Circulating Tumor DNA Assessment to Predict Risk of Recurrence after Surgery in Patients with Locally Advanced Esophageal Squamous Cell Carcinoma: A Prospective Observational Study.

Objective: To investigate the association between perioperative ctDNA status and prognosis in patients with esophageal squamous cell carcinoma (ESCC).

Background: Circulating tumor DNA (ctDNA) has emerged as a promising biomarker for assessing molecular residual disease (MRD) in various malignancies. However, there are limited studies evaluating the utility of ctDNA for predicting recurrence risk in patients with ESCC.

Methods: We prospectively enrolled patients with locally advanced ESCC who were scheduled to receive neoadjuvant chemotherapy (NAC) followed by surgery. This report retrospectively analyzed ctDNA with a personalized, tumor-informed 16-plex mPCR-NGS assay at multiple time points: pre-NAC, post-NAC but before surgery, postoperatively, and longitudinally during follow-up.

Results: A total of 28 patients who underwent curative surgery, and had successful whole-exome sequencing analysis of tumor tissue samples were included in this report. At the pre-NAC time point, ctDNA was detected in 50% of patients with stage I and 100% of those with stages II, III, and IV. Post-NAC but before surgery, ctDNA was detected in 33.3% of patients. The recurrence rate was 77.8% in ctDNA-positive patients compared to 27.8% in ctDNA-negative patients, with significantly worse recurrence-free survival (RFS) for ctDNA-positive patients vs. ctDNA-negative patients (HR: 4.56, P =0.01). In patients analyzed during the MRD window (2-16 weeks post-surgery), the recurrence rate was 100% in ctDNA-positive patients compared to 30.4% in ctDNA-negative patients, with significantly worse RFS (HR: 30.99, P <0.0001). Similarly, during surveillance (>16 weeks post-surgery), detectable ctDNA was significantly associated with poor RFS (HR: 27.34, P =0.003).

Conclusions: This study suggests that ctDNA-based MRD assessment may be valuable for evaluating patients with ESCC, particularly in post-NAC and postsurgical settings.