Circulating tumor DNA detects minimal residual disease and predicts outcomes in esophageal cancer after esophagectomy

Background Circulating tumor DNA (ctDNA) monitoring shows promise for detecting minimal residual disease (MRD) and predicting prognosis in various cancers. This study evaluated ctDNA for detecting MRD and predicting outcomes in patients with esophageal cancer (EC) after esophagectomy. Methods We conducted a two-step observational study with a retrospective cohort (cohort 1) and a prospective cohort (cohort 2) of 40 EC patients who underwent upfront surgery or neoadjuvant chemotherapy (NAC) followed by esophagectomy. Plasma samples were collected at six time points: pre-therapy, post-NAC, and 1, 3, 6, and 12 months post-surgery. ctDNA was assessed using a 250-gene panel and its association with clinical outcomes was analyzed. Results Tumor-informed ctDNA levels were significantly correlated with tumor stage ( P =0.01). Changes in ctDNA levels predicted tumor progression, with an area under the curve of 0.77. Postsurgical ctDNA positivity correlated with reduced recurrence-free survival (RFS) in cohort 1 (n=6, Log-rank P =0.034) and progression-free survival (PFS) in cohort 2 (n=34, Log-rank P =0.025) compared to ctDNA-negative patients. Combined analysis showed that postsurgical ctDNA positivity was associated with shorter PFS (hazard ratio [HR]=12.6, 95% confidence interval [CI]: 1.6-99.0; P =0.002) across all patients (n=40) and shorter RFS (HR=11.1, 95% CI: 1.4-89.0; P =0.006) in those who underwent R0 resection (n=37). ctDNA positivity predicted recurrence at a median of 90 days before radiographic evidence. Conclusions This study showed a strong correlation between ctDNA status and postsurgical prognosis in EC patients. ctDNA assessments can effectively detect MRD and guide postoperative management strategies.