DNA methylation biomarkers of cardiotoxicity risk in breast cancer patients treated with anthracyclines.

12021 Background: Anthracyclines are effective chemotherapeutic agents for treating breast cancer but are associated with significant risks of chemotherapy-related cardiac dysfunction (CTRCD). Current predictors of CTRCD, including patient demographics and clinical characteristics, are insufficient for accurately assessing cardiotoxicity risk before treatment initiation. Here, we examine CTRCD risk associations with pre-treatment DNA methylation (DNAm)-derived biomarkers of biological age, called “epigenetic clocks,” and circulating leukocyte composition. Methods: A retrospective cohort of 137 newly diagnosed breast cancer patients who received anthracycline-based therapy was sampled from the Total Cancer Care cohort at Moffitt Cancer Center. DNAm profiles were assayed using MethylationEPIC v2 BeadChips on pretreatment whole blood samples and used to derive six biological age metrics and percentages of twelve circulating leukocyte subsets. CTRCD events occurring within one year of treatment initiation were identified through medical records and defined as either a reduction in left ventricular ejection fraction (≥10%) or symptomatic heart failure. Logistic regression models, adjusted for chronological age and traditional cardiotoxicity risk factors (e.g., hypertension, diabetes, baseline ejection fraction, and cumulative anthracycline dose), estimated odds ratios (ORs) for associations between DNAm biomarkers and CTRCD. Results: Among 137 newly diagnosed breast cancer patients (mean age: 54 years; 94% white), 33 (24%) experienced CTRCD. In age-adjusted models, the percentage of circulating naïve CD4+ T cells was inversely associated with CTRCD risk, and Horvath18 AgeAccel was positively associated with CTRCD risk, but these associations did not reach statistical significance after additional adjustment for other cardiotoxicity risk factors. In fully adjusted models, a higher percentage of circulating eosinophils was positively associated with CTRCD risk (OR: 1.49; 95% CI: 1.02, 2.24; P = 0.04). Conclusions: A higher percentage of circulating eosinophils appears to be a novel risk factor for CTRCD in breast cancer patients. While eosinophils may contribute to CTRCD susceptibility through mechanisms such as creating a pro-inflammatory environment in cardiac tissue, further studies are needed to clarify the role of eosinophils and confirm these findings. Typically, monocyte/macrophage-mediated pathways, including IL-6 and other cytokines, are thought to play a central role in anthracycline-related cardiac injury, but eosinophil-mediated effects may represent an alternative or complementary pathway. Integrating DNAm biomarker and leukocyte composition assessments into clinical workflows could improve CTRCD risk stratification in newly diagnosed breast cancer patients.