~背景和目的：表皮生长因子受体（EGFR）基因突变的非小细胞肺癌（NSCLC）患者接受表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）治疗疗效明显优于化疗，且副作用更低。但同样具有EGFR敏感突变的患者接受EGFR-TKI治疗可出现明显的疗效差异，导致这一差异的原因目前尚不明确。本研究旨在通过临床特征分析以及组织二代测序，从不同层面寻找导致差异的原因，为精准筛选患者提供理论依据。
方法：筛选 2009年到2018年在就诊于呼吸科，有完善的随访资料，且组织基因检测证实合并EGFR基因突变的患者。对其中经第一代EGFR-TKI治疗后无进展生存时间（PFS）大于24月或小于6月的患者进行回顾性分析。收集患者的临床资料和肿瘤评估信息，同时收集治疗前存档肿瘤组织和配对血液标本应用下一代测序技术（NGS）进行422个基因的靶向测序并计算肿瘤突变复合。结合测序结果分析两组患者的基因差异。
结果：入选患者共64例，测序结果提示两组患者在EGFR敏感突变类型上没有明显差异，但短PFS组患者出现了更多的复合突变，特别是复合20号外显子突变（主要是T790M）。提示复合突变可能是预后不佳的因素。其他EGFR之外的伴随突变包括TP53突变、MAP2K2扩增以及BIM杂合缺失多态性。其中TP53在两组PFS不同患者中的突变位点不同，而MAP2K2扩增仅出现在长PFS组患者中。BIM多态性在两组人群中未发现明显差异。肿瘤突变负荷（TMB）在所有入组患者中均相对较低，具体比较两组患者短PFS患者TMB高的人群的分布相对多，但没有达到显著水平。其他的检出的原发耐药突变包括MTOR以及PTEN基因突变及MET基因扩增，均出现在短PFS组患者中。
结论：合并耐药突变、EGFR复合突变特别是原发T790M是EGFR-TKI疗效不佳的重要因素。NGS在基因层面预测疗效有积极的作用。
 

~Background
Tyrosine kinase inhibitors (TKIs) are clinically effective in non-small cell lung cancer (NSCLC) patients who have epidermal growth factor receptor (EGFR) oncogene mutations.However,some patients with EGFR mutant NSCLC do poorly after an initial response to EGFR TKIs, whereas others can have prolonged lives despite advanced disease.In this study, we sought to identify genetic parameters associated with variable clinical outcome by analyzing EGFR mutant NSCLC patients who were treated with EGFR TKIs.
Methods
A total of 64 patients who had metastatic or recurrent NSCLC with activating EGFR mutation treated first generation TKI retrospectively reviewed. The PFS of these patients were either longer than 24months or shorter than 6 months. Specimens before TKI treatments were collected.Next generation sequencing was performed to identify genetic differences between groups.
Results
Among the 64 patients EGFR-TKIs had equal benefit in exon 19 deletion and in exon 21 L858R mutation.The most frequent type of exon 19 deletion mutation is del746–750. Complex mutations are more offen in short PFS group and associated with shorter PFS. De novo T790M mutation is a negative prognostic factor of TKI therapy. Other mutations included TP53 and MAP2K2 amplification were found to be different between groups.Polymorphism BIM didn’t show different between groups. Other cancer-related genes could be associated with primary resistance, including MTOR mutation, MET amplification, and phosphatase and tensin homolog (PTEN) loss were found mainly in short PFS group.
Conclusion
Primary resistance mutation, complex mutationsespeciallyEGFR T790Mmay be the most common negative prognostic factor of EGFR-TKI therapy.  NGS is a useful tool for identifying properatespatients in TKI treatment.