EGFR敏感型肺腺癌38例TKIs治疗前及进展后EGFR基因变化分析

Epidermal growth factor receptor( EGFR ) mutation status of lung adenocarcinoma patients harboring sensitive EGFR mutations before and after tyrosine kinase inhibitors treatment

目的观察表皮生长因子受体(EGFR)敏感型肺腺癌患者EGFR-TKIs治疗前及进展后EGFR基因变化情况,分析其导致耐药的可能机制。方法回顾性分析38例EGFR-TKIs治疗前及进展后均进行活检取材的肺腺癌患者,所有病例均采用ARMS法检测腺癌组织EGFR和KRAS基因突变状态。结果 38例肺腺癌患者中,临床分期为ⅠA期1例,ⅢA期3例,ⅢB期2例,Ⅳ期32例。EGFR-TKIs治疗前,27例患者检测出EGFR基因19外显子缺失突变(19-del),11例患者检测出EGFR基因21外显子L858R点突变(L858R); EGFR-TKIs治疗进展后,17例患者EGFR基因突变状态没有改变(15例19-del和2例L858R); 19例患者检测出EGFR基因20外显子T790M点突变(T790M),其中12例19-del+T790M双突变,6例L858R+T790M双突变; 1例患者的EGFR基因L858R突变改变为19-del+L858R+T790M复合突变; 1例患者的EGFR基因L858R突变改变为KRAS基因突变(G12 V),1例患者的EGFR基因L858R突变改变为EGFR基因野生型。此外,有2例患者EGFR-TKIs治疗进展后,病理组织学中发现了小细胞癌成分。28例患者给予EGFR-TKIs治疗进展后,T790M突变阳性的患者疾病无进展生存时间为18个月,T790M突变阴性的患者为9个月,差异显著(P <0. 05)。结论 T790M突变是导致EGFR基因产生EGFR-TKIs耐药的主要突变类型,然而EGFR基因也可因发生KRAS基因突变、EGFR敏感突变位点发生丢失或改变等变化而产生耐药。

Objective To analyze the changes of EGFR mutation status before and after TKIs treatment and to investigate the mechanism involved in acquiring drug-resistance.Methods Of 38 patients with EGFR-mutated lung adenocarcinomas receiving re-biopsies after disease progression were reviewed from 2014-2017 at Beijing Chest Hospital.EGFR and KRAS mutations were screened by using amplification refractory mutation system(ARMS)method.Results 38 patients were available to be performed for the clinical stage includingⅠpatient with stageⅠA,3 patients with stageⅢA,2 patients with stageⅢB,and 32 patients with stageⅣ.Before EGFR-TKIs treatment,we found that 27 patients had deletional mutation in exon 19(19-del),and the otherⅡpatients had a point mutation in exon 21(L858R).Alter required resistance to EGFR-TKIs treatment,we identified a second-site EGFR T790M mutation in 12 of 27 patients who harbored 19-del mutations,and in 6 of 11 patients who had L858R+T790M mutations,with ARMS method.The EGFR mutation status of 15 patients harboring 19del and 2 patients harboring L858R did not change.One patient harboring L858R mutation changed into 19-del,E858R and T790M multiple mutations.One patient harboring I858R mutation changed into KRAS mutation(G12V).One patient harboring L858R mutation changed into the wild type.In addition,two patients had evidence of small-cell lung cancer component in rebiopy tissues.T790M-positive patients showed a longer progression-free survival than 1790VI-negative patients(18.0 months vs 9.0 months,P=0.037).Conclusion After acquired resistance to EGFR-TKIs treatment,T790M mutation is the most common change of EGFR mutation status,while KRAS mutation,loss or change of EGFR sensitive mutation site could also exist.