Genetic Polymorphisms in Angiogenesis-Related Genes Are Associated with Worse Progression-Free Survival of Patients with Advanced Gastrointestinal Stromal Tumours Treated with Imatinib

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. (C) 2017 Elsevier Ltd. All rights reserved.