Abstract 3600: Methylation-based biological age and risk of colorectal cancer recurrence: Findings from the ColoCare Study

Abstract Introduction: Approximately 20% of colorectal cancer (CRC) patients experience disease recurrence, contributing significantly to CRC-specific mortality in those with non-metastatic disease. Recurrence risk is typically assessed after treatment, potentially delaying interventions for high-risk patients. Assessing recurrence risk earlier could enable personalized therapy strategies that balance remission potential with treatment side-effects. Although tumor characteristics provide some predictive value, they are insufficient for accurately identifying patients at high risk of recurrence. Biological age metrics derived from blood DNA methylation (DNAm) data, called “epigenetic clocks,” integrate information from known recurrence risk factors and are attractive targets for improving risk assessment. However, the relationship between epigenetic clocks 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, with recurrence cases matched 1:3 to recurrence-free controls by age, sex, body mass index, stage, and follow-up time. Pre-treatment whole blood DNAm profiles were assayed and used to calculate seven epigenetic clocks (Hannum, Horvath13, Horvath18, PhenoAge, GrimAge, DunedinPACE, DNAm Frailty). Logistic regression models, adjusted for matching factors and tumor location, estimated odds ratios (ORs) for associations between each epigenetic clock (per 1-standard deviation [SD] increase) 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 CRC recurrence, and 47 (34%) died. Higher GrimAgeAccel, DunedinPACE, and DNAm Frailty were associated with higher recurrence risk (GrimAgeAccel, OR: 1.60, 95% CI: 1.02, 2.50, P= 0.04; DunedinPACE, OR: 1.47, 95% CI: 0.91, 2.36, P= 0.12; DNAm Frailty, OR: 2.13, 95% CI: 1.17, 3.85, P= 0.01). PhenoAgeAccel, GrimAgeAccel, DunedinPACE, and DNAm Frailty were also positively associated with all-cause mortality (PhenoAgeAccel, OR: 1.52, 95% CI: 0.99, 2.35, P= 0.06; GrimAgeAccel, OR: 1.78, 95% CI: 1.15, 2.76, P= 0.01; DunedinPACE, OR: 1.43, 95% CI: 0.91, 2.23, P= 0.12; DNAm Frailty, OR: 1.69, 95% CI: 0.97, 2.95, P= 0.06). Conclusions: Several epigenetic clocks measured in pre-treatment blood samples are associated with CRC recurrence risk and mortality. These findings suggest epigenetic clocks are novel risk factors for CRC recurrence that may be useful for enhancing risk assessment before treatment initiation. Citation Format: Alicia Richards, Esther Jean-Baptiste, Timothy Barrow, Sheetal Hardikar, Biljana Gigic, Jane Figueiredo, Christopher Li, David Shibata, Adetunji T. Toriola, Doratha A. Byrd, Cornelia M. Ulrich, Paul Stewart, Erin M. Siegel, Jacob K. Kresovich. Methylation-based biological age 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 3600.