• Eur. J. Cancer · May 2006

    Randomized Controlled Trial

    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, EORTC Soft Tissue and Bone Sarcoma Group, Italian Sarcoma Group, and Australasian GastroIntestinal Trials Group.
    • Department of Human Genetics, University of Leuven and University Hospital Gasthuisberg, O&N Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium.
    • Eur. J. Cancer. 2006 May 1; 42 (8): 1093-103.

    AbstractA 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.

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