PD-L1、MDM2在EGFR罕见突变NSCLC患者中的表达及其临床意义

目的:探讨PD-L1和MDM2在表皮生长因子受体（epidermal growth factor receptor,EGFR）罕见突变的非小细胞肺癌（non-small cell lung cancer,NSCLC）患者中的表达，分析其与临床病理特征及预后的关系，探寻EGFR罕见突变人群的预后预测因子及免疫治疗的应用前景。方法:收集并随访69例EGFR罕见突变的NSCLC患者完整的临床病理资料（最终随访到64例，失访率7.25%），采用免疫组化法检测51例保存完整的EGFR罕见突变的NSCLC福尔马林固定石蜡包埋组织中PD-L1、MDM2的表达水平，同时选取9例癌旁组织和8例正常组织的蜡块切片作为对照组，分析其与患者临床病理特征和预后的关系。结果:64例EGFR罕见突变的NSCLC患者，突变类型包括单突变41例（64.06%），复合突变（同时存在两种或两种以上的EGFR突变）23例（35.94%）。NLR中位数为2.63，PD-L1在EGFR罕见突变NSCLC癌组织的阳性表达率为29.41%，在癌旁组织及正常肺泡上皮细胞中阴性表达（P=0.039）。MDM2在癌组织、癌旁组织和正常组织中的阳性表达率分别为86.27%、33.33%、12.5%，差异有明显统计学意义（P=0.000）。I/II期患者PD-L1在肿瘤细胞中的表达高于III/IV期（P=0.013），而III/IV期患者MDM2在肿瘤中的表达高于I/II期患者（P=0.001）。而年龄、性别、是否吸烟、NLR、突变类型、病理分级与EGFR罕见突变癌患者组织中PD-L1、MDM2的表达水平无统计学差异（P>0.05）。64例患者的mOS为22.31个月。年龄、性别、吸烟、EGFR突变类型、PD-L1、MDM2表达与预后无明显相关。NLR<2.63患者的mOS优于NLR≥2.63（46.16个月vs 12.58个月）的患者，差异具有显著统计学意义（χ2=9.72，P=0.002）。病理分级为1/2级患者mOS优于3级患者（41.46个月vs 15.97个月），差异具有明显统计学意义（χ2=6.17，P=0.013）。I/II期患者mOS优于III/IV期患者（59.17个月vs 15.97个月），差异具有明显统计学意义（χ2=18.89，P=0.000）。Cox多因素回归分析:NLR（HR=2.667，P=0.007）、分期（HR=8.778，P=0.000）是EGFR罕见突变NSCLC患者的独立预后因素。结论:NLR可考虑作为EGFR罕见突变NSCLC患者预后的疗效预测因子；PD-L1在EGFR罕见突变的NSCLC中阳性表达率较高，免疫治疗可能获益。

PD-L1 and MDM2 expression in non-small cell lung cancer patients harboring rare EGFR mutation and their role in survival

Objective:To investigate the expression of PD-L1 and MDM2 in non-small cell lung cancer (NSCLC) patients with rare mutations of epidermal growth factor receptor (EGFR),analyze their relationship with clinicopathological characteristics and prognosis,and explore the prognostic factors of rare mutations of EGFR and the application prospect of immunotherapy.Methods:69 patients with rare EGFR mutation were enrolled (from January 2010 to 2017) for this study.IHC was used to assess the expression of PD-L1,MDM2 in 51 NSCLC patients formalin fixed paraffin embedded tissues.Nine para-carcinoma tissues and 8 normal tissues were regarded as control group.The relationship between PD-L1,MDM2 expression,clinicopathological characteristics with overall survival of NSCLC patients with rare EGFR mutation were analysed.Results:There were 64 NSCLC patients with rare EGFR mutation.41 patients (64.06%) harbored single rare mutation,and the other 23 patients (35.94%) harbored complex mutations.The median neutrophil-lymphocyte ratio (NLR) was 2.63，PD-L1 was positively expressed in 29.41% tumor tissues,and was negatively expressed in para-carcinoma tissues and normal tissues.MDM2 was positively expressed in 86.27% tumor tissues,33.33% para-carcinoma tissues and 12.5% normal tissues,respectively.PD-L1 expression level in stage I/II patients were higher than that of stage III/IV (P=0.013),and MDM2 expression level in stage III/IV patients were higher than that of stage I/II（P=0.001）.Expressions levels of PD-L1 and MDM2 had no statistically significant difference among different age,gender,smoking,NLR level,complex mutation and pathological grade (P>0.05).The median overall survival time of 64 NSCLC patients with rare EGFR mutation was 22.31 months.Clinicopathological characteristics,such as age,gender,smoking,complex mutations,PD-L1 expression and MDM2 expression had no influence on patients' overall survival.Median OS (46.16 months) of patients with NLR<2.63 was longer than that of patients with NLR≥2.63 (12.58 months)(χ2=9.72,P=0.002).Tumor pathological grade 1/2 showed a superior mOS than grade 3 patients (41.46 months vs 15.97 months）（χ2=6.17，P=0.013）.Patients with stage I/II showed longer mOS than patients with stage III/IV (59.17 months vs 15.97 months）（χ2=18.89，P=0.000）.The stage (HR=8.778，P=0.000) and NLR level (HR=2.667,P=0.007) were independent factors which affected the prognosis of NSCLC patients with rare EGFR mutation.Conclusion:NLR may serve as a prognosis factor for NSCLC patients with rare EGFR mutation.The positive expression rate of PD-L1 is high in NSCLC with rare EGFR mutation,which may benifit from immunotherapy.