KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours

Maria Debiec-Rychter, Raf Sciot, Axel Le Cesne, Marcus Schlemmer, Peter Hohenberger, Allan T. van Oosterom, Jean Yves Blay, Serge Leyvraz, Michel Stul, Paolo G. Casali, John Zalcberg, Jaap Verweij, Martine Van Glabbeke, Anne Hagemeijer, Ian Judson

Research output: Contribution to journalArticle

Abstract

A recent randomized EORTC phase III trial, comparing two doses of imatinib in patients with advanced gastrointestinal stromal tumours (GISTs), reported dose dependency for progression-free survival. The current analysis of that study aimed to assess if tumour mutational status correlates with clinical response to imatinib. Pre-treatment samples of GISTs from 377 patients enrolled in phase III study were analyzed for mutations of KIT or PDGFRA by combination of D-HPLC and direct sequencing of tumour genomic DNA. Mutation types were correlated with patients' survival data. The presence of exon 9-activating mutations in KIT was the strongest adverse prognostic factor for response to imatinib, increasing the relative risk of progression by 171% (P <0.0001) and the relative risk of death by 190% (P <0.0001) when compared with KIT exon 11 mutants. Similarly, the relative risk of progression was increased by 108% (P <0.0001) and the relative risk of death by 76% (P = 0.028) in patients without detectable KIT or PDGFRA mutations. In patients whose tumours expressed an exon 9 KIT oncoprotein, treatment with the high-dose regimen resulted in a significantly superior progression-free survival (P = 0.0013), with a reduction of the relative risk of 61%. We conclude that tumour genotype is of major prognostic significance for progression-free survival and overall survival in patients treated with imatinib for advanced GISTs. Our findings suggest the need for differential treatment of patients with GISTs, with KIT exon 9 mutant patients benefiting the most from the 800 mg daily dose of the drug.

Original languageEnglish
Pages (from-to)1093-1103
Number of pages11
JournalEuropean Journal of Cancer
Volume42
Issue number8
DOIs
Publication statusPublished - May 2006

Keywords

  • Gastrointestinal stromal tumours
  • Genotype analysis
  • Imatinib mesylate
  • KIT
  • PDGFRA
  • Targeted therapy

ASJC Scopus subject areas

  • Cancer Research
  • Hematology
  • Oncology

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    Debiec-Rychter, M., Sciot, R., Le Cesne, A., Schlemmer, M., Hohenberger, P., van Oosterom, A. T., Blay, J. Y., Leyvraz, S., Stul, M., Casali, P. G., Zalcberg, J., Verweij, J., Van Glabbeke, M., Hagemeijer, A., & Judson, I. (2006). KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. European Journal of Cancer, 42(8), 1093-1103. https://doi.org/10.1016/j.ejca.2006.01.030