Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumours entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group
Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumours entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group
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DOI：
10.1016/j.ejca.2003.11.025
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发表时间：
2004-03-01
影响因子：
8.4
通讯作者：
van Oosterom, AT
中科院分区：
文献类型：
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作者：
Debiec-Rychter, M;Dumez, H;van Oosterom, AT
先前的研究表明，c-KIT/PDGFRA（甲磺酸伊马替尼的潜在治疗靶点）的激活突变与胃肠道间质瘤（gist）的病理生理有关。在这项研究中，来自欧洲癌症研究和治疗组织（EORTC）伊马替尼I/II期临床研究的37名患者的gist检查了c-KIT/PDGFRA突变，以探讨肿瘤的突变状态是否预测了对治疗的临床反应。突变通过变性高压液相色谱（DHPLC）筛选，双向DNA测序鉴定。分别在29例（78%）和2例（6%）gist中发现c-KIT或PDGFRA激活突变。大多数c-KIT突变涉及外显子11（它= 24;83%），除了一个外显子是帧内缺失；未发现孤立的点突变。其他c-KIT突变包括外显子9 AY 502-503重复（it = 4; 14%）和外显子13 Lys- >Glu错义突变（n = 1:3 %）。两个未检测到c-KIT突变的肿瘤显示PDGFRA Asp - Glu（842）氨基酸取代。携带外显子1突变的gist患者更有可能在伊马替尼治疗中获得部分缓解（PR）（83%），而不是所有其他患者（23%）。106周时，整个组的总生存率和无进展生存率分别为78.3%和46.9%。根据Kaplan-Meier分析，与其他患者相比，携带c-KIT突变的gist患者的中位生存时间更长，进展的可能性更小。这些发现表明，c-KIT/PDGFRA癌蛋白的突变状态可能有助于预测患者伊马替尼治疗的临床反应。(C) 2004 Elsevier Ltd.版权所有。
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 (it = 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 (it = 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 1 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 thereapy. (C) 2004 Elsevier Ltd. All rights reserved.