外周血游离DNA的动态变化预测TKI治疗EGFR突变肺腺癌患者的疗效

Dynamic Changes of Circulating Tumor DNA in Peripheral Blood Predict the Efficacy of TKI in the Treatment of Lung Adenocarcinoma with EGFR Mutation

背景与目的有表皮生长因子受体(epidermal growth factor receptor, EGFR)突变的非小细胞肺腺癌,患者在给予酪氨酸激酶抑制剂(tyrosine kinase inhibitors, TKIs)的治疗中获得非常好的疗效,但绝大多数患者都会出现耐药,使得发现出现耐药的时间及可能耐药机制的检测有着越来越大的意义,目前二代基因测序方法(next generation sequencing, NGS)的出现使其成为可能。本文拟通过研究靶向治疗前后有EGFR突变的非小细胞肺癌循环肿瘤DNA(circulating tumor DNA, ctDNA)突变频率及突变谱的变化来监测靶向治疗效果。方法本中心入组22例通过组织活检或外周血ctDNA检查出EGFR突变的患者,分别于治疗前、服用TKI后2个月及临床进展时收集患者的外周血8mL行ctDNA测序。结果 EGFR敏感突变患者应用靶向药物治疗效果显著,EGFR敏感突变的患者在用TKI治疗后,相比治疗前突变基因突变丰度明显降低(P=0.015,3);患者的中位无进展生存期较长(无进展生存时间=390 d)。同时我们发现伴随TP53基因突变时应用针对EGFR敏感突变的靶向药物治疗效果欠佳(中位无进展生存时间为120 d vs 630 d,P=0.000,2)。结论 EGFR敏感突变的患者在用TKI治疗后,突变基因突变丰度明显降低的患者的生存期更长(P<0.05),突变丰度减低不明显或伴有其他突变者预示着TKI耐药。

Background and objective The tyrosine kinase inhibitors(TKI)treatment of non-small cell lung cancer(NSCLC)with epidermal growth factor receptor(EGFR)mutation may have a positive effect,but most patients may develop drug resistance,therefore,the detection of the developing time in drug resistance and the research of the mechanism of drug resistance are need to be solved.While the emerge of next generation sequencing(NGS)have make it possible.The aim of this study is to monitor the efficacy of targeted therapy by studying the variation of circulating tumor DNA(ctDNA)mutation frequency and gene mutation spectrum through the targeted therapy.Methods Our center enrolled 22 patients with EGFR mutation detected by tissue or peripheral blood,and collect 8 mL of peripheral blood of the patients for ctDNA sequencing in different phases,before systematic prior treatment,followed-up by 2 months and disease progression after TKI administration.Results Patients with EGFR gene mutation may acquire a longer median survival time after receiving targeted drug therapy,due to the drop of mutation abundances,while the therapy may have a minor effect in patients which their mutation abundances have slightly decreased compared to the statistics before the cession(P=0.015,3).The significantly reduced group median progression was associated with a longer survival(progression free survival(PFS)=390 d)At the same time,we found out that when related to TP-53 gene mutation,the effect of targeted drug therapy for EGFR-sensitive mutation was unsatisfactory(the median PFS was 120 d compared with 630 d,P=0.000,2).Conclusion Patients who has lower mutation abundance with EGFR sensitive mutations after TKI treatment may have a longer survival period(P<0.05),and the mutation abundance were not significantly dropping or accompanied by other mutations may indicating TKI resistance.