Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor

Michael C. Heinrich, Christopher L. Corless, George D. Demetri, Charles D. Blanke, Margaret Von Mehren, Heikki Joensuu, Laura S. McGreevey, Chang Jie Chen, Annick D. Van Den Abbeele, Brian J. Druker, Beate Kiese, Burton Eisenberg, Peter J. Roberts, Samuel Singer, Christopher D.M. Fletcher, Sandra Silberman, Sasa Dimitrijevic, Jonathan A. Fletcher

Research output: Contribution to journalArticle

1789 Scopus citations

Abstract

Purpose: 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. Patients and Methods: GISTs from 127 patients enrolled onto a phase II clinical study of imatinib were examined for mutations of KIT or PDGFRA, Mutation types were correlated with clinical outcome. Results: Activating mutations of KIT or PDGFRA were found in 112 (88.2%) and six (4.7%) GISTs, respectively. Most KIT 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 KIT mutations, the partial response rate (PR) was 83.5%, whereas patients with tumors containing an exon 9 KIT mutation or no detectable mutation of KIT or PDGFRA had PR rates of 47.8% (P = .0006) and 0.0% (P < .0001), respectively. Patients whose tumors contained exon 11 KIT mutations had a longer event-free and overall survival than those whose tumors expressed either exon 9 KIT mutations or had no detectable kinase mutation. Conclusion: Activating mutations of KIT or PDGFRA are found in the vast majority of GISTs, and the mutational status of these oncoproteins is predictive of clinical response to imatinib. PDGFRA mutations can explain response and sensitivity to imatinib in some GISTs lacking KIT mutations.

Original languageEnglish (US)
Pages (from-to)4342-4349
Number of pages8
JournalJournal of Clinical Oncology
Volume21
Issue number23
DOIs
StatePublished - Dec 1 2003
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Heinrich, M. C., Corless, C. L., Demetri, G. D., Blanke, C. D., Von Mehren, M., Joensuu, H., McGreevey, L. S., Chen, C. J., Van Den Abbeele, A. D., Druker, B. J., Kiese, B., Eisenberg, B., Roberts, P. J., Singer, S., Fletcher, C. D. M., Silberman, S., Dimitrijevic, S., & Fletcher, J. A. (2003). Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. Journal of Clinical Oncology, 21(23), 4342-4349. https://doi.org/10.1200/JCO.2003.04.190