奥希替尼对表皮生长因子受体（EGFR）突变的非小细胞肺癌患者循环肿瘤细胞（CTCs）和循环肿瘤DNA（ctDNA）的影响：液体活检的预后相关性
Effect of Osimertinib on CTCs and ctDNA in EGFR Mutant Non-Small Cell Lung Cancer Patients: The Prognostic Relevance of Liquid Biopsy.
作者信息
Kallergi Galatea, Kontopodis Emmanouil, Ntzifa Aliki, Jordana-Ariza Núria, Karachaliou Niki, Pantazaka Evangelia, Charalambous Haris A, Psyrri Amanda, Tsaroucha Emily, Boukovinas Ioannis, Koumarianou Anna, Hatzidaki Dora, Lianidou Evi, Georgoulias Vassilis, Rosell Rafael, Kotsakis Athanasios
机构信息
Department of Biology, Division of Genetics, Cell and Developmental Biology, University of Patras, 26500 Patras, Greece.
Department of Medical Oncology, "Venizelio-Pananio" General Hospital of Heraklion, 71500 Heraklion, Greece.
出版信息
Cancers (Basel). 2022 Mar 19;14(6):1574. doi: 10.3390/cancers14061574.
INTRODUCTION
Liquid biopsy is a useful tool for monitoring treatment outcome in solid tumors, including lung cancer. The relevance of monitoring CTCs and plasma ctDNA as predictors of clinical outcome was assessed in EGFR-mutant NSCLC patients treated with osimertinib.
METHODS
Forty-seven EGFR-mutant NSCLC patients who had progressed on prior first- or second-generation EGFR inhibitors were enrolled in the study and treated with osimertinib, irrespective of the presence of the T790M mutation in the primary tumor or the plasma. Peripheral blood was collected at baseline ( = 47), post-Cycle 1 ( = 47), and at the end of treatment (EOT; = 39). CTCs were evaluated in 32 patients at the same time points ( = 32, = 27, and = 21, respectively) and phenotypic characterization was performed using triple immunofluorescence staining (CK/VIM/CD45).
RESULTS
Osimertinib resulted in an ORR of 34% (2 CR) and a DCR of 76.6%. The median PFS and OS values were 7.5 (range, 0.8-52.8) and 15.1 (range, 2.1-52.8) months, respectively. ctDNA was detected in 61.7%, 27.7%, and 61.5% of patients at baseline, post-Cycle 1, and EOT, respectively. CTCs (CK+/CD45-) were detected in 68.8%, 48.1%, and 61.9% of patients at the three time points, respectively. CTCs expressing both epithelial and mesenchymal markers (CK+/VIM+/CD45-) were detected in 56.3% and 29.6% of patients at baseline and post-Cycle 1, respectively. The detection of ctDNA at baseline and post-Cycle 1 was associated with shorter PFS and OS, whereas the ctDNA clearance post-Cycle 1 resulted in a significantly longer PFS and OS. Multivariate analysis revealed that male sex and the detection of ctDNA at baseline were independent predictors of shorter PFS (HR: 2.6, 95% C.I.: 1.2-5.5, = 0.015 and HR: 3.0, 95% C.I.: 1.3-6.9; = 0.009, respectively).
CONCLUSIONS
The decrease in both CTCs and ctDNA occurring early during osimertinib treatment is predictive of better outcome, implying that liquid biopsy monitoring may be a valuable tool for the assessment of treatment efficacy.
引言
液体活检是监测实体瘤（包括肺癌）治疗效果的有用工具。在接受奥希替尼治疗的表皮生长因子受体（EGFR）突变的非小细胞肺癌（NSCLC）患者中，评估了监测循环肿瘤细胞（CTC）和血浆循环肿瘤DNA（ctDNA）作为临床结果预测指标的相关性。
方法
47例在先前的第一代或第二代EGFR抑制剂治疗中进展的EGFR突变的NSCLC患者入组本研究，接受奥希替尼治疗，无论原发肿瘤或血浆中是否存在T790M突变。在基线期（n = 47）、第1周期后（n = 47）和治疗结束时（EOT；n = 39）采集外周血。在相同时间点对32例患者评估CTC（分别为n = 32、n = 27和n = 21），并使用三重免疫荧光染色（CK/VIM/CD45）进行表型特征分析。
结果
奥希替尼导致客观缓解率（ORR）为34%（2例完全缓解），疾病控制率（DCR）为76.6%。中位无进展生存期（PFS）和总生存期（OS）分别为7.5（范围0.8 - 52.8）个月和15.1（范围2.1 - 52.8）个月。分别在61.7%、27.7%和61.5%的患者中在基线期、第1周期后和EOT检测到ctDNA。在三个时间点分别在68.8%、48.1%和61.9%的患者中检测到CTC（CK+/CD45-）。分别在56.3%和29.6%的患者中在基线期和第1周期后检测到同时表达上皮和间充质标志物的CTC（CK+/VIM+/CD45-）。在基线期和第1周期后检测到ctDNA与较短的PFS和OS相关，而第1周期后ctDNA清除导致PFS和OS显著延长。多因素分析显示，男性和基线期检测到ctDNA是较短PFS的独立预测因素（风险比：2.6，95%置信区间：1.2 - 5.5，P = 0.015；风险比：3.0，95%置信区间：1.3 - 6.9；P = 0.009）。
结论
奥希替尼治疗早期CTC和ctDNA的减少预示着更好的结果，这意味着液体活检监测可能是评估治疗疗效的有价值工具。
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