Prognostic value of cfDNA methylation in locally advanced esophageal squamous cell cancer treated with neoadjuvant immunochemoradiotherapy.

Abstract

We prospectively evaluated whether longitudinal cfDNA methylation predicts pathological complete response (pCR) and survival in 70 patients with esophageal squamous cell carcinoma (ESCC) receiving neoadjuvant immunochemoradiotherapy. Serial plasma samples (n = 183) were collected at four time points: pre-neoadjuvant treatment (NAT), post-NAT, pre-surgery, and post-surgery. Targeted whole-genome cfDNA methylation sequencing was performed, and cancer detection (CD) values were calculated with positivity, defined as CD ≥ 0.7. CD positivity dropped from 74% pre-NAT to 31% post-NAT (p < 0.001). Pre-surgery CD positivity was significantly higher in non-pCR versus pCR patients (33% vs. 0%; p = 0.028). A model incorporating post-NAT CD value and clinical factors achieved an area under the curve (AUC) of 0.764 for pCR. Post-NAT CD-negative patients had significantly improved disease-free survival (DFS; hazard ratio [HR] = 0.33; p = 0.035). Findings were reproduced in an expanded 30-patient cohort. Dynamic cfDNA methylation monitoring is associated with pCR and DFS, warranting further validation in larger cohorts.