EGFR敏感突变中晚期肺腺癌患者外周血中可溶性程序性死亡配体1的水平及其临床意义

Level of soluble programmed death-1 ligand 1 in peripheral blood of patients with advanced epidermal growth factor receptor mutated lung adenocarcinoma and its clinical implications

目的探讨表皮生长因子受体（EGFR）敏感突变中晚期肺腺癌患者外周血中可溶性程序性死亡配体1（sPD-L1）的水平及其临床意义。方法收集2015年5月至2016年7月苏州大学附属第二医院呼吸科收治的72例经EGFR-酪氨酸激酶抑制剂（TKI）治疗的EGFR敏感突变中晚期肺腺癌患者（EGFR突变组），同时选择性别、年龄、分期匹配的31例经EGFR—TKI治疗的中晚期经气管镜或经皮穿刺肺活检小标本确诊的EGFR野生型肺腺癌患者（EGFR野生组）作为对照。酶联免疫吸附（ELISA）法检测两组患者外周血中sPD-L1水平。根据EGFR—TKI治疗2个月的临床效果将EGFR突变组分为疾病进展组（PD组，36例）和疾病控制组（DC组，36例），观察其外周血中sPD—L1水平差异，分析EGFR突变组的外周血中sPD—L1水平与TNM分期的相关性，同时通过ROC曲线分析外周血sPD—L1和癌胚抗原（CEA）对突变组患者的临床评估价值。结果经EGFR—TKI治疗2个月后EGFR突变组外周血sPD—L1水平显著低于EGFR野生组[0．75（0．15～2．78）比1．56（0．85～3．29）μg/L，P〈0．001]。EGFR突变组中PD组外周血sPD—L1水平显著高于DC组[1．175（0．62～2．78）比0．625（0．15～2．27）μg/L，P〈0．001]。外周血sPD—L1水平增高与淋巴结转移及远处转移相关（x。=10．985、4．662，均P〈0．05）。外周血sPD．L1和CEA的ROC曲线下面积分别为0．893（95％CI：0．830～0．956）和0．745（95％CI：0．652—0．839）。sPD—L1为0．815ng／L时，Youden指数最大，其灵敏度和特异度分别为77．8％、91．4％。结论经EGFR-TKI治疗后EGFR敏感突变中晚期肺腺癌患者外周血中sPD-L1降低，提示sPD-L1可能依赖EGFR信号通路的调控，sPD-L1水平可反映治疗的效果。

Objective To analyze the expression of soluble programmed death ligand 1 （sPD-L1） in the serum of patients with advanced epidermal growth factor receptor （EGFR） mutated lung adenocarcinoma and to explore its clinical implications. Methods Seventy-two patients with EGFR mutated advanced lung adenocarcinoma （EGFR mutation group） were included from the Department of Respiratory Diseases in The Second Affiliated Hospital of Soochow University from May 2015 to July 2016. Thirty-one patients with advanced EGFR wild type （WT） lung adenocareinoma [ EGFR WT group, diagnosed via mini specimens from bronchoscopy or transthoracic needle aspiration biopsy （TNAB） , matching in sex, age and tumor stage with EGFR mutation group ] were also enrolled as controls. The sPD-L1 protein expression in serum was determined by enzyme-linked immunosorbent assay （ELISA） kit. According to the clinical response of two-month EGFR-tyrosine kinase inhibitor （TKI） treatment, all patients were divided into two groups： 36 cases in disease progression groups （PD group） and 36 cases in disease control group （DC group）. The sPD-L1 level in peripheral blood between the two groups was analyzed. In EGFR mutation group, the relationship of serum sPD-L1 with TNM staging was analyzed. At the same time, the value of serum sPD-L1 and cancer embryo antigen （CEA） in clinical evaluation of advanced EGFR mutated lung adenocarcinoma was evaluated by analyzing the receiver operating characteristic （ROC） curve. Results A lower level of sPD-L1 level in EGFR mutation group [0. 75（0. 15 -2. 78） μg/L] was found compared with the control group [ 1.56 （0.85 - 3.29 ） μg/L ] （ P 〈 0.001 ）. The expression of sPD-L1 in PD group was significantly higher than that in DC group [ 1. 175 （0. 62 - 2. 78 ） μg/L vs 0. 625 （0. 15 - 2. 27 ） μg/L, P 〈 0. 001]. High expression of sPD-L1 in the serum of patients with advanced EGFR mutated lung adenocarcinoma was closely correlated to lymph node metastasis and distant metastasis （X2 = 10. 985, 4. 662; both P 〈0. 05）. The area under ROC curve of serum sPD-L1 and CEA was 0. 893 （95% CI： 0. 830 -0. 956） and 0. 745 （95% CI： 0. 652 - 0. 839） respectively. Youden index was the maximum when the cutoff value of sPD-L1 was set to 0. 815 μg/L, and the sensitivity and specificity were 77. 8% and 91.4% , respectively. Conclusions After EGFR-TKI treatment, the level of sPD-L1 in the serum of patients with advanced EGFR mutated lung adenocarcinoma is lower, which suggests that sPD-L1 expression may depend on the regulation of EGFR signaling pathway. The level of sPD-L1 can reflect the clinical response of EGFR mutated lung adenocarcinoma to EGFR-TKI.