Genomic alterations and dynamic molecular residual disease monitoring predict pathological response to neoadjuvant chemoimmunotherapy in esophageal squamous cell carcinoma.

BACKGROUND: Approximately 40-60% of patients with locally advanced esophageal squamous cell carcinoma (ESCC) exhibit suboptimal responses to neoadjuvant chemoimmunotherapy (NCIT), highlighting the need for predictive biomarkers of pathological response.

METHODS: We prospectively enrolled 29 stage II-III ESCC patients receiving NCIT (albumin-paclitaxel/carboplatin + anti-PD-1). Baseline tumor tissues were firstly analyzed via 437-gene targeted sequencing. Serial preoperative plasma samples collected before NCIT, during NCIT and post-NCIT/pre-surgery, along with baseline tissue, were profiled using a 2365-gene panel for tumor-informed molecular residual disease (MRD) monitoring. Associations between clinicopathological features, genomic alterations, MRD status, and major pathological response (MPR) were evaluated.

RESULTS: No clinicopathological feature significantly correlated with MPR. MPR was significantly associated with baseline NOTCH1 mutations (p = 0.014) and higher chromosomal instability score (CIS, p = 0.032). Absence of MRD and lower ctDNA levels after NCIT completion, but not before and during, strongly correlated with MPR. Distinct change patterns of ctDNA level from on- to post-NCIT were observed in MPR versus non-MPR patients. A model integrating baseline NOTCH1 mutation and post-NCIT MRD status achieved superior MPR prediction (AUC = 0.954), outperforming either factor alone (NOTCH1, AUC = 0.769; post-NCIT MRD, AUC = 0.882).

CONCLUSIONS: Dynamic MRD monitoring, particularly post-treatment, provides strong predictive value for pathological response to NCIT in locally advanced ESCC. Integrating baseline NOTCH1 mutation status with post-NCIT MRD assessment significantly improves MPR prediction, indicating the potential to inform clinical decision-making for these patients.