Presurgical ablative radiation associates 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. 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 cardinality matching with distance-optimized pairing, and conducted multivariable stepwise-AIC-optimized 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 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 = .003). 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 resulted in improved pathological outcomes, enhanced local control, and maintained survival while inducing a distinct immune response. The role of neoadjuvant SAbR should be further evaluated in well powered studies to define clinical benefits.