EGFR Mutation Heterogeneity and the Mixed Response to EGFR Tyrosine Kinase Inhibitors of Lung Adenocarcinomas

Background. Non‐small cell lung cancer patients with epidermal growth factor receptor (EGFR) mutations have mixed responses to tyrosine kinase inhibitors (TKIs). Intertumor heterogeneity in EGFR mutations is one potential explanation for this phenomenon. Methods. We performed direct sequencing to identify EGFR mutations in 180 pairs of lung adenocarcinoma samples (from 3,071 patients). The high‐resolution melting method was used in discordant cases to confirm EGFR mutation status. Matching samples were divided into four groups: primary lesions detected at different times, primary tumors with matched metastatic lymph nodes, multiple pulmonary nodules, and primary tumors with matched distant metastases. Multivariate analyses were performed to evaluate correlations between heterogeneity and patient characteristics. Results. In the study population, the discordance rate was 13.9% (25 of 180). The multiple pulmonary nodules group had the highest discordance rate of 24.4% (10 of 41; odds ratio for heterogeneity in primary lesions detected at different times, 6.37; 95% confidence interval, 1.71–23.72; p = .006). Discordance rates in the metachronous and synchronous settings were 15.7% (22 of 140) and 7.5% (three of 40), respectively. In the 34 patients who developed EGFR TKI resistance, 10 (29.4%) cases exhibited heterogeneity and five (14.7%) patients exhibited a mixed response to the drug. Three (8.8%) of the patients with a mixed response also exhibited discordant EGFR mutations. Conclusions. The overall discordance rate of EGFR mutation heterogeneity in Asian patients with pulmonary adenocarcinoma is relatively low, but the rate in patients with multiple pulmonary nodules is significantly higher. This observation may explain the mixed tumor response to EGFR TKIs. 摘要： 研究背景：表皮生长因子受体(EGFR)突变的非小细胞肺癌患者对酪氨酸激酶抑制剂（TKIs）的药物反应不一致。EGFR基因突变的肿瘤内异质性有望对这一现象作出解释。 方法：本实验通过直接测序确定180对肺腺癌样本（来自3071为患者）的EGFR突变。采用高分辨率溶解曲线法确定EGFR突变状态。将符合要求的样本分为4组：原发灶不同时间检测组，原发灶与相应淋巴结转移组，多发性肺结节组，原发灶及相应远处转移组。采用多变量分析，以评估异质性和患者临床病理生理特征的相关性。 结果：在研究对象中，不一致率为13.9%（25/180）。多发性肺结节组的不一致率最高，为24.4%（10/41；与原发灶不同时间检测组异质性的比值比为6.37；95%置信区间，1.71–23.72；p=0.006）。异时性肿瘤和同步多重性肿瘤的不一致率分别为15.7%（22/140）和7.5%（3/40）。在34位反映出EGFR酪氨酸激酶抑制剂耐药性的患者中，10例（29.4%）表现出异质性，5例（14.7%）表现出对药物反应不一致。3例（8.8%）对药物反应不一致的患者也表现出不一致的EGFR突变。 结论：EGFR突变异质性的整体不一致率在亚洲肺腺癌患者中较低，但此不一致率在多发性肺结节患者中有显著提高。这一发现有可能对肿瘤对EGFR酪氨酸激酶抑制剂的反应不一致性作出解释。 Direct sequencing was used to identify EGFR mutations in 180 pairs of lung adenocarcinoma samples from the primary tumor and on