Abstract 3612: Three aging biomarkers differentially mediate cardiotoxicity after irradiation to the heart or exposure of anthracyclines in survivors of childhood cancer

Background: Childhood cancer survivors experience accelerated aging, largely due to treatment toxicity. We investigated how aging biomarkers, which quantify accelerated aging and capture multifaceted mechanisms, differentially mediate treatment-related cardiotoxicity. Methods: Peripheral blood samples from survivors in the St Jude Lifetime Cohort were profiled with EPIC BeadChip to generate DNA methylation (DNAm) data, from which three established aging biomarkers were subsequently derived: epigenetic age (EA, reflecting epigenetic alterations), leukocyte telomere length (LTL, reflecting cellular senescence), and C-reactive protein (CRP, reflecting chronic inflammation). EA (Levine's PhenoAge) and LTL were calculated with the methylCIPHER R package, while CRP was computed as a weighted (regression coefficients from a prior study) sum of serum CRP-associated CpGs. Cardiomyopathy (CMP) with a CTCAE (Common Terminology Criteria for Adverse Events) grade ≥2 and myocardial infarction (MI) with a CTCAE-grade ≥3 were analyzed. Multivariable logistic regression assessed associations of CMP or MI with each biomarker (standardized sample age adjusted residuals), adjusting for sex, attained age, age at primary cancer diagnosis, and cardiotoxic exposures including mean heart irradiation (heart-RT) dose and cumulative anthracycline dose. Linear regression evaluated associations between each biomarker and cardiotoxic exposures, adjusting for sex, age at blood draw and other treatments. Results: Among 3,059 survivors (all of European ancestry; 46.85% female; mean [SD] = 29.35 [0.22] years of age at blood draw), the incidence of CMP and MI was 8.0% and 1.6%, respectively. Biomarker correlations ranged from moderate to high (r2 = 0.32 to 0.67). CRP was associated with increased risk of CMP (Odds ratio [95% CI] = 1.28 [1.11-1.47], P = 8.30 × 10-4) and MI (1.43 [1.09-1.88], P = 1.08 × 10-2). EA was associated with MI risk only (1.76 [1.30-2.38], P = 2.45 × 10-4), and LTL was associated with risk of CMP (1.23 [1.05-1.42], P = 7.86 × 10-3) and MI (1.71 [1.26-2.31], P = 1.19 × 10-3). Furthermore, CRP specifically mediated the cardiotoxicity of heart-RT (13.87%, P < 2.00x10-16) and anthracyclines (3.07%, P = 1.20 × 10-2) on CMP, whereas EA specifically mediated the cardiotoxicity of heart-RT on MI (24.36%, P = 2.00 × 10-3). In contrast, LTL mediated the cardiotoxicity of heart-RT on both CMP (15.06%, P = 8.0 × 10-3) and MI (20.77%, P = 4.00 × 10-3), albeit less significantly. Conclusion: These findings suggest specific aging biomarkers are more informative for certain outcomes, potentially driven by various underlying aging mechanisms. There is no one-fits-all biomarker to identify survivors with greater accelerated aging and hence higher risk of particular adverse outcomes, emphasizing the need for integrative approaches in future clinical research. Citation Format: Xiaoxi Meng, Tiffany Eulalio, Noel-Marie Plonski, John Easton, Heather Mulder, Emily Walker, Geoffrey Neale, Kyla Shelton, Deo Kumar Srivastava, Stephanie B. Dixon, Jinghui Zhang, Melissa M. Hudson, Kirsten K. Ness, Gregory T. Armstrong, Zhaoming Wang. Three aging biomarkers differentially mediate cardiotoxicity after irradiation to the heart or exposure of anthracyclines in survivors of childhood cancer [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 3612.