Department of Oncology, The First Medical Center of Chinese PLA General Hospital, Beijing, China.
Medical School of Chinese PLA, Beijing, China.
Front Immunol. 2020 Jun 10;11:1173. doi: 10.3389/fimmu.2020.01173. eCollection 2020.
Serum tumor markers carcinoembryonic antigen (CEA), cancer antigen 125 (CA125), cytokeratin 19 fragment (CYFRA21-1) and squamous-cell carcinoma-related antigen (SCC-Ag) are routinely used for monitoring the response to chemotherapy or targeted therapy in advanced-stage non-small cell lung cancer (NSCLC), however their role in immunotherapy remains unclear. The aim of this study was to investigate whether dynamics of these serum markers were associated with the efficacy and prognosis of Chinese late-stage NSCLC patients treated with programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors. We initiated a longitudinal prospective study on advanced NSCLC patients treated with PD-1/PD-L1 inhibitors in Chinese PLA general hospital (Beijing, China). Blood samples of baseline and after 6 weeks' treatment were collected. CT scan were used by all patients to evaluate treatment efficacy according to RECIST 1.1. Serum tumor markers levels were measured with an electrochemical luminescence for SCC-Ag and with a chemiluminescent microparticle immunoassay for serum CEA, CA125, and CYFRA21-1. At least 20% decreases of the biomarkers from baseline were considered as meaningful improvements after 6 weeks of treatment with immune checkpoint inhibitors (ICIs). Optimization-based method was used to balance baseline covariates between different groups. Associations between serum tumor biomarker improvements and objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were analyzed. A total of 308 Chinese patients with advanced NSCLC were enrolled in the study. After balancing baseline covariates, patients with meaningful improvements in <2 out of 4 biomarkers (CEA, CA125, CYFRA21-1, and SCC-Ag) was ended up with lower ORR (0.08 vs. 0.35, < 0.001), shorten PFS (median: 5.4 vs. 12.5 months, < 0.001), and OS (median: 11.7 vs. 25.6 months, < 0.001) in the total population. Subgroup analysis of patients with adenocarcinoma revealed that patients with meaningful improvements in <2 out of 4 biomarkers had significant lower ORR (0.06 vs. 0.36, < 0.001), shorten PFS (median: 4.1 vs. 11.9 months, < 0.001), and OS (median: 11.9 vs. 24.2 months, < 0.001). So as in patients with squamous cell carcinoma, meaningful improvements in at least 2 out of 4 biomarkers were linked to better ORR (0.42 vs. 0.08, = 0.014), longer PFS (median: 13.1 vs. 5.6 months, = 0.001), and OS (median: 25.6 vs. 10.9 months, = 0.06). The dynamic change of CEA, CA125, CYFRA21-1, and SCC-Ag from baseline have prognostic value for late-stage NSCLC patients treated with PD-1/PD-L1 inhibitors. Decrease of associated biomarkers serum levels were associated with favorable clinical outcomes.
血清肿瘤标志物癌胚抗原（CEA）、癌抗原 125（CA125）、细胞角蛋白 19 片段（CYFRA21-1）和鳞状细胞癌相关抗原（SCC-Ag）常用于监测晚期非小细胞肺癌（NSCLC）患者接受化疗或靶向治疗的反应，但它们在免疫治疗中的作用尚不清楚。本研究旨在探讨这些血清标志物的动态变化是否与接受程序性细胞死亡-1/程序性细胞死亡配体-1（PD-1/PD-L1）抑制剂治疗的中国晚期 NSCLC 患者的疗效和预后相关。
我们在中国人民解放军总医院（北京）对接受 PD-1/PD-L1 抑制剂治疗的晚期 NSCLC 患者进行了一项纵向前瞻性研究。在基线和治疗 6 周后采集血样。所有患者均采用 CT 扫描根据 RECIST 1.1 评估治疗效果。采用电化学发光法检测 SCC-Ag，采用化学发光微粒子免疫分析法检测血清 CEA、CA125 和 CYFRA21-1。治疗后 6 周内，标志物水平至少下降 20%被认为是免疫检查点抑制剂（ICI）治疗后的有意义改善。采用基于优化的方法平衡不同组间的基线协变量。分析血清肿瘤标志物改善与客观缓解率（ORR）、无进展生存期（PFS）和总生存期（OS）之间的关系。
共有 308 例中国晚期 NSCLC 患者入组本研究。在平衡基线协变量后，4 项标志物中仅有<2 项有意义改善的患者的 ORR（0.08 对 0.35，<0.001）更低，PFS（中位：5.4 对 12.5 个月，<0.001）和 OS（中位：11.7 对 25.6 个月，<0.001）更短。腺癌患者的亚组分析显示，4 项标志物中仅有<2 项有意义改善的患者 ORR（0.06 对 0.36，<0.001）更低，PFS（中位：4.1 对 11.9 个月，<0.001）和 OS（中位：11.9 对 24.2 个月，<0.001）更短。在鳞状细胞癌患者中也是如此，至少有 2 项标志物有意义改善的患者 ORR（0.42 对 0.08，=0.014）更好，PFS（中位：13.1 对 5.6 个月，=0.001）和 OS（中位：25.6 对 10.9 个月，=0.06）更长。
从基线开始，CEA、CA125、CYFRA21-1 和 SCC-Ag 的动态变化对接受 PD-1/PD-L1 抑制剂治疗的晚期 NSCLC 患者具有预后价值。相关生物标志物血清水平的下降与良好的临床结局相关。
