晚期肺腺癌患者奥希替尼后线治疗耐药后基因突变模式研究

Gene mutation pattern after drug resistance treated by osimertinib in patients with advanced lung adenocarcinoma

目的分析外周血表皮生长因子受体(epidermal growth factor receptor,EGFR)基因T790M突变的晚期肺腺癌患者后线应用奥希替尼治疗耐药后的基因突变情况,探讨可能的耐药机制。方法晚期肺腺癌患者52例,均给予奥希替尼后线治疗,并于入院次日清晨采集外周血,提取循环肿瘤DNA,采用微滴数字PCR法检测EGFR基因T790M突变情况。对外周血检出EGFR基因T790M突变者,至病情进展时再次采集外周血,采用高通量测序进行实体瘤常见突变基因检测。结果 52例患者中36例检出外周血EGFR基因T790M突变。36例患者奥希替尼耐药后再次检测,发现10例T790M突变丢失;26例T790M突变保留,其中24例新发C797S突变;4例检出EGFR基因L718Q、L718V和L792F突变;29例检出旁路基因突变,其中MET基因突变21例(8例MET基因扩增,12例单核苷酸位点变异,1例多MET基因位点突变),12例ERBB2基因突变,7例BRAF基因突变,3例KRAS/NRAS基因突变,5例PIK3CA基因突变,1例PTEN基因突变,1例NF1基因突变,17例检出2种及以上旁路基因突变,18例同时存在EGFR基因继发突变和旁路基因突变。结论获得性C797S突变是T790M突变保留肺腺癌患者奥希替尼耐药的主要机制,MET基因突变是T790M突变丢失肺腺癌患者奥希替尼耐药的主要机制。

Objective To analyze the epidermal growth factor receptor(EGFR) T790 M mutation pattern in patients with advanced lung adenocarcinoma after treatment of drug resistance with osimertinib, and to explore the possible mechanism of drug resistance. Methods Fifty-two advanced lung adenocarcinoma patients were treated with osimertinib, and the peripheral blood was collected on the next morning to extract circulating tumor DNA. T790 M mutation of EGFR gene was detected by droplet digital PCR. The patients with T790 M mutation detected in peripheral blood were collected the peripheral blood again when the disease progressed, and gene mutation was detected by high-throughput sequencing. Results T790 M mutation was detected in the peripheral blood of 36 patients. And these 36 patients with osimertinib resistance were detected again, showing T790 M mutation loss in 10 patients. In 26 patients with retained T790 M mutation, 24 patients had a new C797 S mutation. Mutations of L718 Q, L718 V and L792 F of EGFR gene were detected in 4 patients. In 29 patients with bypass gene mutations, 21 patients were detected MET gene mutation, including 8 patients with MET gene amplification, 12 patients with single nucleotide site mutations and 1 patient with multiple MET gene site mutation. There were 12 patients with ERBB2 gene mutation, 7 patients with BRAF gene mutation, 3 patients with KRAS/NRAS gene mutation, 5 patients with PIK3 CA gene mutation, 1 patient with PTEN gene mutation, 1 patient with NF1 gene mutation, 17 patients with two or more bypass gene mutations, and 18 patients with secondary EGFR gene mutation and bypass gene mutation. Conclusion Acquired C797 S mutation is the main mechanism for osimertinib resistance in lung adenocarcinoma patients with T790 M mutation retention, and MET gene mutation is the main mechanism for osimertinib resistance in lung adenocarcinoma patients with T790 M mutation loss.