吉非替尼作为NSCLC患者一线用药，毒性反应严重、耐药率高，疗效个体差异大。常规的肿瘤组织活检获得的体细胞基因突变不能很好地预测靶人群，单纯的给药前非靶向内源性代谢组学研究尚未发现有临床指导意义的生物标志物。我们前期研究发现ABCB1、AKT1等胚系基因突变影响其毒性与疗效、主要代谢产物M1、M2与毒性及疗效关系密切。 因而，本课题将在前期研究的基础上，扩大样本量，通过检测外周血白细胞分析胚系基因突变情况、通过动态检测循环肿瘤DNA(ctDNA)和miRNA水平更特异准确地监测体细胞遗传和表观遗传的变化、再结合靶向代谢组和非靶向代谢组学动态分析内外源性代谢产物水平，综合分析遗传结构和代谢物等因素与疗效及毒性的关系，建立基于大样本的多变量回归模型准确预测吉非替尼原发、继发耐药及重度毒性的发生，通过新的综合检测体系为吉非替尼精准安全应用提供理论依据。

Gefitinib, as a first-line drug for NSCLC patients, has serious toxicity, high drug resistance rate and great individual difference in efficacy. Somatic gene mutations obtained from conventional tumor biopsy did not predict the target population well, and no pre-targeted non-targeted endogenous metabolomics studies have found clinically meaningful biomarkers. Our previous study found that germline mutations such as ABCB1 and AKT1 affect gefitinib toxicity and efficacy, and the main metabolites M1 and M2 were closely related to toxicity and efficacy. CtDNA is a new biomarker for tumor therapy that is more effective than tissue biopsy to detect somatic variation. Therefore, based on the previous research, this subject will expand the sample size, detect the germline mutation by detecting peripheral blood leukocytes, monitor the changes of somatic and epigenetic changes by dynamically detecting ctDNA and miRNA levels, and then combine the targeted metabolomics and untargeted metabolomics dynamic analysis of the level of endogenous metabolites, comprehensive analysis of the relationship between genetic structure and metabolites and efficacy and toxicity.To explore the relationship between factors and efficacy and toxicity, explore specific biomarkers related to efficacy and toxicity of gefitinib, and establish a multivariate regression model of gefitinib based on large samples to predict drug resistance and toxicity of gefitinib, so as to achieve precise application of gefitinib.