晚期肺腺癌患者血浆表皮生长因子受体突变丰度与表皮生长因子受体酪氨酸激酶抑制剂疗效的相关性研究

Plasma relative abundance of epidermal growth factor receptor mutations predicts clinical response to epidermal growth factor receptor-tyrosine kinase inhibitors in patients with advanced lung adenocarcinoma

目的探讨晚期肺腺癌患者血浆循环肿瘤DNA表皮生长因子受体(EGFR)相对突变丰度与表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)疗效的相关性。方法选2016年4月1日至2017年1月1日温州医科大学附属第一医院住院且初次诊断为晚期肺腺癌患者。采用艾德生物扩增阻滞突变系统(ADx-ARMS)检测组织样本EGFR基因突变,同时采用ADx-ARMS和艾德生物超级扩增阻滞突变系统(ADx-SuperARMS)检测配对血浆循环肿瘤DNA中EGFR基因突变。入选组织样本EGFR基因敏感突变、使用一线EGFR-TKI治疗并于我院规律随访的患者。将血浆ADx-ARMS和ADx-SuperARMS检测EGFR结果均为阳性的患者纳入高突变丰度者;将血浆ADx-ARMS检测EGFR结果为阴性,而ADx-SuperARMS检测EGFR结果为阳性的患者纳入中突变丰度者;将检测EGFR结果均为阴性的患者纳入低突变丰度者。对比不同突变丰度者经EGFR-TKI治疗后的客观缓解率(ORR)和无进展生存时间(PFS),评估血浆EGFR突变丰度与EGFR-TKI疗效的相关性。结果共71例肺腺癌患者纳入本研究,ADx-ARMS检测出42例患者血浆EGFR基因突变,ADx-SuperARMS检测出53例患者血浆EGFR基因突变。高突变丰度者42例,中突变丰度者11例,低突变丰度者18例。高突变丰度者ORR较中、低突变丰度者高[69.0%(29/42)比7/11、10/18]。高突变丰度者中位PFS明显长于中、低突变丰度者(11.0个月比8.5个月、9.0个月,P值均<0.05)。19-Del突变者中,高突变丰度者ORR、中位PFS均优于中、低突变丰度者(ORR:70.4%比5/7、6/11;中位PFS:12.0个月比9.0个月、9.0个月)。L858R突变者中,高、中、低突变丰度者ORR分别为10/15、2/4、3/6,中位PFS分别为9.6个月、5.5个月、9.5个月。结论血浆EGFR相对突变丰度在一定程度上可以预测EGFR-TKI疗效,血浆EGFR相对突变丰度越高,EGFR-TKI疗效越好。

Objective To determine whether relative abundance of epidermal growth factor receptor (EGFR) mutations in plasma predicts clinical response to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in patients with advanced lung adenocarcinoma. Methods In this prospective study, adult patients with advanced lung adenocarcinoma were enrolled in our hospital from 1 April 2016 to 1 January 2017. EGFR mutations in tumor tissues were detected by ADx-amplification refractory mutation system (ADx-ARMS). EGFR mutations of plasma free tumor DNA were detected by ADx-ARMS and ADx-super amplification refractory mutation system (ADx-SuperARMS) at the same time. Patients with EGFR-mutant in tumor tissues and receiving EGFR-TKIs were finally enrolled. Plasma mutation-positive patients with both methods were high abundance group.Patients with positive mutations by ADx-SuperARMS but negative by ADx-ARMS were medium abundance group. Mutation-negative patients with both methods were recognized as low abundance group. The correlation between EGFR mutation abundance and clinical response to EGFR-TKIs were analyzed. Results Among 71 patients enrolled, 42 harbored EGFR mutations in plasma were detected by ADx-ARMS, while 53 were found by ADx-SuperARMS.There were 42 patients in high abundance group, 11 in medium group while the other 18 in low group. The objective response rates (ORRs) were 69.0%, 7/11 and 10/18 in high, medium and low groups, respectively. The difference was significant between high and low abundances groups (P=0.006). Median progression-free survival (PFS) in high, medium and low groups were 11.0, 8.5 and 9.0 monthes, respectively (P<0.001). In patients with tumor 19-Del, the ORRs were 70.4%, 5/7 and 6/11 in high, medium and low abundance groups, respectively. The median PFS of high abundance group was significantly longer than the other two groups (12.0 monthes vs 9.0, 9.0 monthes). As to subjects with L858R mutation, the ORRs were 10/15, 2/4 and 3/6, respectively, with median PFS 9.6, 5.5 and 9.5 monthes. Conclusions The relative abundance of EGFR mutations in plasma predicts clinical response to EGFR-TKIs in patients with advanced lung adenocarcinoma. The higher the mutation abundance is, the better the efficacy of EGFR-TKIs is.