Circulating Free DNA as a Predictive Biomarker for Response to Nivolumab and Platinum-Based Chemotherapy in Metastatic Esophageal Adenocarcinoma: A Prospective Pilot Study

Qing Sheng DuBo Fan^*

• First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China

Background: Reliable biomarkers are urgently needed to predict response to immune checkpoint inhibitors in metastatic esophageal adenocarcinoma (mEAC). This study evaluated early circulating free DNA (cfDNA) dynamics as a predictor of treatment response and survival in patients receiving platinum-based chemotherapy plus Nivolumab. Methods: In this prospective pilot study, 95 patients with mEAC were treated with Nivolumab and platinum-based chemotherapy. Plasma cfDNA levels were measured at baseline, Day 15, and Day 30 using digital droplet PCR. The primary outcome was objective treatment response; secondary outcomes included progression-free survival (PFS) and overall survival (OS). Tumor mutational burden (TMB), PD-L1 expression, liver metastasis, and ECOG status were also assessed. Results: Patients with a cfDNA Day 30/Baseline ratio <0.4 had significantly improved median PFS (11 vs. 4 months) and OS (14 vs. 7 months) compared to those with ratios >0.8 (p for trend <0.001). Early decline in cfDNA correlated with treatment response. High TMB (≥10 mut/Mb) was independently associated with increased response (adjusted OR: 2.5, 95% CI: 1.2–5.2, p=0.015). ECOG >1 was inversely associated with response (adjusted OR: 0.35, p=0.01). PD-L1 expression and liver metastasis were not significantly predictive. Conclusion: Early cfDNA kinetics—particularly a Day 30/Baseline ratio <0.4—strongly predicted response and survival in mEAC patients receiving chemoimmunotherapy. cfDNA monitoring offers a promising non-invasive tool for early treatment stratification and response assessment in this population.