KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours.
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.
Debiec-Rychter
Maria
M
Department of Human Genetics, University of Leuven and University Hospital Gasthuisberg, O&N Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium.
Sciot
Raf
R
Le Cesne
Axel
A
Schlemmer
Marcus
M
Hohenberger
Peter
P
van Oosterom
Allan T
AT
Blay
Jean-Yves
JY
Leyvraz
Serge
S
Stul
Michel
M
Casali
Paolo G
PG
Zalcberg
John
J
Verweij
Jaap
J
Van Glabbeke
Martine
M
Hagemeijer
Anne
A
Judson
Ian
I
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D018572:Disease-Free Survival; D005091:Exons; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics; D005838:Genotype; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010879:Piperazines / Q000627:therapeutic use*; D011379:Prognosis; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D011743:Pyrimidines / Q000627:therapeutic use*; D012189:Retrospective Studies
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit