Abstract 5310: Dynamic changes in ctDNA methylation predict early response to immunotherapy in advanced esophageal cancer.

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. 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). Citation Format: Hui Zhang#, Yu Lang#, Yaping Dong#, Wei Li#, Jialin Lin, Lu Yang, Jiapeng Kang, Wenqiang Yu, Changshun Yang, Jingxun Wu, Qiyuan Li, Feng Ye, Weiwei Tang. Dynamic changes in ctDNA methylation predict early response to immunotherapy in advanced esophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5310.