血浆NGS-ctDNA对EGFR-TKIs治疗晚期NSCLC患者的预后意义  

Prognostic significance of plasma NGS⁃ctDNA in patients with advanced NSCLC treated with EGFR⁃TKIs

作　　者：赵海燕 靳海涛 孔莺 何瑞远 Zhao Haiyan;Jin Haitao;Kong ying;He Ruiyuan(Department of Medical Oncology,East District of The First Affiliated Hospital of Xi′an Jiaotong University,Xi′an,Shaanxi 710089,China)

机构地区：[1]西安交通大学第一附属医院东院肿瘤内科,西安710089

出　　处：《中华肺部疾病杂志（电子版）》2024年第3期385-391,共7页Chinese Journal of Lung Diseases(Electronic Edition)

基　　金：陕西省自然科学基础研究计划项目(2020JM-369)。

摘　　要：目的分析血浆循环肿瘤DNA(circulating tumor DNA,ctDNA)对表皮生长因子受体(epidermal growth factor receptor,EGFR)⁃酪氨酸激酶抑制剂(tyrosine kinase inhibitors,TKIs)治疗晚期非小细胞肺癌(non⁃small cell lung cancer,NSCLC)患者的预后意义。方法选取2019年2月至2022年12月我院收治的EGFR⁃TKI治疗前进行基线ctDNA和早期动态血浆ctDNA测试的患者81例。使用基于二代测序(next⁃generation sequencing,NGS)的平台对患者进行血浆ctDNA突变检测,记录基线血浆ctDNA最大突变等位基因频率(mutated allele frequency,MAF),监测治疗第1周期81例和第2周期21例血浆ctDNA状态。主要结局为总生存期(overall survival,OS)和无进展生存期(progression⁃free survival,PFS)。次要结局为TKIs靶向治疗治疗2个周期后的疾病控制率(disase control rate,DCR)。结果81例患者的基线ctDNA评估中,EGFR⁃TKI敏感突变和其他频繁突变的驱动基因,其中38例存在双重或三重突变,最常见的EGFR+TP53突变19例(50.00%)。治疗后第1周期,ctDNA早期清除率为58.02%。21例第2周期进行重复测试的患者,早期ctDNA清除的患者可能具有持续性(76.47%vs.0%,P=0.005)。基线血浆ctDNA突变基因个数与EGFR⁃TKIs治疗后DCR有关,DCR组血浆ctDNA突变≥2个的例数35.94%低于疾病进展88.24%(P<0.05)。单因素和多因素COX回归分析显示,血浆ctDNA突变≥2个是影响NSCLC患者PFS(HR=2.900;95%CI:1.583~5.312;P=0.001)和OS(HR=2.063;95%CI:1.183~3.600;P=0.011)预后的危险因素。与血浆ctDNA突变<2个的患者相比,血浆ctDNA突变≥2个的患者累积PFS率和中位PFS明显变小(χ^(2)=13.730,P<0.001);累积OS率和中位OS明显变小(χ^(2)=7.791,P=0.005)。结论血浆NGS⁃ctDNA突变≥2个与晚期NSCLC患者EGFR⁃TKIs治疗无效和预后不良高风险有关。Objective To investigate the prognostic value of plasma circulating tumor DNA(ctDNA)in epidermal growth factor receptor(EGFR)⁃tyrosine kinase inhibitors(TKIs)in patients with advanced non⁃small cell lung cancer(NSCLC).Methods Between February 2019 and December 2022,a total of 81 patients who underwent baseline ctDNA and at least one early dynamic plasma ctDNA test prior to EGFR⁃TKI treatment were enrolled.All patients were tested for plasma ctDNA mutations using a platform based on second⁃generation sequencing(NGS),and the maximum mutated allele frequency(MAF)of baseline plasma ctDNA was recorded,and to monitor the plasma ctDNA status in the first cycle(n=81)and the second cycle(n=21)of treatment.The main outcomes were overall survival(OS)and progression⁃free survival(PFS).The secondary outcome was disease control rate(DCR)after 2 cycles of TKIs targeted therapy.Results In a baseline ctDNA assessment of 81 patients,all had EGFR⁃TKI sensitive mutations and other frequently mutated driver genes,and 38 had double or triple mutations,the most common being the EGFR+TP53 mutation 50.0%(19/38).In the first cycle after treatment,the early ctDNA clearance rate was 58.02%.For the 21 patients who had repeated testing at cycle 2,those with early ctDNA clearance were more likely to have sustained ctDNA clearance compared to those without early ctDNA clearance(76.47%vs.0%,P=0.005).The number of ctDNA mutations in baseline plasma was associated with DCR after EGFR⁃TKIs treatment,and fewer patients in the DCR group had≥2 ctDNA mutations(35.94%vs.88.24%,P=0.001).Univariate and multivariate COX regression analysis showed that plasma ctDNA mutations≥2 affected PFS in NSCLC patients(HR=2.900;95%CI:1.583⁃5.312;P=0.001)and OS(HR=2.063;95%CI:1.183⁃3.600;P=0.011)Independent risk factors for prognosis.Compared with patients with<2 plasma ctDNA mutations,patients with≥2 plasma ctDNA mutations had significantly lower cumulative PFS rate and median PFS(χ^(2)=13.730,P<0.001).The cumulative OS rate and median OS were

关 键 词：晚期非小细胞肺癌 血浆循环肿瘤DNA 二代测序 表皮生长因子受体-酪氨酸激酶抑制剂 预后 

分 类 号：R734.2[医药卫生—肿瘤]