免疫环境因子IEF在EGFR-TKIs治疗的EGFR突变阳性晚期非小细胞肺癌中预后价值研究

The Predictive Value of Immune Environment Factors (IEF) for the Prognosis of EGFR Mutations Positive Non-Small Cell Lung Cancer Treated with Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors (EGFR-TKIs)

摘要: 目的：表皮生长因子受体–酪氨酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinase inhibitors, EGFR-TKIs)厄洛替尼、吉非替尼，埃克替尼治疗前血清免疫环境因子IEF (immune environment factor)水平对晚期非小细胞肺癌(non-small cell lung cancer, NSCLC)伴有EGFR (epidermal growth factor receptor)基因突变阳性患者预后价值研究。方法：收集从2015年6月1日至2020年5月1日在青岛大学附属青岛市立医院诊断的73例接受了厄洛替尼，吉非替尼或者埃克替尼治疗的EGFR突变阳性的晚期非小细胞肺癌患者的临床资料。患者服用TKIs前1~2周完成血常规、肝肾功、凝血功能检测。利用公式IEF = Mon#(10^9/L)Neu#(10^9/L) × Fibro#(10^9/L)/Lym#(10^9/L)/ALB(g/L)，其中Mon#、Neu#、Fibro#、Lym#和ALB分别代表单核细胞数目，中性粒细胞数目，纤维蛋白原数目，淋巴细胞数目和血清白蛋白水平，得出IEF值，IEF的最佳临界值将通过ROC (Receiver Operating Characteristic)曲线确定，将所有入组患者分为高IEF组和低IEF组。同时，使用COX比例风险模型(Cox Proportional-Hazards Model)分析患者预后预测因素。通过Kaplan-Meier法分析，得出高IEF组和低IEF组患者mPFS (median progression free survival)，使用Log-rank检验比较组间差异。结果：根据ROC分析结果，以IEF = 1.066 × 10^17为临界值。Kaplan-Meier法分析：低IEF组的mPFS为18.0个月，而高IEF组的mPFS为8.0个月(P < 0.001)。应用Cox多因素回归方法分析显示IEF (HR = 5.215, 95%CI: 2.372~11.464; P = 0.0001)，年龄，肿瘤分期，中性粒细胞计数，单核细胞计数，淋巴细胞计数是应用EGFR-TKIs治疗的EGFR突变型晚期NSCLC患者mPFS的独立影响因素，均P < 0.05。同时，COX单因素分析结果显示患者的血清白蛋白，淋巴细胞计数，IEF值对患者mPFS的影响有意义，均P < 0.01。结论：治疗前免疫环境因子IEF水平可作为表皮生长因子受体–酪氨酸激酶抑制剂治疗EGFR突变阳性III-IV期NSCLC患者的预后评价指标。

Abstract: Objectives: To investigate the predictive value of pretreatment immune environmental factors in serum for the prognosis of EGFR mutations positive non-small cell lung cancer (NSCLC) treated with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Methods: The clinical data of 73 patients with EGFR mutation positive stage IV NSCLC who were treated with erlotinib, gefitinib or icotinib from June 1, 2015 to May 1, 2020 in Qingdao Municipal Hospital were collected. The venous blood samples were taken from patients 1~2 weeks before taking TKIs, and blood routine, liver and kidney function and coagulation function were tested. According to receiver operating characteristic curve (ROC), patients were divided into high and low groups. Meanwhile, Cox proportional hazards model was used to analyze the independent prognostic factors. Kaplan Meier method was used to analyze the progression free survival (mPFs), and log rank test was used to compare the differences between the two groups. Results: According to the ROC curve, the appropriate cut-off point of IEF was 1.066 × 10^17. The mPFS in the lower IEF group was longer than mPFS in the high IEF group (18.0 vs. 8.0 months, P < 0.001). Cox regression analysis showed that serum albumin, lymphocyte count and IEF value had significant effect on mPFS (P < 0.01). Cox multivariate regression analysis showed that IEF (HR = 5.215, 95%CI: 2.372~11.464; P = 0.0001) was significantly higher than that of control group; age, tumor stage, neutrophil count, monocyte count and lymphocyte count were independent influencing factors of mPFS (P < 0.05). Conclusions: Pretreatment serum immune environment factors level can be used as a prognostic index for EGFR TKIs in patients with EGFR mutation positive stage IV NSCLC.