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.

Gastrointestinal stromal tumours, Genotype analysis, Imatinib mesylate, KIT, PDGFRA, Targeted therapy
dx.doi.org/10.1016/j.ejca.2006.01.030, hdl.handle.net/1765/68869
European Journal of Cancer
Erasmus MC: University Medical Center Rotterdam

Debiec-Rychter, M, Sciot, R, le Cesne, A, Schlemmer, M, Hohenberger, P, van Oosterom, A.T, … Judson, I.R. (2006). KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. European Journal of Cancer, 42(8), 1093–1103. doi:10.1016/j.ejca.2006.01.030