Defining the metabolomic profile associated with early cardiotoxicity in patients with breast cancer treated with anthracyclines

Background Anthracycline (ANT) therapy has dramatically improved clinical outcomes for patients with breast cancer, but it causes cardiotoxicity (CTX) in a dose-dependent manner. Current cardiac biomarkers (troponin, brain natriuretic peptide) and 2D echocardiography only detect CTX in advanced and often irreversible stages. Metabolomic analysis may allow early diagnosis of CTX, and prompt initiation of cardio protective therapies. Purpose To diagnose early CTX via speckle tracking echocardiography (STE), and to characterize the metabolomic fingerprint of patients affected by ANT-mediated CTX. Methods In 2019, patients with breast cancer and normal baseline ejection fraction (EF) were enrolled and longitudinally monitored through clinical assessment, blood sample collection and echocardiography, before initiation of ANT therapy and at 180, 270 and 360 mg/m2 of ANT. CTX, defined as >15% reduction in Global Longitudinal Strain (GLS), was monitored at each ANT dose increment. Unsupervised Principal Component Analysis, supervised Partial Least Square and Partial Least-Square Discriminant Analyses were used to compare the metabolomic profiles of patients who did and did not develop CTX during the study period. Results In the study sample (n=33), no patient developed clinical heart failure, but 8 patients (25%) developed CTX by GLS criteria. Patients with CTX had a significant decrease in GLS compared to patients without CTX at 270 mg/m2 (GLS 20.5 vs 17.9, p=0.01) and 360 mg/m2 ANT (GLS 21.6 vs 17.7, p Conclusions For the first time in a human population of breast cancer patients, we show that early ANT-induced CTX (diagnosed via asymptomatic GLS reduction) is associated with a unique metabolomic profile, which affects molecular pathways of energy production. Notably, CTX damage upregulates similar metabolites to those previously identified in clinical heart failure and in mouse CTX models. Our results suggest that a metabolomic fingerprint can be leveraged to create prediction models to identify patients at higher risk of developing cardiovascular complications from ANT therapy. This, in turn, will allow to personalize both chemotherapy and cardioprotective treatments. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): University of Cagliari