Presurgical ablative radiation is associated with local control and immune response in pancreatic cancer

Purpose: To compare outcomes and molecular characteristics of patients who had surgery after neoadjuvant chemotherapy, with and without ablative radiotherapy (SAbR) for pancreas cancer. Insight could clarify the benefits of SAbR and provide molecular guidance for future therapeutic regimens. Experimental Design: This single-institution, tertiary care academic center cohort study included all patients diagnosed with pancreatic cancer between 2012–2023 treated with neoadjuvant chemotherapy, with or without SAbR. We compared therapeutic responses, performed patient matching, and conducted Cox modeling to identify differences between groups. We assessed molecular response using RNA sequencing to identify SAbR-induced biologic differences. Results: Among 133 patients receiving chemotherapy and 48 receiving chemotherapy + SAbR, RNA sequencing was available for 29 and 14 patients, respectively. Despite more advanced baseline disease, the SAbR group showed better post-treatment pathology and similar overall survival (HR = 0.97, 95% CI = 0.58–1.60, P = .9). Patient matching indicated that SAbR improved locoregional recurrence-free survival (HR = 0.24, 95% CI = 0.07–0.88, P = .009). Arterial involvement raised local failure risk with chemotherapy alone (HR = 3.37, 95% CI = 1.74–6.54, P < .001), which was significantly reduced with SAbR (HR = 0.28; 95% CI = 0.12–0.68; P = .005). Gene set enrichment analysis showed immune activation, with CD8 and NK/NKT cell signatures associated with local control and Treg signatures associated with worse control. Conclusion: Neoadjuvant SAbR is associated with improved pathological outcomes, enhanced local control, and maintained survival while inducing a distinct immune response. Well-powered studies are needed to clarify its clinical benefits.