Presurgical ablative radiation downstages high-risk features and alters immune response in pancreatic cancer

Neoadjuvant (NA) stereotactic ablative radiotherapy (SAbR) may improve outcomes in pancreatic cancer. We compared outcomes and molecular characteristics of patients who had surgery after neoadjuvant chemotherapy, with and without SAbR. We compared clinical data from surgically resected patients treated with either NA chemotherapy or NA chemotherapy plus SAbR. Recurrence-free and overall survival (RFS/OS) were analyzed using stepwise-AIC-optimized multivariable Cox modeling and log-rank tests. When available, we used transcriptomic analyses (GSEA, CIBERSORTx, and SCISSOR) to link clinical outcomes to gene expression patterns. We reviewed 133 patients treated with NA chemotherapy and 48 with NA chemotherapy + SAbR, including RNA sequencing data from 29 and 14 patients, respectively. Before surgery, the SAbR group had more advanced disease with arterial involvement, yet still achieved similar OS and RFS. Patients treated with SAbR had better post-treatment pathology linked to improved OS and RFS. RNA sequencing showed that patients with nodal involvement had enriched MYC targets and worse distant RFS. Those with arterial involvement had worse locoregional RFS with chemotherapy alone, but not in the SAbR group. GSEA highlighted immune-related changes in myeloid and T cell activation, suggesting treatment-related functional changes. SCISSOR analysis revealed cytotoxic CD8 and NK/NKT cell signatures correlating with better local control, while Treg signatures were linked to worse LRFS. Patients treated with NA chemotherapy + SAbR showed better pathologic outcomes, improved local control, and comparable survival, along with a distinct immune response. Further evaluation of SAbR in the neoadjuvant setting, combined with enhanced chemotherapy and novel treatment combinations, may lead to even greater clinical benefits.