Molecular Characterization of Tumor-Microenvironment Interactions to Predict Drug Resistance in Gastric and GEJ Adenocarcinoma

Surgical resection remains the only curative option for resectable gastric cancer, but perioperative FLOT chemotherapy is associated with substantial rates of chemoresistance and recurrence, largely driven by marked tumor heterogeneity. Recent data from the MATTERHORN phase III trial have shown that adding durvalumab to perioperative FLOT improves pathological complete response and survival, supporting this combination as a new standard of care for resectable gastric and gastroesophageal junction adenocarcinoma. This observational multicenter study aims to characterize angiogenic and immune profiles within the tumor microenvironment and peripheral blood, in order to identify cellular and molecular signatures associated with response or resistance to perioperative FLOT plus durvalumab. Longitudinal biospecimen collection (PBMCs, serum, plasma, endoscopic biopsies, surgical specimens) will be integrated with multiparametric flow cytometry, single-cell transcriptomics and TCR/BCR sequencing, immunohistochemistry, pathomics and multiplex immunoassays, to provide mechanistic insights and potential predictive biomarkers.

Inclusion Criteria: 1. Histologically confirmed adenocarcinoma of the stomach (gastric cancer, GC) or gastroesophageal junction (GEJ) 2. Operable, locally advanced disease (T \>= 2 and/or node-positive) according to AJCC 8th edition staging 3. Candidate for perioperative chemotherapy with FLOT regimen combined with durvalumab, as per clinical practice 4. Age \>= 18 years 5. Provision of written informed consent prior to any study-specific procedure Exclusion Criteria: 1. Presence of another active malignant disease 2. Advanced or metastatic gastric/GEJ cancer not eligible for surgical treatment 3. Inability or unwillingness to provide written informed consent