Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumors entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group

Glu(642) missense mutation (n=1; 3%). Two tumours with no detectable c-KIT mutations demonstrated PDGFRA Asp-->Glu(842) amino acid substitutions. Patients with GISTs harbouring exon 11 mutations were more likely to achieve a partial response (PR) on imatinib therapy (83%) than all of the others (23%). The overall survival and progression-free survival rates for the entire group at 106 weeks were 78.3% and 46.9%, respectively. Based on a Kaplan-Meier analysis, patients with GISTs harbouring c-KIT mutations had longer median survival times and were less likely to progress than the other patients. These findings indicate that the mutational status of the c-KIT/PDGFRA oncoproteins could be useful to predict the clinical response of patients imatinib therapy. -->
ISSN: 1879-0852
0959-8049
DOI: 10.1016/j.ejca.2003.11.025
Přístupová URL adresa: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c7c6e6a35cdd4ae5cab942faae6e784b
https://doi.org/10.1016/j.ejca.2003.11.025
Rights: CLOSED
Přírůstkové číslo: edsair.doi.dedup.....c7c6e6a35cdd4ae5cab942faae6e784b
Autor: Michel Stul, H. Vranck, Maria Debiec-Rychter, Anne Hagemeijer, Ian Judson, Bartosz Wasag, Raphael Sciot, M. Brown, A.T. Van Oosterom, H. Dumez, Michelle Scurr, M. van Glabbeke, Jaap Verweij, Sasa Dimitrijevic
Přispěvatelé: Medical Oncology
Rok vydání: 2004
Předmět:
Zdroj: European Journal of Cancer, 40, 689-695. Elsevier Ltd.
ISSN: 1879-0852
0959-8049
DOI: 10.1016/j.ejca.2003.11.025
Popis: Previous studies have shown that activating mutations of c-KIT/PDGFRA, potential therapeutic targets for imatinib mesylate, are implicated in the pathophysiology of gastrointestinal stromal tumours (GISTs). In this study, GISTs from 37 patients enrolled in an European Organisation for Research and Treatment of Cancer (EORTC) phase I/II clinical study of imatinib were examined for mutations of c-KIT/PDGFRA in order to explore whether the mutational status of the tumour predicts the clinical response to therapy. Mutations were screened by denaturing high-pressure liquid chromatography (DHPLC) and characterised by bi-directional DNA sequencing. Activating mutations of c-KIT or PDGFRA were found in 29 (78%) and 2 (6%) GISTs, respectively. Most c-KIT mutations involved exon 11 (n=24; 83%), all but one being an in-frame deletion; no isolated point mutations were found. The other c-KIT mutations included exon 9 AY 502-503 duplication (n=4; 14%) and exon 13 Lys-->Glu(642) missense mutation (n=1; 3%). Two tumours with no detectable c-KIT mutations demonstrated PDGFRA Asp-->Glu(842) amino acid substitutions. Patients with GISTs harbouring exon 11 mutations were more likely to achieve a partial response (PR) on imatinib therapy (83%) than all of the others (23%). The overall survival and progression-free survival rates for the entire group at 106 weeks were 78.3% and 46.9%, respectively. Based on a Kaplan-Meier analysis, patients with GISTs harbouring c-KIT mutations had longer median survival times and were less likely to progress than the other patients. These findings indicate that the mutational status of the c-KIT/PDGFRA oncoproteins could be useful to predict the clinical response of patients imatinib therapy.
Databáze: OpenAIRE
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