Postoperative molecular residual disease status refines recurrence risk stratification beyond pathologic response after neoadjuvant chemoradiotherapy for esophageal squamous cell carcinoma.

Abstract

Accurate postoperative recurrence-risk stratification is essential for adjuvant treatment decisions in esophageal cancer after neoadjuvant chemoradiotherapy. Pathologic complete response is widely used for risk assessment but shows limited discrimination. This study evaluated whether integrating postoperative molecular residual disease with pathologic response improves recurrence prediction. This was a post hoc analysis of the preSINO trial. Patients with locally advanced esophageal squamous cell carcinoma who underwent neoadjuvant chemoradiotherapy followed by esophagectomy (2019-2023) and had molecular residual disease assessment were included. Molecular residual disease status was determined 3 to 4 weeks postsurgery using a tumor-informed personalized circulating tumor DNA assay. Recurrence-free survival and recurrence patterns were analyzed. Ninety-three patients were included, of whom 30 experienced recurrences during a median follow-up of 36.5 months. Most recurrences (73.3%) occurred within the first year postsurgery. A trend toward a lower 1-year recurrence rate was observed in patients with a pathologic complete response (13.5%) compared with patients without a pathologic complete response (30.4%) (P = .061). Molecular residual disease status significantly stratified recurrence-free survival and early recurrence risk, with 1-year recurrence rates of 6.1% versus 66.7% for molecular residual disease-negative versus molecular residual disease-positive groups (P < .001). Multivariable Cox-regression analysis demonstrated molecular residual disease positivity (hazard ratio, 13.62; P < .001) as an independent predictor of recurrence-free survival, whereas pathologic response was not. A classification combining pathologic complete response/non-pathologic complete response and molecular residual disease status identified 4 distinct recurrence risk subgroups: The 1-year recurrence rates were 3.7% of pathologic complete response and molecular residual disease negative, 7.7% of non-pathologic complete response and molecular residual disease negative, 40% of pathologic complete response and molecular residual disease positive, and 82.4% of non-pathologic complete response and molecular residual disease positive (P < .001), with distant recurrence predominating in molecular residual disease-positive groups. Integrating postoperative molecular residual disease with pathologic response improves recurrence risk stratification that may facilitate adjuvant therapy decisions but warrants prospective validation.