PO.CL01.10 · 临床研究

ctDNA甲基化的动态变化可预测晚期食管癌对免疫治疗的早期应答

Dynamic changes in ctDNA methylation predict early response to immunotherapy in advanced esophageal cancer

编号 5310 展板 5 时间 4/21 09:00–12:00 区域 Section 45 主讲 Zhang Hui

分会场 Liquid Biopsies: Circulating Nucleic Acids 4

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作者与单位 Authors & Affiliations

Hui Zhang#¹, Yu Lang#¹, Yaping Dong#², Wei Li#³, Jialin Lin⁴, Lu Yang⁵, Jiapeng Kang⁶, Wenqiang Yu*⁷, Changshun Yang*⁸, Jingxun Wu*¹, Qiyuan Li*⁹, Feng Ye*¹, Weiwei Tang*¹

¹Department of Medical Oncology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, The School of Clinical Medicine of Fujian, Medical University, Xiamen, China,²Department of research and development，Shanghai Epiprobe Biotechnology Co.,Ltd, Shanghai, China,³Fudan University Shanghai Cancer Center, Department of Radiotherapy, Shanghai Medical College, Fudan University, Shanghai, China,⁴Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China,⁵Department of Medical Oncology,Weifang people's Hospital, Weifang Medical University, Weifang, China,⁶Department of Medical Oncology, Zhangzhou Municipal Hospital, Zhangzhou Municipal Hospital Affiliated of Fujian Medical University, Zhangzhou, China,⁷Shanghai Public Health Clinical Center and Department of General Surgery, Huashan Hospital, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China,⁸Department of Surgical Oncology, Fujian Provincial Hospital, Fuzhou, China,⁹Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, China

摘要 Abstract

中文摘要

背景：免疫检查点抑制剂（ICI）改善了晚期食管癌（ESCA）的预后，然而准确的应答预测仍具挑战性。传统生物标志物和影像学往往缺乏对疾病进展的及时反映。循环肿瘤DNA（ctDNA）甲基化提供了一种新颖、无创、实时的监测手段。在本研究中，我们评估了晚期ESCA中早期动态ctDNA甲基化变化，并预测ICI应答和生存。方法：这项观察性探索研究纳入接受ICI治疗的晚期ESCA患者。在基线及整个治疗期间定期采集外周血样本。对血浆ctDNA进行甲基化测序。根据动态变化将患者分为"下降"组（甲基化评分较基线降低）和"未下降"组（评分稳定或升高）。Kaplan-Meier和log-rank检验评估甲基化评分动态与无进展生存期（PFS）和总生存期（OS）的关联。还评估了ctDNA动态与影像学疗效（RECIST 1.1）之间的一致性。结果：基线ctDNA甲基化水平与结局无显著相关（p=0.1）；然而，动态变化具有很强的预后价值。"下降"组与"未下降"组相比，PFS（26.0对15.85个月；p<0.05）和中位OS（35.0对27.0个月；p=0.01）显著更长。ctDNA定义的应答显著早于影像学应答（1.55对4.0个月，p<0.05）。ctDNA定义的进展的中位时间（2.52对4.0个月）也早于影像学进展，但无统计学意义（p=0.15）。结论：动态ctDNA甲基化监测为评估晚期ESCA中ICI疗效提供了一种有前景的无创方法。治疗后ctDNA甲基化水平的降低与生存期延长显著相关。ctDNA动态相比影像学评估能够更早地预测治疗应答和进展，凸显其及时检测的潜力。这些发现强调了动态ctDNA甲基化分析作为一种新颖早期疗效标志物的价值。 #这些作者贡献相同：Hui Zhang、Yu Lang、Yaping Dong、Wei Li *通讯作者：Weiwei Tang博士，weiweitang008@xmu.edu.cn；Feng Ye博士，yefengdoctor@xmu.edu.cn；Qiyuan Li博士，qiyuan.li@xmu.edu.cn；Jingxun Wu博士，wujingxun@xmu.edu.cn；Changshun Yang博士，282483331@qq.com；Wenqiang Yu博士，wenqiangyu@fudan.edu.cn 资助：本研究由国家自然科学基金（批准号81702414）、福建省自然科学基金（批准号2020J05306）和厦门市医疗卫生指导性项目（批准号3502Z20244ZD1023）资助。

查看英文原文 English abstract

Background : Immune checkpoint inhibitors (ICIs) improve the prognosis of advanced esophageal cancer (ESCA), yet accurate response prediction remains challenging. Traditional biomarkers and imaging often lack timely reflection of disease progression. Circulating tumor DNA (ctDNA) methylation offers novel, non-invasive, real-time monitoring. In this study, we evaluated the early dynamic ctDNA methylation changes in advanced ESCA and predicted ICI response and survival. Methods : This observational exploratory study enrolled advanced ESCA patients on ICI treatment.Peripheral blood samples were collected at baseline and regularly throughout treatment.Plasma ctDNA was subjected to methylation sequencing. Patients were stratified into "decreased" (methylation score reduction from baseline) and "non-decreased" (stable or increased scores) groups based on dynamic changes. Kaplan-Meier and log-rank tests assessed methylation score dynamics' association with progression-free survival (PFS) and overall survival (OS). Consistency between ctDNA dynamics and imaging efficacy (RECIST 1.1) was also evaluated. Results : Baseline ctDNA methylation levels did not significantly correlate with outcomes ( p =0.1); however,dynamic changes were strongly prognostic. The "decreased" group demonstrated significantly longer PFS (26.0 vs. 15.85 months; p <0.05) and median OS (35.0 vs. 27.0 months; p =0.01) compared to the "non-decreased" group. CtDNA-defined response occurred significantly earlier than radiological response (1.55 vs. 4.0 months, p <0.05). Median time to ctDNA-defined progression (2.52 vs. 4.0 months) also preceded imaging progression, without statistical significance ( p =0.15). Conclusion : Dynamic ctDNA methylation monitoring presents a promising non-invasive approach for assessing ICI efficacy in advanced ESCA. A reduction in post-treatment ctDNA methylation levels significantly correlated with prolonged survival. ctDNA dynamics enabled earlier prediction of treatment response and progression than radiological assessment, highlighting its potential for timely detection. These findings underscore the value of dynamic ctDNA methylation analysis as a novel early efficacy marker. #These authors contributed equally: Hui Zhang, Yu Lang,Yaping Dong,Wei Li *Correspondence to:Dr. Weiwei Tang, weiweitang008@xmu.edu.cn;Dr. Feng Ye, yefengdoctor@xmu.edu.cn;Dr. Qiyuan Li, qiyuan.li@xmu.edu.cn; Dr.Jingxun Wu,wujingxun@xmu.edu.cn;Dr. Changshun Yang, 282483331@qq.com;Dr. Wenqiang Yu .wenqiangyu@fudan.edu.cn FUNDING: This study was supported by the National Natural Science Foundation of China (Grant No. 81702414), Natural Science Foundation of Fujian Province of China (Grant No. 2020J05306) and Xiamen Medical and Health Guidance Project (Grant No. 3502Z20244ZD1023).

利益披露 Disclosure

H. Zhang#, None.. Y. Lang#, None.. Y. Dong#, None.. W. Li#, None.. J. Lin, None.. L. Yang, None.. J. Kang, None.. W. Yu*, None.. C. Yang*, None.. J. Wu*, None.. Q. Li*, None.. F. Ye*, None.. W. Tang*, None.

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