Pathway-driven therapeutic stratification in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) remains clinically managed largely through anatomical stage and performance status, despite major inter-patient heterogeneity and dynamic pathway adaptation during progression. In this review, we propose a hypothesis-generating, stage-aware framework in which clinical stage and established molecular subtypes are considered complementary rather than competing stratification axes. Stage-resolved transcriptomic modeling identified a directional separation across up-front resectable, borderline/locally advanced, primary metastatic and liver metastatic samples, with PC1 explaining 51.1% of the variance and separating early from metastatic states, whereas PC2 explained 30.2% and captured immune/stromal remodeling. We interpret these observations cautiously as pathway-level signals that require functional and clinical validation, not as an established biological paradigm. The model suggests a transition from MAPK-enriched, proliferative and partially immune-competent tumors toward metastatic ecosystems characterized by PI3K-AKT-mTOR engagement, MYC amplification, mitochondrial metabolism, proteostasis support and immune exclusion. We further distinguish approved standards, negative clinical experiences, early clinical signals and preclinical hypotheses. The central conclusion is that PDAC therapeutic stratification should integrate stage, molecular subtype, treatment line, tissue context and evidence level before pathway-directed interventions are clinically prioritized. Accordingly, this review should be read as a translational prioritization framework rather than as a treatment algorithm: it organizes where pathway-directed hypotheses are most biologically plausible, where they are clinically supported, and where they remain insufficiently validated for routine decision-making.