Intratumor heterogeneity of epidermal growth factor receptor mutations in lung cancer and its correlation to the response to gefitinib
Intratumor heterogeneity of epidermal growth factor receptor mutations in lung cancer and its correlation to the response to gefitinib
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DOI：
10.1111/j.1349-7006.2008.00782.x
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发表时间：
2008-05-01
期刊：
影响因子：
5.7
通讯作者：
Kato, Kikuya
中科院分区：
文献类型：
--
作者：
Taniguchi, Kazuya;Okami, Jiro;Kato, Kikuya
非小细胞肺癌（NSCLC）中表皮生长因子受体（EGFR）基因的体细胞突变是决定吉非替尼治疗反应的重要因素。目前的诊断测试测量癌组织的总体EGFR突变状态，并且可能忽略非突变的、吉非替尼无反应的癌细胞的存在。本研究招募了21例EGFR突变的NSCLC患者。所有患者均在手术治疗后给予吉非替尼治疗。从每个组织中采集50至60个NSCLC肿瘤区域的样本，并通过引物延伸试验确定其EGFR突变状态。该测定区分单个肿瘤组织内EGFR突变阳性和阴性癌细胞。15个组织仅由EGFR突变的细胞组成，但其余6个组织含有突变和非突变细胞。在EGFR异质性患者中，吉非替尼治疗后的疾病进展时间和总生存期显著缩短（分别为P = 0.009和P = 0.003）。相当大比例的NSCLC包含EGFR突变和非突变癌细胞的异质群体，导致对吉非替尼的应答降低。当用分子靶向药物治疗患者时，靶分子（如EGFR）的肿瘤内遗传异质性将是需要考虑的重要因素。
Somatic mutations introduced into the epidermal growth factor receptor (EGFR) gene in non-small-cell lung cancer (NSCLC) are important factors to determine therapeutic responses to gefitinib. The current diagnostic test measures the overall EGFR mutation status of the cancer tissue, and may ignore the presence of non-mutated, gefitinib-unresponsive cancer cells. Twenty-one NSCLC patients with EGFR mutations were recruited for the study. All patients were treated with gefitinib after surgical treatment. Fifty to sixty areas of NSCLC tumors were sampled from each tissue, and their EGFR mutation states were determined by a primer extension assay. This assay discriminates between EGFR mutation-positive and -negative cancer cells within a single tumor tissue. Fifteen tissues consisted only of cells with EGFR mutations, but the remaining six tissues contained both mutated and non-mutated cells. Time to disease progression and overall survival after gefitinib treatment were significantly shorter in those patients with EGFR heterogeneity (P = 0.009 and P = 0.003, respectively). A considerable proportion of NSCLC contains a heterogeneous population of both EGFR mutated and non-mutated cancer cells, resulting in a reduced response to gefitinib. The intratumor genetic heterogeneity of a target molecule such as EGFR would be an important factor to consider when treating patients with molecular target agents.