TY - JOUR
T1 - Kinase Mutations and Imatinib Response in Patients with Metastatic Gastrointestinal Stromal Tumor
AU - Heinrich, Michael C.
AU - Corless, Christopher L.
AU - Demetri, George D.
AU - Blanke, Charles D.
AU - Von Mehren, Margaret
AU - Joensuu, Heikki
AU - McGreevey, Laura S.
AU - Chen, Chang Jie
AU - Van Den Abbeele, Annick D.
AU - Druker, Brian J.
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.
N1 - Publisher Copyright:
© 2023 American Society of Clinical Oncology. All rights reserved.
PY - 2023/11/1
Y1 - 2023/11/1
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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UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=purepublist2023&SrcAuth=WosAPI&KeyUT=WOS:001096174500002&DestLinkType=FullRecord&DestApp=WOS
U2 - 10.1200/JCO.22.02771
DO - 10.1200/JCO.22.02771
M3 - Article
C2 - 37890277
SN - 0732-183X
VL - 41
SP - 4829
EP - 4836
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 31
ER -