Michiel C Verboom1, Jacqueline S L Kloth2, Jesse J Swen3, Tahar van der Straaten3, Judith V M G Bovée4, Stefan Sleijfer2, Anna K L Reyners5, Ron H J Mathijssen2, Henk-Jan Guchelaar3, Neeltje Steeghs6, Hans Gelderblom7. 1. Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: m.c.verboom@lumc.nl. 2. Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands. 3. Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands. 4. Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands. 5. Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 6. Department of Medical Oncology, Antoni van Leeuwenhoek - Netherlands Cancer Institute, Amsterdam, The Netherlands. 7. Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
Abstract
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.
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.
Authors: Stavros P Papadakos; Christos Tsagkaris; Marios Papadakis; Andreas S Papazoglou; Dimitrios V Moysidis; Constantinos G Zografos; Stamatios Theocharis Journal: World J Gastrointest Oncol Date: 2022-08-15