晚期肺腺癌患者一线使用EGFR-TKI获得性耐药后T790M与预后的相关性
| 作者: |
1,2沈凯凯,
2魏雨晴,
3汪向海,
2吕镗烽
1 皖南医学院，安徽 芜湖 241001 2 南京大学医学院附属金陵医院(南京总医院)呼吸与危重症医学科，南京 210002 3 皖南医学院弋矶山医院呼吸内科，安徽 芜湖 241001 |
| 通讯: |
吕镗烽
Email: bairoushui@163.com |
| DOI: | 10.3978/j.issn.2095-6959.2018.11.023 |
| 基金: | 国家自然科学基金(81772500)。 |
摘要
目的：探讨循环肿瘤DNA(circulating tumor DNA，ctDNA)鉴定的EGFR基因20位外显子T790M突变状态与晚期肺腺癌(lung adenocarcinoma，LUAD)患者一线使用EGFR-TKI获得性耐药和预后的相关性。方法：回顾性分析2012年1月至2016年1月南京总医院一线使用EGFR-TKI获得性耐药的晚期LUAD患者93例，按照QIAamp循环核酸试剂盒说明提取外周血ctDNA，采用二代测序(next generation sequencing，NGS)的方法对ctDNA中T790M突变进行鉴定，分析其与临床特征和预后的相关性。结果：在93例一线使用EGFR-TKI获得性耐药的晚期LUAD患者，T790M阳性突变率为52.7%(49/93)，T790M突变与晚期LUAD患者的年龄、临床分期、组织学亚型、ECOG评分、初始EGFR突变类型、EGFR-TKI种类差异均无统计学意义(P>0.05)；但与性别、吸烟史、EGFR-TKI耐药后进展类型、EGFR-TKI耐药后血CEA水平、EGFR-TKI耐药后治疗方案比较差异有统计学意义(P<0.05)，EGFR-TKI耐药后血CEA预测T790M阳性的cut-off值为90.1 μg/L，其中敏感度44.9%、特异度90.9%，曲线下面积0.639(95%CI 0.526~0.752)；T790M阳性突变患者的中位无进展生存期(progression-free survival，PFS)和总生存期(overall survival，OS)分别为12.4，29.5个月，均较T790M突变阴性的6.2，18.1个月显著延长(P<0.001)；Cox单因素和多因素回归分析均提示T790M突变阳性是PFS(RR=0.302，95%CI 0.162~0.560；P<0.001)和OS(RR=0.422，95%CI 0.250~0.715；P=0.001)的独立影响因素。结论：T790M突变与晚期LUAD患者的性别、吸烟史、EGFR-TKI耐药后进展类型、EGFR-TKI耐药后血CEA水平、EGFR-TKI耐药后治疗方案有关，同时是PFS和OS的独立影响因素。
关键词：
肺腺癌；二代测序；T790M；表皮生长因子受体酪氨酸激酶抑制剂；循环肿瘤DNA；预后
Correlation with EGFR-TKI in the first-line treatment of advanced lung adenocarcinoma acquired T790M and prognosis
CorrespondingAuthor: LÜ Tangfeng Email: bairoushui@163.com
DOI: 10.3978/j.issn.2095-6959.2018.11.023
Foundation: This work was supported by the National Natural Science Foundation, China (81772500).
Abstract
Objective: T790M mutation is the main resistance mechanism of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI). Serum circulating tumor DNA (ctDNA) is an ideal method to detect T790M mutations. This study aimed to explore the relationship between ctDNA identified EGFR T790M mutation status and EGFR-TKI acquired resistance and prognosis in patients with advanced lung adenocarcinoma (LUAD). Methods: Ninety-three patients with advanced LUAD who acquired resistance with EGFR-TKI in the first-line of Nanjing general hospital from January 2012 to January 2016 were analyzed retrospectively. The ctDNA was extracted from peripheral blood according to the instructions of circulating nucleic acid kit QIAamp and mutational status of T790M in ctDNA was tested using next generation sequencing (NGS), which clinical features and prognosis were further to analyzed. Results: In 93 cases of advanced LUAD patients who were treated with EGFR-TKI in the first-line, T790M mutation was 52.7% (49/93). There was no statistically significant difference between T790M mutation and age, clinical stage, histological subtype, ECOG score, initial EGFR mutant type, EGFR-TKI types of drugs (all P>0.05). However, it was related to sex, smoking history, type of progression after EGFR-TKI resistance, level of serum CEA after EGFR-TKI resistance and therapeutic regimen after EGFR-TKI resistance (all P<0.05). The cut-off value of serum CEA after EGFR-TKI resistance predicting T790M positive was 90.1 μg/L, with a sensitivity and a specificity was 44.9% and 90.9%, respectively. The area under curve was 0.639 (95% CI 0.526–0.752). T790M mutation positive patients had prolonged PFS and OS compared with T790M negative patients (PFS, 12.4 months vs 6.2 months, P<0.001; OS, 29.5 months vs 18.1months, P<0.001). Cox univariate and multivariate regression analysis indicated that T790M mutation positive was PFS (RR =0.302; 95% CI 0.162–0.560; P<0.001) and OS (RR =0.422; 95% CI 0.250–0.715; P=0.001) independent influencing factors. Conclusion: T790M mutation was related to sex, smoking history, the level of serum CEA after EGFR-TKI resistance, type of progression after EGFR-TKI resistance, which was an independent influencing factors of PFS and OS.
Keywords：
lung adenocarcinoma; next generation sequence; T790M; epidermal growth factor receptor-tyrosine kinase inhibitor; circulating tumor DNA; prognosis