Spatial Conformation of Pancreatic Cancer Is Associated with Disease Recurrence after Curative-Intent Total Neoadjuvant Therapy

Pancreatic ductal adenocarcinoma (PDAC) frequently recurs after total neoadjuvant therapy (TNT) and curative-intent resection. Traditional histopathologic response assessments demonstrate that major pathologic response (<5-10% viable residual cancer) is associated with favorable outcomes. However, most TNT cases achieve only a minor response. We investigated whether the spatial organization of residual PDAC encodes clinically meaningful biology beyond residual tumor burden. In a retrospective cohort of 203 resected PDAC patients, all with minor pathologic response, H&E whole-slide images were segmented into cancer and stroma to subsequently quantify spatial composition (e.g., patch size/density, edge density) and configuration (e.g., patch complexity/compactness, spatial intermixing) to model treatment-resistant tumor architecture. Non-response was associated with a more fragmented interface-rich ecology, higher edge density and diversity, and reduced homotypic aggregation, independent of conventional clinicopathologic features. This demonstrates a link between emergent tissue architecture of treated PDAC and therapeutic resistance. Further, two multivariable, spatial risk models were independently associated with disease-free survival (DFS): (1) cancer mean shape index and stromal shape-index variability (high-risk median DFS 7.23 vs 11.57 months; adjusted HR 1.75, p=0.007) and (2) mean stromal area with edge density (high- vs low-risk adjusted HR 1.94, p=0.006), outperforming traditional treatment response assessments. Quantifying residual cancer-stroma topology thus yields independent, prognostic signals in post-TNT PDAC and motivates prospective, spatially informed adjuvant strategies and mechanistic studies of edge habitats and mixing as therapeutic vulnerabilities.