Abstract A022: Neoadjuvant ablative radiation downstages high-risk features and alters immune response in pancreatic cancer

Abstract Purpose: Increasing evidence shows neoadjuvant (NA) therapy benefits surgical selection and survival in localized pancreatic cancer. However, the optimal NA therapy for resectable, borderline resectable (BRPC), and locally advanced pancreatic cancer (LAPC) remains unclear. We hypothesize that NA stereotactic ablative radiotherapy (SAbR) benefits patients with BRPC and LAPC who do not progress on chemotherapy (CTH), especially with arterial involvement. To evaluate this, we retrospectively reviewed outcomes and molecular features of patients treated with NA CTH and NA CTH followed by SAbR to understand the contribution of radiation. Methods: We retrospectively reviewed clinical data for 133 patients treated with NA CTH and 48 with NA CTH + SAbR. Bulk RNA sequencing was performed on fresh surgical tissue from 29 CTH-treated and 14 CTH + SABR-treated patients. We conducted gene set enrichment analysis (GSEA), CIBERSORTx cellular deconvolution, and Single-Cell Identification of Subpopulations with Bulk Sample Phenotype Correlation (Scissor) analysis to correlate clinical outcomes with transcriptomic features. Results: Molecular subtyping of PDAC transcriptomic signatures from post-treatment tissues revealed similar subtype proportions after both treatments. However, at baseline and before surgery, patients receiving SABR had more advanced clinical T staging, NCCN resectability, and arterial involvement. Despite this, the NA CTH + SAbR cohort showed similar overall survival, local-regional progression-free survival (LRPFS), and distant metastasis progression-free survival (DPFS) compared to NA CTH only. NA CTH + SABR-treated patients had significantly improved post-treatment T and N staging, tumor size, and treatment effect. These improvements correlated with better survival, LRPFS, and DPFS. RNAseq analysis indicated that patients with nodal involvement had significantly increased GSEA of MYC targets and worse DPFS. Tumor-arterial involvement at diagnosis significantly reduced local-regional control for NA CTH only. In contrast, patients with arterial involvement receiving NA CTH + SAbR had significantly improved local control. CIBERSORTx cell fraction deconvolution revealed no significant differences in tumor and immune cell subsets between treatments, but GSEA indicated substantial changes in immune-related gene sets, particularly those related to myeloid and T cell activation, suggesting functional changes correlating with treatment response and local control. Scissor identified gene signatures from activated CD8 T cells correlating with improved local control, while signatures from Treg and naïve T cells negatively impacted LRPFS. Conclusions: Molecular analysis and clinical features showed that patients treated with NA CTH + SAbR experienced downstaging and had similar outcomes, with indications of a differential immune response. Given these findings, the role of SAbR in the NA setting should be further evaluated, especially in the context of improved chemotherapy and novel combination therapies that leverage biological responses. Citation Format: Peter Q. Leung, Eslam A. Elghonaimy, Ahmed M. Elamir, Megan Wachsmann, Song Zhang, Neha Barrows, Rachel von Ebers, Cassandra Hamilton, Grace Josephson, Salwan Al Mutar, Patricio M. Polanco, Nina N. Sanford, Syed M. Ali Kazmi, Matthew R. Porembka, David Hsieh, Adam C. Yopp, Muhammad S. Beg, Herbert J. Zeh, Todd A. Aguilera. Neoadjuvant ablative radiation downstages high-risk features and alters immune response in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A022.