatinib therapy.

Additional Metadata
Keywords GIST, Imatinib, Pharmacogenetic pathway analysis, SNPs, Survival, VEGF
Persistent URL dx.doi.org/10.1016/j.ejca.2017.09.025, hdl.handle.net/1765/102491
Journal European Journal of Cancer
Citation
Verboom, M.C, Kloth, J.S.L, Swen, J.J, van der Straaten, T.J, Bovée, J.V.M.G, Sleijfer, S, … Gelderblom, H. (2017). Genetic polymorphisms in angiogenesis-related genes are associated with worse progression-free survival of patients with advanced gastrointestinal stromal tumours treated with imatinib. European Journal of Cancer, 86, 226–232. doi:10.1016/j.ejca.2017.09.025