Tumor-informed versus tumor-agnostic ctDNA assays for molecular residual disease detection in colorectal cancer: A systematic review and meta-analysis.

3595 Background: Circulating tumor DNA (ctDNA) is increasingly used for detection of molecular residual disease (MRD) following curative-intent treatment for colorectal cancer (CRC). Two principal assay strategies exist: tumor-informed (TI) assays requiring prior tumor sequencing, and tumor-agnostic (TA) assays using fixed plasma-based panels. The relative prognostic and diagnostic performance of these approaches remain uncertain. Despite growing clinical adoption, no systematic comparison of their relative performance exists to guide assay selection. Methods: We performed a systematic review and meta-analysis in accordance with PRISMA 2020 guidelines. PubMed, Embase, Cochrane Library, and Web of Science were searched from inception to January 2025 for original studies evaluating ctDNA-based MRD detection after curative-intent treatment for CRC. Primary outcomes were hazard ratios (HRs) for recurrence-free survival (RFS) and diagnostic accuracy metrics (sensitivity and specificity). Random-effects models (DerSimonian-Laird estimator) were used to pool effect estimates; heterogeneity was assessed using I² statistics. Subgroup analyses were conducted by assay type (tumor-informed vs tumor-agnostic) and sampling strategy (landmark vs serial). Quality assessment was performed using QUADAS-2 for diagnostic studies and Newcastle-Ottawa Scale for prognostic studies. Results: Twenty-three studies comprising 9,847 patients met inclusion criteria. Eighteen studies evaluated tumor-informed assays (n=7,892) and eight evaluated tumor-agnostic assays (n=2,156), with three directly comparing both approaches. For tumor-informed assays, the pooled HR for recurrence in ctDNA-positive versus ctDNA-negative patients was 7.58 (95% CI, 6.21–9.25; I²=24%). For tumor-agnostic assays, the pooled HR was 4.12 (95% CI, 3.18–5.34; I²=18%). Subgroup analysis demonstrated significantly stronger prognostic discrimination for tumor-informed assays (ratio of HRs 1.84; 95% CI, 1.38–2.45; p