Methylation-based biological age and cardiotoxicity risk in breast cancer patients treated with trastuzumab.

Background: Trastuzumab is an effective treatment for HER2-positive cancers that has known cardiotoxic properties. Discovering biomarkers that assess cardiotoxicity risk before trastuzumab therapy is essential for protecting the cardiovascular health of cancer patients.

Objective: To examine the associations between pre-treatment epigenetic age acceleration, circulating leukocyte composition, and candidate single nucleotide polymorphisms (SNPs) with cardiotoxicity risk in breast cancer patients receiving trastuzumab.

Methods: Among a retrospective cohort of HER2-positive breast cancer patients treated with trastuzumab at Moffitt Cancer Center, we profiled blood DNA methylation and genetic profiles. Epigenetic clocks and circulating leukocyte subsets were derived from MethylationEPIC BeadChip data, and candidate SNPs were measured using the Global Screening Array. Cardiotoxicity events (i.e., reductions in left ventricular ejection fraction, symptomatic heart failure), were identified in medical records. Logistic regression models, adjusted for traditional risk factors, estimated odds ratios (ORs) for biomarker associations with cardiotoxicity risk.

Results: Among 157 patients selected for this study, 39 (25%) experienced cardiotoxicities within one year of treatment initiation. rs776746 was inversely associated with cardiotoxicity risk (OR: 0.38, 95% CI: 0.14, 1.00, P = 0.05). After adjusting for traditional risk factors and leukocyte composition, the Hannum AgeAccel, Horvath AgeAccel, and Horvath Skin and Blood AgeAccel metrics were significantly positively associated with cardiotoxicity risk (ORs ranging between 1.62 and 1.89). Adding Horvath Skin and Blood AgeAccel to traditional cardiotoxicity risk factors significantly improved cardiotoxicity risk prediction (AUC: 0.75 vs. 0.79; P-diff = 0.04).

Conclusions: Pre-treatment epigenetic age acceleration appears to be a novel biomarker for cardiotoxicity risk that improves cardiotoxicity risk prediction.