Debiec-Rychter Maria, Sciot Raf, Le Cesne Axel, Schlemmer Marcus, Hohenberger Peter, van Oosterom Allan T, Blay Jean-Yves, Leyvraz Serge, Stul Michel, Casali Paolo G, Zalcberg John, Verweij Jaap, Van Glabbeke Martine, Hagemeijer Anne, Judson Ian
Department of Human Genetics, University of Leuven and University Hospital Gasthuisberg, O&N Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium.
Eur J Cancer. 2006 May;42(8):1093-103. doi: 10.1016/j.ejca.2006.01.030. Epub 2006 Apr 18.
A recent randomized EORTC phase III trial, comparing two doses of imatinib in patients with advanced gastrointestinal stromal tumours (GISTs), reported dose dependency for progression-free survival. The current analysis of that study aimed to assess if tumour mutational status correlates with clinical response to imatinib. Pre-treatment samples of GISTs from 377 patients enrolled in phase III study were analyzed for mutations of KIT or PDGFRA by combination of D-HPLC and direct sequencing of tumour genomic DNA. Mutation types were correlated with patients' survival data. The presence of exon 9-activating mutations in KIT was the strongest adverse prognostic factor for response to imatinib, increasing the relative risk of progression by 171% (P<0.0001) and the relative risk of death by 190% (P<0.0001) when compared with KIT exon 11 mutants. Similarly, the relative risk of progression was increased by 108% (P<0.0001) and the relative risk of death by 76% (P=0.028) in patients without detectable KIT or PDGFRA mutations. In patients whose tumours expressed an exon 9 KIT oncoprotein, treatment with the high-dose regimen resulted in a significantly superior progression-free survival (P=0.0013), with a reduction of the relative risk of 61%. We conclude that tumour genotype is of major prognostic significance for progression-free survival and overall survival in patients treated with imatinib for advanced GISTs. Our findings suggest the need for differential treatment of patients with GISTs, with KIT exon 9 mutant patients benefiting the most from the 800 mg daily dose of the drug.
近期一项欧洲癌症研究与治疗组织（EORTC）的随机III期试验，比较了两种剂量伊马替尼用于晚期胃肠道间质瘤（GIST）患者的疗效，报告了无进展生存期的剂量依赖性。该研究的当前分析旨在评估肿瘤突变状态是否与伊马替尼的临床反应相关。对III期研究中入组的377例患者的GIST预处理样本，通过变性高效液相色谱（D-HPLC）与肿瘤基因组DNA直接测序相结合的方法分析KIT或血小板衍生生长因子受体A（PDGFRA）的突变情况。将突变类型与患者的生存数据进行关联分析。与KIT外显子11突变体相比，KIT外显子9激活突变的存在是伊马替尼反应最强的不良预后因素，进展相对风险增加171%（P<0.0001），死亡相对风险增加190%（P<0.0001）。同样，在未检测到KIT或PDGFRA突变的患者中，进展相对风险增加108%（P<0.0001），死亡相对风险增加76%（P=0.028）。在肿瘤表达外显子9 KIT癌蛋白的患者中，高剂量方案治疗导致无进展生存期显著更长（P=0.0013），相对风险降低61%。我们得出结论，对于接受伊马替尼治疗的晚期GIST患者，肿瘤基因型对无进展生存期和总生存期具有重要的预后意义。我们的研究结果表明需要对GIST患者进行差异化治疗，KIT外显子9突变患者从每日800 mg剂量的药物中获益最大。
