Optimizing Esophageal Cancer Treatment: Personalized Ctdna Improves Residual Disease Detection After Neoadjuvant Chemoradiotherapy and Guides Adaptive Adjuvant Immunotherapy

Background Accurate detection of residual disease after neoadjuvant therapy in patients with locally-advanced esophageal squamous cell carcinoma (ESCC) is important within a strategy of active surveillance (watch and wait). Current diagnostic modalities reported from the preSINO/SANO studies used for clinical response evaluation (CRE) primarily focus on locoregional assessment of tumor response but fall short in detecting systemic minimal residual disease (MRD). This study assessed the feasibility of circulating-tumor DNA (ctDNA) in detecting residual disease after neoadjuvant chemoradiotherapy (nCRT) to improve the selection of patients for a watch and wait strategy and stratification of postsurgical recurrence risk to guide adjuvant immunotherapy. Methods In the subset of ESCC patients with adequate biospecimens who participated in the preSINO trial (NCT03937362) which assessed the accuracy of CRE for the detection of residual disease by using diagnostic tests post-nCRT, ctDNA assessment was performed for serial blood samples at different time points: baseline, post-nCRT (CRE-1 and CRE-2), and post-surgery (1 month [F1] and 3-to-6 month [F2]). MRD status was assessed by three ctDNA assays: a tumor-informed personalized panel, a tumor-naïve fixed panel, and a tumor-informed fixed panel. A total of 132 patients with available qualified paired tissue and blood samples were included for the ctDNA analysis. Results Tumor-informed personalized panel showed the highest ctDNA detection rate (99.2%) at baseline compared to other assays (Figure) and detected a lower ctDNA fraction. After nCRT, incorporating MRD detection using personalized ctDNA into conventional diagnostic modalities further increased the sensitivity for predicting non-pathologically complete response (non-pCR) from 78.4% (endoscopic biopsy) to 92.0% (endoscopic biopsy combined ctDNA). Post-operative MRD positivity at F1 and/or F2 correlated with worse disease-free survival (DFS). Furthermore, non-pCR patients with MRD-positivity at F1 who received adjuvant immunotherapy showed improved DFS than those without adjuvant immunotherapy, while no survival benefit was observed in patients with MRD-negativity at F1. Conclusion These findings highlight the clinical potential of tumor-informed personalized ctDNA analysis in enhancing residual disease detection after neoadjuvant treatment for a watch-and-wait active surveillance strategy, and in defining postoperative risk assessment to inform adjuvant therapy decision in patients with locally advanced ESCC. Integration of ctDNA into the clinical setting may facilitate a more adaptive treatment management in ESCC.