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

Michael Heinrich, Christopher Corless, George D. Demetri, Charles Blanke, Margaret Von Mehren, Heikki Joensuu, Laura S. McGreevey, Chang Jie Chen, Annick D. Van Den Abbeele, Brian 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

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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

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Gastrointestinal Stromal Tumors
Phosphotransferases
Platelet-Derived Growth Factor alpha Receptor
Mutation
Exons
Protein Isoforms
Imatinib Mesylate
Neoplasms
Oncogene Proteins
Disease-Free Survival

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. / Heinrich, Michael; Corless, Christopher; Demetri, George D.; Blanke, Charles; Von Mehren, Margaret; Joensuu, Heikki; McGreevey, Laura S.; Chen, Chang Jie; Van Den Abbeele, Annick D.; Druker, Brian; Kiese, Beate; Eisenberg, Burton; Roberts, Peter J.; Singer, Samuel; Fletcher, Christopher D M; Silberman, Sandra; Dimitrijevic, Sasa; Fletcher, Jonathan A.

In: Journal of Clinical Oncology, Vol. 21, No. 23, 01.12.2003, p. 4342-4349.

Research output: Contribution to journalArticle

Heinrich, M, Corless, C, Demetri, GD, Blanke, C, Von Mehren, M, Joensuu, H, McGreevey, LS, Chen, CJ, Van Den Abbeele, AD, Druker, B, Kiese, B, Eisenberg, B, Roberts, PJ, Singer, S, Fletcher, CDM, Silberman, S, Dimitrijevic, S & Fletcher, JA 2003, 'Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor', Journal of Clinical Oncology, vol. 21, no. 23, pp. 4342-4349. https://doi.org/10.1200/JCO.2003.04.190
Heinrich, Michael ; Corless, Christopher ; Demetri, George D. ; Blanke, Charles ; Von Mehren, Margaret ; Joensuu, Heikki ; McGreevey, Laura S. ; Chen, Chang Jie ; Van Den Abbeele, Annick D. ; Druker, Brian ; Kiese, Beate ; Eisenberg, Burton ; Roberts, Peter J. ; Singer, Samuel ; Fletcher, Christopher D M ; Silberman, Sandra ; Dimitrijevic, Sasa ; Fletcher, Jonathan A. / Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. In: Journal of Clinical Oncology. 2003 ; Vol. 21, No. 23. pp. 4342-4349.
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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.",
author = "Michael Heinrich and Christopher Corless and Demetri, {George D.} and Charles Blanke and {Von Mehren}, Margaret and Heikki Joensuu and McGreevey, {Laura S.} and Chen, {Chang Jie} and {Van Den Abbeele}, {Annick D.} and Brian Druker and Beate Kiese and Burton Eisenberg and Roberts, {Peter J.} and Samuel Singer and Fletcher, {Christopher D M} and Sandra Silberman and Sasa Dimitrijevic and Fletcher, {Jonathan A.}",
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T1 - Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor

AU - Heinrich, Michael

AU - Corless, Christopher

AU - Demetri, George D.

AU - Blanke, Charles

AU - Von Mehren, Margaret

AU - Joensuu, Heikki

AU - McGreevey, Laura S.

AU - Chen, Chang Jie

AU - Van Den Abbeele, Annick D.

AU - Druker, Brian

AU - Kiese, Beate

AU - Eisenberg, Burton

AU - Roberts, Peter J.

AU - Singer, Samuel

AU - Fletcher, Christopher D M

AU - Silberman, Sandra

AU - Dimitrijevic, Sasa

AU - Fletcher, Jonathan A.

PY - 2003/12/1

Y1 - 2003/12/1

N2 - 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.

AB - 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.

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