T790 M及COX-2在晚期非小细胞肺癌EGFR-TKI耐药中的临床研究

Clinical study of T790 M and COX-2 in EGFR-TKI resistance in advanced non-small cell lung cancer

目的探讨晚期非小细胞肺癌患者外周血T790 M及COX-2表达与EGFR-TKI耐药及预后之间的相关性。方法收集60例晚期非小细胞肺癌患者血清,运用ARMS、ELISA法分别对晚期NSCLC患者进行T790 M、COX-2检测,同时收集治疗前后的临床资料。依据RECIST1.1实体瘤评价标准,分为有效组(CR、PR、SD之和)和耐药组(PD),分析两组患者外周血T790 M及COX-2表达与EGFR-TKI耐药及预后之间的差异性。结果60例患者中有58例完成实验,失访1例,DNA提取失败1例。58例完成实验的患者经过EGFR-TKI靶向治疗后,总有效率为25.9%;两组患者治疗前T790 M基因阳性突变均较低,差异无统计学意义(P=0.345),EGFR-TKI靶向治疗后,两组患者T790 M基因阳性突变均提高(χ^2=35.153,P<0.001),耐药组治疗前后T790 M基因阳性突变升高,比较差异有统计学意义;靶向治疗前有效组患者血清COX-2基线水平高于耐药组患者(t=44.159,P<0.001),靶向治疗后的血清COX-2水平与治疗前相比,有效组患者降低(t=36.180,P<0.001),耐药组患者升高(t=-17.852,P<0.001)。Spearman等级相关分析示,EGFR-TKI治疗后晚期非小细胞肺癌患者中T790 M基因状态分析与COX-2表达呈正相关(r=0.747,P<0.001);COX多因素分析显示,T790 M基因突变状态(HR=0.168,95%CI为0.056~0.509,P=0.002)和COX-2水平(HR=0.245,95%CI为0.066~0.911,P=0.036)是影响PFS的独立因素。结论血清COX-2水平与T790 M基因突变之间可能存在相关性,而且通过二者的检测可有助于判断晚期NSCLC患者治疗的疗效及作为预测EGFR-TKI药物预后,为临床治疗NSCLC提供新的思路。

Objective To investigate the relationship between T790 M and COX-2 expression and EGFR-TKI resistance and prognosis in peripheral blood of patients with advanced non-small cell lung cancer. Methods Serum was collected from 60 patients with advanced non-small cell lung cancer. T790 M and COX-2 were detected in patients with advanced NSCLC by ARMS and ELISA, and clinical data before and after treatment were collected. According to the evaluation criteria of RECIST1.1 solid tumor, it was divided into effective group(sum of CR, PR, SD) and drug resistant group(PD), to analyze the difference between T790 M and COX-2 expression and EGFR-TKI resistance and prognosis in peripheral blood of two groups of patients. Results In 60 patients, 58 cases was succeed for experiment, lost to follow-up in 1 case, DNA extraction failed in 1 case. In 58 patients who complete the test, the total effective rate was 25.9% after EGFR-TKI targeted therapy. The T790 M gene-positive mutations were lower in the two groups before treatment, and the difference was not statistically significant(P=0.345);After EGFR-TKI targeted therapy,T790 M gene-positive mutations were increased in both groups(χ^2=35.153, P<0.001). The positive mutation of T790 M gene was increased in the drug resistant group before and after treatment, and the difference was statistically significant;baseline levels of serum COX-2 in the effective group before targeted therapy were higher than those in the drug resistant group(t=44.159, P<0.001);the level of serum COX-2 after targeted therapy was lower in the effective group than before treatment(t=36.180, P<0.001), and higher in the drug-resistant group(t=-17.852, P<0.001). Spearman rank correlation analysis showed that T790 M gene status analysis was positively correlated with COX-2 expression in patients with advanced non-small cell lung cancer after EGFR-TKI treatment(r=0.747,P<0.001). COX multivariate analysis showed that the T790 M mutations(HR=0.168, 95% CI 0.056-0.509, P=0.002) and COX-2 level(HR=0.245, 95% CI 0.066-0.911, P=0.036) affected the PFS independently. Conclusion There may be a correlation between serum COX-2 level and T790 M gene mutation, and the detection of both can help to judge the therapeutic effect of patients with advanced NSCLC. As a predictor of EGFR-TKI drug prognosis, it is providing new ideas for clinical treatment of NSCLC.