Correlation of EGFR, IDH1 and PTEN status with the outcome of patients with recurrent glioblastoma treated in a phase II clinical trial with the EGFR-blocking monoclonal antibody cetuximab
Correlation of EGFR, IDH1 and PTEN status with the outcome of patients with recurrent glioblastoma treated in a phase II clinical trial with the EGFR-blocking monoclonal antibody cetuximab
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DOI：
10.3892/ijo.2012.1539
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发表时间：
2012-09-01
影响因子：
5.2
通讯作者：
Neyns, Bart
中科院分区：
文献类型：
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作者：
Lv, Shasha;Teugels, Erik;Neyns, Bart
上皮生长因子受体（EGFR）的突变和基因扩增是胶质母细胞瘤（GB）中最常见的遗传学改变之一。因此，EGFR是用于治疗GB的有吸引力的分子靶标。然而，EGFR靶向治疗在临床试验中基本无效。在这项研究中，我们研究了EGFR基因扩增状态、EGFR变体III表达与EGFR基因突变之间的相关性。（EGFRvIII）和EGFR变体IV（EGFRvIV）突变，10号染色体上磷酸酶和张力蛋白同源基因（PTEN）的表达和异柠檬酸脱氢酶1（IDH 1）基因的突变与用EGFR-1治疗的复发性胶质母细胞瘤患者的存活率之间的关系。靶向单克隆抗体西妥昔单抗在前瞻性II期临床试验。在35个GB中的19个（54%）中检测到EGFR扩增，在11个（31.4%）中检测到EGFRvIII表达，在7个（20%）中检测到EGFRvIV表达。EGFRvIII和EGFRvIV突变仅在具有EGFR扩增的GB中发现，并且与IDH 1突变几乎相互排斥（在11个具有IDH 1突变的GB中发现1个EGFRvIII突变）。EGFR扩增缺乏EGFRvIII表达的患者接受西妥昔单抗治疗后，无进展生存期（PFS）显著上级，总生存期（OS）数值更优[中位PFS 3.03 vs. 1.63个月（p=0.006）;中位OS 5.57 vs. 3.97个月（p=0.12）]。在EGFR扩增患者亚组中，EGFRvIII阳性胶质母细胞瘤患者的生存期更差[中位PFS 1.63 vs. 3.03个月（p=0.01）;中位OS 3.27 vs. 5.57个月（p=0.08）]。我们的观察表明，EGFR突变的类型可能决定GB患者接受西妥昔单抗治疗的结果。在GB EGFR靶向治疗的临床试验中，对EGFR扩增和突变状态进行前瞻性研究。
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.