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.
Histologically confirmed adenocarcinoma of the stomach (gastric cancer, GC) or gastroesophageal junction (GEJ)
Operable, locally advanced disease (T >= 2 and/or node-positive) according to AJCC 8th edition staging
Candidate for perioperative chemotherapy with FLOT regimen combined with durvalumab, as per clinical practice
Age >= 18 years
Presence of another active malignant disease
Advanced or metastatic gastric/GEJ cancer not eligible for surgical treatment
Inability or unwillingness to provide written informed consent
Adult patients (age \>= 18 years) with histologically confirmed, operable, locally advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma, candidate to perioperative treatment with FLOT plus durvalumab at the participating IRCCS centers. Patients are enrolled consecutively as they start perioperative treatment in clinical practice.
Cohort
Prospective
Not listed
Identification of immune and angiogenic cellular subsets associated with pathological response to perioperative FLOT plus durvalumab
Identification of specific cellular subsets and activation/exhaustion states, assessed by scRNA-seq, TCR/BCR sequencing, and multiparametric spectral flow cytometry of tumor-infiltrating lymphocytes (TILs) and PBMCs, associated with pathological response (Tumor Regression Grade TRG 1-2) or resistance (TRG 3-4) to perioperative FLOT plus durvalumab.
Association between angiogenic and immune signatures and clinical outcomes
Correlation of angiogenic and immune profiles (serum cytokine/chemokine panels by Luminex xMAP, pathomic biomarkers from whole-slide HE images, and flow cytometry data) with clinical outcomes including Tumor Regression Grade (TRG), early recurrence, and short-term survival.
Validation of a pathomic biomarker related to angiogenesis and immune response
Validation of a previously developed pathomic biomarker derived from whole-slide HE digital histology, related to vascular architecture and immune cell spatial distribution, as a predictor of response to perioperative FLOT plus durvalumab in gastric and GEJ adenocarcinoma.
Characterization of immune evasion mechanisms in non-responders
Characterization of immune evasion mechanisms in the tumor microenvironment of non-responders (TRG 3-4) based on single-cell analyses (scRNA-seq, TCR/BCR-seq) of TILs and PBMCs, including identification of exhausted T cell populations, immunosuppressive cell subsets, and altered antigen presentation pathways.
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Azienda Ospedaliera Specializzata in Gastroenterologia Saverio de Bellis
Lead sponsor
Humanitas Research Hospital IRCCS, Rozzano-Milan
Collaborator
University of Genova
Collaborator
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