Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.
Ann Oncol. 2013 Aug;24(8):2080-7. doi: 10.1093/annonc/mdt127. Epub 2013 Apr 4.
The mechanism of primary resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small-cell lung cancer (NSCLC) has not been clearly understood.
Eleven patients exhibiting primary resistance (disease progression <3 months) were identified among 197 consecutive NSCLC patients with TKI-sensitive EGFR mutations who received EGFR TKIs at Seoul National University Hospital. Treatment-naïve tumors were examined for concurrent genetic alterations using fluorescence in situ hybridization and targeted deep sequencing of cancer-related genes. Deletion polymorphism of Bcl-2-interacting mediator of cell death (BIM) gene was examined to validate its predictive role for TKI outcome.
The median progression-free survival (PFS) for patients receiving EGFR TKIs was 11.9 months, and the response rate 78.8%. Among the 11 patients exhibiting primary resistance, a de novo T790M mutation was identified in one patient, and two exhibited mesenchymal-epithelial transition amplification and anaplastic lymphoma kinase fusion. Targeted deep sequencing identified no recurrent, coexistent drivers of NSCLC. Survival analysis revealed that patients with recurrent disease after surgery had a longer PFS than those with initial stage IV disease. However, BIM deletion polymorphism, line of treatment, EGFR genotype, and smoking were not predictive of PFS for EGFR TKIs.
We identified coexistent genetic alterations of cancer-related genes that could explain primary resistance in a small proportion of patients. Our result suggests that the mechanism of primary resistance might be heterogeneous.
表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）在 EGFR 突变型非小细胞肺癌（NSCLC）中产生原发性耐药的机制尚未明确。
在首尔国立大学医院接受 EGFR TKI 治疗的 197 例 EGFR 突变、TKI 敏感的 NSCLC 患者中，有 11 例患者（疾病进展<3 个月）出现原发性耐药。采用荧光原位杂交和靶向深度测序分析治疗前肿瘤中同时存在的基因改变，以研究 Bcl-2 相互作用介导细胞死亡（BIM）基因缺失多态性是否对 TKI 疗效有预测作用。
接受 EGFR TKI 治疗的患者中位无进展生存期（PFS）为 11.9 个月，缓解率为 78.8%。在 11 例出现原发性耐药的患者中，1 例患者存在新出现的 T790M 突变，2 例患者存在间充质上皮转化扩增和间变性淋巴瘤激酶融合。靶向深度测序未发现 NSCLC 复发性共存在驱动基因。生存分析显示，手术后疾病复发的患者 PFS 长于初始 IV 期疾病患者。然而，BIM 缺失多态性、治疗线、EGFR 基因型和吸烟状况不能预测 EGFR TKI 的 PFS。
我们发现了一些同时存在的与癌症相关的基因改变，这些改变可能可以解释一小部分患者的原发性耐药。我们的结果表明，原发性耐药的机制可能是异质性的。
