Haematological pre-staging of colorectal cancer: Longitudinal trends identify high-risk metastatic phenotypes 24 months prior to diagnosis

BACKGROUND: The latent systemic phase of colorectal cancer (CRC) offers a critical but often missed window for early intervention. This study evaluates whether longitudinal Complete Blood Count (CBC) trajectories can stratify metastatic risk before diagnosis. METHODS: A retrospective cohort of CRC patients from the Health Department of La Ribera (Spain) was analysed using serial CBC data collected up to 24 months prior to diagnosis. Linear Mixed-Effects Models characterized patient-specific longitudinal trajectories, capturing intra-individual variability over time. In parallel, supervised machine learning models (Random Forest) were applied to evaluate the discriminative capacity of these haematological variables to distinguish synchronous metastatic phenotypes from non-metastatic cases. RESULTS: Consistent haematological deviations were detected at least 24 months before diagnosis. A distinct "metastatic gradient" emerged, where patients presenting with synchronous metastases exhibited significantly accelerated trajectories, specifically steeper declines in haemoglobin and sharper rises in inflammatory indices (neutrophil and platelet-to-lymphocyte ratios), compared to non-metastatic cases. These alterations were statistically significant even within clinically normal reference ranges. The predictive models achieved effective risk stratification, demonstrating a robust negative predictive value capable of excluding low-risk phenotypes. CONCLUSIONS: Longitudinal CBC monitoring reveals early systemic "red flags" that anticipate aggressive metastatic behaviour, supporting its use as a haematological pre-staging approach. Assessing the velocity of haematological change, could transform routine historical into a cost-effective resource for risk-adapted imaging and personalized surveillance. However, these findings represent a retrospective proof-of-concept; the approach remains investigational and should not be clinically implemented until validated prospectively in independent external cohorts.