Abstract 4937: Circulating leukocyte composition and risk of colorectal cancer recurrence: Findings from the ColoCare Study

Abstract Introduction: Disease recurrence occurs in approximately 20% of colorectal cancer (CRC) patients and is a major driver of CRC-specific mortality in those with non-metastatic CRC. Interactions between the immune system and malignant tumors can select for immune-resistant cell populations, increasing the risk of recurrence. Although immune cell profiles of the tumor microenvironment are associated with CRC recurrence, less is known about how recurrence risk is influenced by the composition of circulating leukocytes. Circulating leukocyte profiles reflect systemic immune activation and may provide unique mechanistic insights and predictive value for recurrence risk that can personalize treatment strategies and improve patient outcomes. However, the relationship between circulating leukocyte profiles and CRC recurrence risk has not been examined in detail. Methods: The ColoCare Study is an international, multi-center, prospective cohort of newly diagnosed CRC patients. For this study, we selected a nested case-control sample of 137 patients enrolled at Moffitt Cancer Center, matching recurrence cases 1:3 to recurrence-free controls by age, sex, body mass index, stage, and follow-up time. Pre-treatment whole blood DNA methylation profiles were assayed and deconvolved to estimate proportions of twelve circulating leukocyte subsets (naïve and memory B cells, CD8+ T cells, and CD4+ T cells, Tregs, natural killers, monocytes, eosinophils, basophils, and neutrophils). Absolute counts were calculated by multiplying cell proportions by total leukocyte count at the time of blood draw. Logistic regression models, adjusted for matching factors and tumor location, estimated odds ratios (ORs) for associations between each leukocyte subset (count and proportion; per 1-standard deviation [SD] change) and risks of CRC recurrence and all-cause mortality. Results: Patients had a mean age of 62.7 years at diagnosis (SD= 13), with a majority being male (57%), overweight (78%), and White (90%). During follow-up, 35 (25%) patients experienced disease recurrence, and 47 (34%) died. Higher proportions and counts of circulating memory B cells were positively associated with CRC recurrence risk (proportions, OR: 1.84, 95% CI: 1.20, 2.84, P= 0.006; counts, OR: 2.33, 95% CI: 1.33, 4.06, P= 0.003). Higher proportions and counts of circulating neutrophils were positively associated with all-cause mortality (proportions, OR: 1.52, 95% CI: 0.95, 2.44, P= 0.08; counts, OR: 1.59, 95% CI: 1.06, 2.40, P= 0.03). Conclusions: The composition of circulating leukocyte in pre-treatment blood samples is associated with CRC recurrence risk and mortality. These findings suggest that specific leukocyte subsets may be novel risk factors for CRC recurrence, providing insights into mechanisms underlying disease progression. Citation Format: Alicia Richards, Esther Jean-Baptiste, Timothy Barrow, Sheetal Hardikar, Biljana Gigic, Jane Figueiredo, Christopher Li, David Shibata, Adetunji T. Toriola, Doratha Byrd, Cornelia M. Ulrich, Paul Stewart, Erin M. Siegel, Jacob K. Kresovich. Circulating leukocyte composition and risk of colorectal cancer recurrence: Findings from the ColoCare Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4937.