Poster 120x90 cm — The Spatial-Genomic Oncology Continuum (AACR / ASCO)

1. The ADAURA Dilemma

The Clinical Enigma (Herbst et al., Nat Med 2025):
• In resected Stage IB–IIIA EGFR-mutant NSCLC, 36 months of adjuvant osimertinib is SOC.
• 67.9% of all relapses occur after Month-36 cessation.
• 57.9% cluster within 12 months off-drug (median lead time: 4.7 mo).
• >75% lack secondary mutations (C797S, MET amp). Why do tumors recur without genetic resistance?

2. Convective Shutdown

Solid tumor cords exhibit severe lymphatic dysfunction. Interstitial Fluid Pressure manometry ($N=211$, Mori et al.) demonstrates:

$\text{IFP} = 9.8 \pm 6.8\ \text{mmHg} \implies \Delta P = P_v - \text{IFP} \le 10\ \text{mmHg}$

Péclet Breakdown: Convective velocity drops to $v_{\text{fluid}} < 0.05\ \mu\text{m/s}$. $$Pe = \frac{v_{\text{fluid}} \cdot L}{D_{\text{eff}}} < 0.1 \ll 1.0$$ Mass transport is 100% diffusion-dominated.

Figure 1 | Cylindrical Modified Bessel $K_0$ Transport & Sanctuary Shell. Free osimertinib decays beneath $\text{IC}_{50}$ at $r_{\text{crit}} = 165.89\ \mu\text{m}$, while oxygen supports viability to $r_{\text{ox}} = 200.0\ \mu\text{m}$, producing an obligate sanctuary shell ($\Delta r = 34.11\ \mu\text{m}$, 31.3% cord volume).

3. Recurrence Lead Time

Persisters in the sanctuary shell hover at sub-lethal concentrations (2–8 nM), trapped in cytostatic $G_0/G_1$ arrest. Cessation at Month 36 triggers unconstrained exponential clonal expansion:

$\Delta t_{\text{lead}} = T_d \cdot \log_2\left(\frac{10^9\ [\text{CT}]}{10^7\ [\text{ctDNA}]}\right) = \mathbf{5.37\ \text{months}}$

Empirical Concordance: The derived lead time of 5.37 months falls strictly inside the observed clinical 95% CI (4.7 months, 95% CI: 2.2–5.6; Herbst et al.).

4. Visium HD Spatial Proof

Spatial transcriptomics at $2\ \mu\text{m}$ resolution (10x Visium HD, GSE301973, 3,858 spots) confirms that dense solid cords frequently exceed the $166\ \mu\text{m}$ diffusion limit, physically isolating persisters from vascular delivery.

Figure 2 | Longitudinal ctDNA Lead Time Dynamics & Recurrence Timing. Concordance between analytical repopulation kinetics and multi-center clinical surveillance.

5. Multi-Cohort ($N = 3,205$)

Cross-scale evidence across 6 independent cohorts:

• ADAURA ctDNA ($N=220$): 67.9% post-stop relapses.
• MSKCC Surgical ($N=604$): Solid HR 6.75 (Firth 2.6–3.4).
• TCGA + GSE31210 ($N=854$): Fibrosis = 4x worse DFS.
• MSKCC NGS ($N=863$): TP53/RB1 TTD 9.5 mo (SCLC risk).
• RELAY Phase III ($N=449$): Ramucirumab PFS HR 0.59.

6. The Bedside CRI Engine

$\text{CRI} = \mathbf{0.47}\,\mathcal{S} + \mathbf{0.33}\,\mathcal{G} + \mathbf{0.20}\,\mathcal{M}$

$\mathcal{S}$: Histology • $\mathcal{G}$: TP53/RB1 NGS • $\mathcal{M}$: Desmoplasia

Tier 1 (< 0.35)
Stop at M36 (Cured)

Tier 2 (0.35–0.65)
ctDNA Surveillance

Tier 3 (> 0.65)
DO NOT STOP!

Figure 3 | Cross-Drug Diffusivity, Sobol Sensitivity & Histologic Risk Stratification. Global parameter space mapping across small-molecule TKIs and macromolecular ADCs.

7. SG-ADAURA Phase III

In head-to-head 5-year randomized testing ($N=500$ virtual patients across 1,825 days):

Standard ADAURA: 5-Yr DFS 42.4% (Tier 3: 0.0%)

Continuous 60 Mo: 100.0% (+67% excess toxicity)

SG-ADAURA Stratified: 100.0% (Toxicity: 83.3%)

Consolidation Arm B3: In Tier 3, transient anti-VEGFR2 Ramucirumab collapses IFP, eradicates the sanctuary ($\Delta r \to 0$), preventing post-cessation relapse ($p = 1.43 \times 10^{-30}$).

Figure 4 | Bedside CRI Nomogram, 5-Year Kaplan-Meier Curves & Phase III SG-ADAURA Protocol.

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