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. Overall design: To investigate the transcriptomic differences of PDAC patients treated with either neoadjuvant chemotherapy or neoadjuvant chemotherapy plus SAbR. Surgically resected samples were used. Performed bulk-RNAseq from resected tissues to link clinical outcomes to gene expression patterns.

新辅助（Neoadjuvant，NA）立体定向消融放疗（Stereotactic Ablative Radiotherapy，SAbR）或可改善胰腺癌患者的预后。本研究对比了接受新辅助化疗联合/不联合SAbR后接受手术的患者的预后与分子特征。我们比较了仅接受新辅助化疗，或接受新辅助化疗联合SAbR的手术切除患者的临床数据。采用逐步AIC优化的多变量Cox回归模型与对数秩检验分析无复发生存期（Recurrence-free Survival，RFS）与总生存期（Overall Survival，OS）。若样本可用，我们通过转录组分析（GSEA、CIBERSORTx及SCISSOR）将临床结局与基因表达模式相关联。
本研究共纳入133例仅接受新辅助化疗的患者，以及48例接受新辅助化疗联合SAbR的患者，其中分别有29例与14例患者具备RNA测序数据。术前，SAbR组患者的疾病分期更晚且存在动脉受累，但仍获得了与对照组相当的OS与RFS。接受SAbR治疗的患者术后病理缓解更佳，且该特征与更优的OS及RFS显著相关。RNA测序结果显示，存在淋巴结受累的患者其MYC靶基因集富集，且远端无复发生存期更差。仅接受化疗的患者中，存在动脉受累者的局部区域无复发生存期更差，但该关联未在SAbR组中观察到。GSEA分析揭示了髓系细胞与T细胞活化相关的免疫通路改变，提示存在治疗相关的细胞功能变化。SCISSOR分析显示，细胞毒性CD8+T细胞及NK/NKT细胞特征与更佳的局部控制效果相关，而调节性T细胞（Regulatory T cell，Treg）特征则与更差的局部区域无复发生存期（Locoregional Recurrence-free Survival，LRFS）相关。接受新辅助化疗联合SAbR的患者展现出更优的病理结局、更佳的局部控制效果与相当的生存获益，同时伴随独特的免疫应答特征。
在新辅助治疗场景中进一步评估SAbR，联合强化化疗与新型治疗组合，或可带来更显著的临床获益。
整体研究设计：旨在探究接受新辅助化疗，或新辅助化疗联合SAbR的胰腺导管腺癌（Pancreatic Ductal Adenocarcinoma，PDAC）患者的转录组差异。本研究采用手术切除的组织样本，通过对切除组织进行批量RNA测序，将临床结局与基因表达模式相关联。