Resolving Non-Genetic Osimertinib Resistance in Compact EGFR-Mutant Lung Adenocarcinoma via Reaction-Diffusion Transport Physics & Replicator Dynamics
Explaining post-ADAURA treatment cessation recurrence: an unbroken multi-scale pipeline from subcellular Bessel reaction-diffusion transport physics to evolutionary game dynamics and authentic MSKCC 2020 patient histopathology.
Solves cylindrical reaction-diffusion: osimertinib screening length λ = 627.7 µm drops below IC50 at rcrit = 165.9 µm, creating a viable 34.1 µm sanctuary shell within Krogh's hypoxia limit.
Proves asymptotic Lyapunov stability of persister cell coexistence (Nash equilibrium x* = 0.6133, λeig = -1.7934 < 0), matching post-cessation ctDNA (10.7 mo) and CT (16.1 mo) timelines.
Validates architectural recurrence risk in N = 604 resected lung adenocarcinoma patients across IASLC patterns (Lepidic 4.55% to Solid 30.88%, Log-Rank p = 6.33e-6, HR = 6.75).
Democratizes high-cost spatial transcriptomics via Gated Attention-MIL neural networks extracting microvascular sanctuary risk directly from routine diagnostic H&E slides.