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Preoperative Circulating Tumor DNA Detection and Risk Stratification in Esophageal Squamous Cell Carcinoma
2026-02-19
Abstract
Preoperative circulating tumor DNA (ctDNA) detection may help identify patients with early-stage esophageal squamous cell carcinoma (ESCC) who harbor occult nodal metastasis or are at high risk of recurrence.
In this cohort study of 74 patients with clinical stage I (T1b) or stage II (T2N0) ESCC who underwent upfront curative surgery without neoadjuvant therapy, tumor-informed ctDNA sequencing was performed on preoperative plasma samples.
Preoperative ctDNA positivity was significantly associated with both pathologic nodal upstaging and worse survival outcomes (recurrence-free survival and overall survival).
Incorporation of ctDNA status into guideline-based risk prediction models substantially improved the ability to predict occult lymph node metastasis, particularly in the T2N0 subgroup.
The findings suggest that ctDNA may be a valuable preoperative biomarker for refining risk stratification and informing treatment decisions in early-stage ESCC.
Purpose
The purpose of this study was to determine whether preoperative detection of circulating tumor DNA (ctDNA) in patients with early-stage esophageal squamous cell carcinoma
(clinical T1b or T2N0 ESCC) is associated with (1) pathologic nodal upstaging (occult lymph node metastasis discovered after surgery) and (2) postoperative recurrence and survival outcomes.
The study also aimed to evaluate whether adding ctDNA status to existing guideline-based risk models could improve the prediction of occult nodal metastasis, particularly in patients with T2N0 disease
where clinical decision-making regarding neoadjuvant therapy remains uncertain.
Results
- Preoperative ctDNA was detected in 36 patients (48.6%) — 27 (54.0%) in the SMC cohort and 9 (37.5%) in the YUSH cohort. Detection was more frequent among patients with clinical T2N0 than T1b disease.
- During a median follow-up of 37.7 months, ctDNA-positive patients had significantly worse recurrence-free survival (RFS) (HR, 4.15; P = .005) and overall survival (OS) (HR, 4.02; P = .006) compared with ctDNA-negative patients.
- In the T2N0 subgroup specifically, ctDNA positivity showed very high positive predictive value for occult nodal metastasis, reaching 100% in the SMC cohort and 88.9% in the YUSH cohort.
- In multivariable analysis, ctDNA positivity remained strongly associated with pathologic nodal metastasis (OR, ~19.98; P < .001), outperforming standard guideline-based risk factors
- Incorporating ctDNA status into predictive models significantly improved the area under the ROC curve for predicting occult nodal metastasis (e.g., from 0.66 to 0.91 in the SMC cohort).
Conclusions
Preoperative ctDNA detection in patients with early-stage ESCC was significantly associated with occult nodal metastasis and poorer survival outcomes.
Among patients with clinical T2N0 disease, ctDNA may serve as a complementary biomarker to current guideline-based risk criteria for refining preoperative risk stratification.
Incorporating ctDNA status into clinical models could help clinicians identify high-risk patients who might benefit from neoadjuvant treatment escalation and
support more personalized therapeutic strategies in early-stage ESCC. Prospective validation of ctDNA-guided treatment approaches is needed before clinical implementation.