血清肿瘤标志物与非小细胞肺癌驱动基因突变发生率的相关性分析

Correlation of serum tumor markers and incidence of driver gene mutations in non-small cell lung cancer

目的 探讨血清肿瘤标志物与非小细胞肺癌(non-small cell lung cancer, NSCLC)驱动基因突变与否是否存在相关性,为血清肿瘤标志物指导NSCLC靶向治疗提供参考。方法 本研究采用横断面研究设计,自2015年12月到2021年3月,回顾性纳入陆军特色医学中心呼吸科、肿瘤科、胸外科共1 008例行组织活检以及驱动基因检测的NSCLC患者。收集患者的临床资料、血清肿瘤标志物以及肺癌基因检测结果,通过相关性分析和受试者工作特征曲线(receiver operating characteristic curve, ROC)评价多种驱动基因突变与患者临床特征或特定血清肿瘤标志物的相关性。并根据肿瘤标志物升高的水平以及是否具备手术指针进行分组分析,观察不同分组患者驱动基因突变类型及突变率的差别。结果 本研究纳入1 008例患者中男性674例,女性334例,平均年龄58.4岁。驱动基因突变的总发生率为64.5%。其中,血清癌胚抗原(carcinoembryonic antigen, CEA)升高(49.9%vs.32.6%,P<0.001)和细胞角蛋白19的可溶性片段(cytokeratin fragment 19,CYFRA21-1)未升高(48.5%vs.38.3%,P=0.003)患者的表皮生长因子受体(epidermal growth factor receptor,EGFR)基因突变发生率较高。与此同时,EGFR突变患者的血清CEA水平显著高于EGFR野生型患者[12.19(3.49,79.05)vs. 4.93(2.47,17.29) ng/mL,P<0.001]。随着血清CEA的升高,EGFR突变发生率逐渐增高。分层分析显示:在Ⅰ~ⅢA期患者中,EGFR突变患者的血清CEA水平与野生型患者无差异。血清神经元特异性烯醇化酶(neuron-specific enolase, NSE)异常升高的患者较NSE正常水平患者发生鼠类肉瘤病毒癌基因(kirsten rat sarcoma viral oncogene,KRAS)基因突变的可能性更大。结论 NSCLC患者血清CEA水平与EGFR突变发生存在相关性;尤其是在ⅢB~Ⅵ期肺癌患者中,血清CEA水平越高的患者EGFR的突变率越高,提示在CEA明显升高的晚期肺癌患者更应推荐行肺癌基因检测评,明确是否具有靶向治疗指征。

Objective To explore the correlation between serum tumor markers and mutations of driver genes in non-small cell lung cancer(NSCLC) patients, so as to provide references for serum tumor markers-guided targeted therapies for NSCLC. Methods A cross-sectional study was performed on 1 008 NSCLC patients admitted in the respiratory, oncology and thoracic surgery departments of our medical center from December 2015 to March 2021. All these patients underwent tissue biopsies and driver gene tests. Their clinical data and results of serum tumor markers and lung cancer-specific gene test were collected. The correlation of mutations of driver genes with clinical characteristics and serum tumor markers were analyzed with correlation analysis and receiver operating characteristic(ROC) curve analysis. Then the patients were grouped according to the elevated levels of these tumor markers and presence of surgical indicators or not. The differences in mutation types and rates in the driver genes were observed among different groups of patients. Results In the 1 008 patients, there were 674 males and 334 females, with an average age of 58.4 years. The total incidence of driver gene mutations was 64.5%. Higher mutation rate of epidermal growth factor receptor(EGFR) was observed in the patients with increased serum carcinoembryonic antigen(CEA) level than those without(49.9% vs 32.6%, P<0.001) and in the patients with unraised cytokeratin fragment 19(CYFRA21-1) level than those with unchanged or elevated level(48.5% vs 38.3%, P=0.003). And, the serum CEA level was significantly higher in the EGFR mutant patients than those with EGFR wild-type [12.19(3.49~79.05) vs 4.93(2.47~17.29) ng/mL, P<0.001]. With the increase of serum CEA level, the occurrence of EGFR mutations was gradually increased. Stratified analysis showed that in stage ⅢB to Ⅵ patients, the serum CEA level was obviously higher in patients with EGFR mutation than those with EGFR wild-type. The patients with abnormally elevated serum neuron-specific enolase(NSE) level showed higher mutation rate of kirsten rat sarcoma viral oncogene(KRAS) than those with normal NSE level. Conclusion In NSCLC patients, serum CEA level is correlated with occurrence of EGFR mutations. Especially for those with stage ⅢB to Ⅵ, higher serum CEA level indicates higher mutation rate of EGFR. Lung cancer-specific gene test should be recommended to carry out in advanced lung cancer patients with significantly elevated CEA in order to determine whether there are indications for target therapy.