ctDNA MRD combined with CODEX2 to identify high-risk colorectal cancer with potential sensitivity to immunotherapy.

e15664 Background: Circulating tumour DNA (ctDNA)-based minimal residual disease (MRD) detection identifies colorectal cancer (CRC) patients at high risk of relapse after curative surgery, but lacks associated therapeutic stratification. We developed CODEX2, a validated histological H-score quantifying CDX2 silencing, and hypothesised that integrating MRD status with tumour-intrinsic biology could refine post-surgical risk stratification and identify biologically actionable subsets. Methods: Forty-six resected CRC patients with whole-exome sequencing-based ctDNA MRD assessment 6 weeks post-surgery were analysed (21 MRD-, 25 MRD+). CDX2 expression was evaluated in matched FFPE primary tumours using the CODEX2 H-score and classified as high or low. Multivariable Cox models included MRD, CODEX2, MSI status and clinicopathological variables, with Akaike information criterion (AIC) for model selection. Transcriptomic analyses assessed immune pathways and Consensus Molecular Subtypes (CMS). Results: Eight patients were MRD+/CODEX2-low, six of whom were microsatellite stable (MSS). These MSS tumours displayed a CMS1-like, immune-inflamed transcriptomic profile enriched for interferon-γ signalling despite microsatellite stability. Combined stratification identified MRD+/CODEX2-low patients as the highest-risk group for relapse (HR 47.0; p = 0.00004), followed by MRD+/CODEX2-high cases (HR 5.8; p = 0.016), compared with MRD-/CODEX2-high patients. In multivariable analysis, both MRD positivity (HR 2.8; p = 0.01) and CODEX2-low status (HR 2.1; p = 0.04) independently predicted shorter relapse-free survival, while MSI status was not retained. The combined MRD+CODEX2 model outperformed MRD alone (ΔAIC -12.4). Conclusions: Integrating ctDNA-based MRD detection with CODEX2 refines post-surgical risk stratification in CRC. MRD-positive patients with CODEX2-low MSS tumours represent a biologically distinct, immune-inflamed, high-risk subgroup with MSI-like features and potential susceptibility to immunotherapeutic strategies.