Tumor regression grades in locally advanced gastroesophageal adenocarcinoma: associations with survival, pathological risk factors, and molecular biomarkers in a 19-year real-world cohort.

Background: Tumor regression grade (TRG) after neoadjuvant therapy has been proposed as a prognostic marker in resectable gastroesophageal adenocarcinoma, yet its independent value beyond pathological staging remains uncertain. Materials and methods: This retrospective single-center study included 692 patients with locally advanced, resectable gastroesophageal adenocarcinoma treated between 2006 and 2024 at the Medical University of Vienna. Among 394 patients receiving neoadjuvant systemic therapy, 175 had documented TRG according to Mandard and/or Becker. Temporal trends in treatment and TRG reporting were assessed. Associations between TRG, clinicopathological factors, mismatch repair, programmed cell death receptor ligand 1, and human epidermal growth factor receptor 2 status were analyzed. Disease-free survival (DFS) and overall survival (OS) were evaluated using Kaplan-Meier and univariable Cox regression models. Results: The use of neoadjuvant/perioperative chemotherapy and documentation of TRG increased substantially over time. Tumor regression was heterogeneous, with a predominance of poor responders. Lower TRG scores were strongly associated with favorable ypT and ypN categories and absence of lymphatic, venous, and perineural invasion (all Conclusion: In this long-term real-world cohort, Mandard TRG was associated with survival, although its prognostic impact appears closely linked to pathological stage and molecular context. Prospective studies integrating standardized TRG assessment with pathological TNM (tumor-node-metastasis) staging and biomarkers are warranted, particularly in the evolving era of perioperative chemo-immunotherapy.