Kinase Mutations and Imatinib Response in Patients With Metastatic Gastrointestinal Stromal Tumor.

Abstract

Most gastrointestinal stromal tumors (GISTs) express constitutively activated mutant isoforms of KIT or kinase platelet-derived growth factor receptor alpha (PDGFRA) that are potential therapeutic targets for imatinib mesylate. The relationship between mutations in these kinases and clinical response to imatinib was examined in a group of patients with advanced GIST. GISTs from 127 patients enrolled onto a phase II clinical study of imatinib were examined for mutations of <i>KIT</i> or <i>PDGFRA</i>. Mutation types were correlated with clinical outcome. Activating mutations of <i>KIT</i> or <i>PDGFRA</i> were found in 112 (88.2%) and six (4.7%) GISTs, respectively. Most <i>KIT</i> mutations involved exon 9 (n = 23) or exon 11 (n = 85). All KIT mutant isoforms, but only a subset of PDGFRA mutant isoforms, were sensitive to imatinib, in vitro. In patients with GISTs harboring exon 11 <i>KIT</i> mutations, the partial response rate (PR) was 83.5%, whereas patients with tumors containing an exon 9 <i>KIT</i> mutation or no detectable mutation of <i>KIT</i> or <i>PDGFRA</i> had PR rates of 47.8% (<i>P</i> = .0006) and 0.0% (<i>P</i> < .0001), respectively. Patients whose tumors contained exon 11 <i>KIT</i> mutations had a longer event-free and overall survival than those whose tumors expressed either exon 9 <i>KIT</i> mutations or had no detectable kinase mutation. Activating mutations of <i>KIT</i> or <i>PDGFRA</i> are found in the vast majority of GISTs, and the mutational status of these oncoproteins is predictive of clinical response to imatinib. <i>PDGFRA</i> mutations can explain response and sensitivity to imatinib in some GISTs lacking <i>KIT</i> mutations.