Clinical Application of Circulating Tumor DNA in Surgically Treated Esophageal Squamous Cell Carcinoma

Background: Esophageal squamous cell carcinoma (ESCC) is associated with a high recurrence rate and is one of the most aggressive malignancies. Recurrence is mainly detected via imaging modalities; however, postoperative imaging surveillance has disadvantages, including reduced sensitivity in postoperative or irradiated tissues, high cost, and repeated radiation exposure. Research elucidating the diagnostic utility of circulating tumor DNA (ctDNA) in ESCC remains limited. In this prospective study, we evaluated the clinical value of ctDNA as a biomarker for ESCC diagnosis and longitudinal monitoring. Methods: Eighty-four patients with pathologically confirmed ESCC who underwent curative resection were prospectively enrolled (mean age, 63.7±8.3 yrs; men, 92.9%; pathological stage 0-I, 41.7%; II, 31.0%; III-IV, 26.2%; neoadjuvant therapy, 10.7%). In total, 334 samples (84 at initial diagnosis and 250 during follow-up at 4-month intervals with computed tomography) were analyzed. Ultra-high-depth sequencing (mean effective depth, >30,000×) was performed using a customized panel targeting 27 ESCC-related genes. Matched leukocyte DNA was used to exclude germline and clonal hematopoiesis variants; variants with allele frequencies ≥ 0.25% were interpreted according to the AMP/ASCO/CAP tiers. Results: ) were detected in 31 patients (36.9%). Detection rates were higher in advanced stages (63.6%) than in early-stage cancers (28.3%). While the initial ctDNA detection rate correlated with pTNM stages, no significant association was found with other pathological features. Follow-up assessments revealed that 18 of 24 patients with recurrence (75%) harbored detectable ctDNA variants. Notably, in three cases, ctDNA positivity preceded radiological recurrence by 3-6 months. Conclusions: The ctDNA detection rate using a customized gene panel correlated with tumor burden. Accordingly, ctDNA may be helpful for monitoring recurrence in patients with ESCC.