Guangdong Lung Cancer Institute, Guangdong Academy of Medical Sciences, Guangzhou, China.
Oncologist. 2012;17(7):978-85. doi: 10.1634/theoncologist.2011-0385. Epub 2012 Jun 6.
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.
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.
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.
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.
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（TKI）的反应存在混合。EGFR 突变的肿瘤间异质性是这种现象的一个潜在解释。
我们对 180 对肺腺癌样本（来自 3071 例患者）进行直接测序以鉴定 EGFR 突变。在不一致的病例中使用高分辨率熔解法来确认 EGFR 突变状态。匹配样本分为四组：不同时间检测到的原发性病变、原发性肿瘤伴匹配的转移淋巴结、多个肺结节和原发性肿瘤伴匹配的远处转移。进行多变量分析以评估异质性与患者特征之间的相关性。
在研究人群中，不一致率为 13.9%（180 例中的 25 例）。多个肺结节组的不一致率最高，为 24.4%（41 例中的 10 例；不同时间检测到的原发性病变的异质性的优势比为 6.37；95%置信区间为 1.71-23.72；p =.006）。在同时性和异时性设置中，不一致率分别为 15.7%（140 例中的 22 例）和 7.5%（40 例中的 3 例）。在 34 例出现 EGFR TKI 耐药的患者中，10 例（29.4%）出现异质性，5 例（14.7%）患者对药物出现混合反应。混合反应的 3 例（8.8%）患者也表现出 EGFR 突变的不一致。
亚洲肺腺癌患者 EGFR 突变异质性的总体不一致率相对较低，但多发性肺结节患者的不一致率明显更高。这种观察结果可能解释了 EGFR TKI 的混合肿瘤反应。
