KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours.
Eur J Cancer
; 42(8): 1093-103, 2006 May.
Article
en En
| MEDLINE
| ID: mdl-16624552
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.
Buscar en Google
Bases de datos:
MEDLINE
Asunto principal:
Piperazinas
/
Pirimidinas
/
Proteínas Proto-Oncogénicas c-kit
/
Tumores del Estroma Gastrointestinal
/
Mutación
/
Antineoplásicos
Tipo de estudio:
Etiology_studies
/
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Límite:
Adult
/
Aged
/
Female
/
Humans
/
Male
/
Middle aged
Idioma:
En
Revista:
Eur J Cancer
Año:
2006
Tipo del documento:
Article
País de afiliación:
Bélgica