Laboratory of Molecular Oncology and Department of Medical Oncology, University Hospital Brussels, Free University Brussels, 1090 Brussels, Belgium.
Int J Oncol. 2012 Sep;41(3):1029-35. doi: 10.3892/ijo.2012.1539. Epub 2012 Jun 29.
Mutation and gene amplification of the epithelial growth factor receptor (EGFR) is one of the most common genetic alterations in glioblastoma (GB). EGFR is, therefore, an attractive molecular target for the treatment of GB. EGFR-targeted therapies however have been largely ineffective in clinical trials. In this study, we investigated the correlation between the EGFR gene amplification status, expression of the EGFR variant III (EGFRvIII) and EGFR variant IV (EGFRvIV) mutations, expression of the phosphatase and tensin homologue gene on chromosome 10 (PTEN) and mutation of the isocitrate dehydrogenase 1 (IDH1) gene and the survival of patients suffering from recurrent glioblastoma who were treated with the EGFR-targeted monoclonal antibody cetuximab in a prospective phase II clinical trial. EGFR amplification was detected in 19 out of 35 GB (54%), EGFRvIII expression in 11 (31.4%) and EGFRvIV expression in 7 (20%). The EGFRvIII and EGFRvIV mutations were exclusively found in GB with EGFR amplification and were almost mutually exclusive with IDH1 mutation (EGFRvIII mutation was found in 1 out of 11 GB with an IDH1 mutation). Patients with an EGFR amplification lacking EGFRvIII expression had a significantly superior progression free survival (PFS) and a numerical better overall survival (OS) following treatment with cetuximab [median PFS 3.03 vs. 1.63 months (p=0.006); median OS 5.57 vs. 3.97 months (p=0.12)]. Within the subgroup of patients with EGFR amplification, patients with EGFRvIII positive glioblastoma had a worse survival [median PFS 1.63 vs. 3.03 months (p=0.01); median OS 3.27 vs. 5.57 months (p=0.08)]. Our observations indicate that the type of EGFR mutation may determine the outcome of GB patients treated with cetuximab. Prospective investigation of both the EGFR amplification and mutation status in clinical trials with EGFR-targeted therapies for GB is indicated.
表皮生长因子受体（EGFR）的突变和基因扩增是胶质母细胞瘤（GB）中最常见的遗传改变之一。因此，EGFR 是治疗 GB 的一个有吸引力的分子靶标。然而，EGFR 靶向治疗在临床试验中基本上没有效果。在这项研究中，我们研究了 EGFR 基因扩增状态、EGFR 变体 III（EGFRvIII）和 EGFR 变体 IV（EGFRvIV）突变的表达、10 号染色体磷酸酶和张力蛋白同源物基因（PTEN）的表达与异柠檬酸脱氢酶 1（IDH1）基因突变之间的相关性，并在一项前瞻性 II 期临床试验中，用 EGFR 靶向单克隆抗体西妥昔单抗治疗复发性胶质母细胞瘤患者的生存情况。在 35 例 GB 中检测到 19 例（54%）EGFR 扩增，11 例（31.4%）EGFRvIII 表达和 7 例（20%）EGFRvIV 表达。EGFRvIII 和 EGFRvIV 突变仅在 EGFR 扩增的 GB 中发现，并且几乎与 IDH1 突变相互排斥（在 11 例 IDH1 突变的 GB 中发现了 1 例 EGFRvIII 突变）。缺乏 EGFRvIII 表达的 EGFR 扩增患者在接受西妥昔单抗治疗后无进展生存期（PFS）显著延长，总生存期（OS）也有改善的趋势[中位 PFS 3.03 与 1.63 个月（p=0.006）；中位 OS 5.57 与 3.97 个月（p=0.12）]。在 EGFR 扩增亚组中，EGFRvIII 阳性胶质母细胞瘤患者的生存更差[中位 PFS 1.63 与 3.03 个月（p=0.01）；中位 OS 3.27 与 5.57 个月（p=0.08）]。我们的观察结果表明，EGFR 突变类型可能决定接受西妥昔单抗治疗的 GB 患者的预后。在针对 EGFR 靶向治疗的胶质母细胞瘤临床试验中，有必要对 EGFR 扩增和突变状态进行前瞻性研究。
