Favorable histo-molecular remodeling of pancreatic ductal adenocarcinoma after neoadjuvant FOLFIRINOX followed by high-dose stereotactic body radiotherapy

BACKGROUND: Combining high-dose stereotactic body radiation therapy (SBRT) with FOLFIRINOX (FFX) is promising as neoadjuvant strategy for pancreatic ductal adenocarcinoma (PDAC). This study provides an in-depth histo-molecular characterisation of resected PDAC samples from patients treated with FFX ± SBRT. METHODS: Residual tumour tissues from 56 non-metastatic PDAC patients were analysed: seventeen underwent upfront surgery, seventeen received neoadjuvant FFX alone and twenty-two FFX followed by radiotherapy (sixteen SBRT, six radiochemotherapy [RT-CT]). Samples were assessed using RNAseq and immunohistochemistry/fluorescence, including multiplex. RESULTS: Addition of SBRT to FFX favourably remodelled PDAC, influencing stromal, immune, metabolic and molecular features. Unlike RT-CT, SBRT counteracted several detrimental effects induced by FFX alone. Notably, FFX + SBRT enriched tumours with 'Classical' and 'Inactive stroma' signatures-linked to better prognosis - while reducing 'Basal-like' cell enrichment. SBRT promoted COL1A1-driven stromal remodelling while globally preserving T-lymphocyte infiltration, including cytotoxic T cells, which maintained close proximity to tumour cells despite increased desmoplasia. Key transcriptional alterations induced by SBRT were identified, offering targets for future combination therapies. CONCLUSIONS: Highlighting a more favourable stromal and molecular profile after integration of high-dose SBRT to FFX, this study supports the development, rationale and validation in prospective trials of using this treatment combination in non-metastatic PDAC.