Dynamic Changes of ctDNA ‐Based MRD and Genomic Mutations Predict Prognosis in ESCC Treated With Definitive Radiotherapy

ABSTRACT This study characterized the genomic profile of esophageal squamous cell carcinoma (ESCC) via circulating tumor DNA (ctDNA) to identify predictive biomarkers for efficacy of definitive radiotherapy combined with systemic therapy. In this prospective cohort of 40 ESCC patients, 7 tumor tissues and 71 serial plasma samples were analyzed using a 340‐gene panel. TP53 (45%) and PIK3CA (12.5%) were the most frequent SNVs, followed by NOTCH1/2 (7.5%). The 11q13.2–13.4 amplification (including CCND1/FGF19) occurred in 12.5% of cases. TP53 mutation rate was significantly higher in cT4 than cT2–3 stages (60% vs. 20%, p = 0.010). Notably, patients with persistent TP53 positivity posttreatment had significantly shorter PFS than those converting to negativity (HR = 5.090, p = 0.035); the 2‐year PFS rates were 33.3% vs. 75%, respectively, with OS showing a borderline difference ( p = 0.053). Posttreatment ctDNA‐based minimal residual disease (MRD) positivity was 18.8%, correlating with a trend toward worse PFS (HR = 3.027, p = 0.067). Among the 31 patients with paired pre‐ and post‐treatment plasma samples, the positive detection rate of nucleosome‐positioning (left‐shifted profile) decreased from 67.9% at baseline to 35.7% after treatment ( χ 2 = 5.793, p = 0.016). This work based on plasma ctDNA profiling demonstrated that posttreatment clearance of TP53 mutations may represent a favorable prognostic biomarker in ESCC treated with definitive radiotherapy and systemic therapy. ctDNA‐derived MRD status and nucleosome positioning constitute promising non‐invasive biomarkers for treatment response monitoring and risk stratification for ESCC. Trial Registration: This study was registered with the Chinese Clinical Trial Registry (ChiCTR) on December 6, 2019 (Registration No. ChiCTR1900027936)