Changes in Citric Acid Cycle and Nucleoside Metabolism Are Associated with Anthracycline Cardiotoxicity in Patients with Breast Cancer
Anthracyclines and HER2-targeted antibodies are very effective for the treatment of breast cancer, but their use is limited by cardiotoxicity. In this nested case-control study, we assessed the role of intermediary metabolism in 38 women with breast cancer treated with anthracyclines and trastuzumab. Using targeted mass spectrometry to measure 71 metabolites in the plasma, we identified changes in citric acid and aconitic acid that differentiated patients who developed cardiotoxicity from those who did not. In patients with cardiotoxicity, the magnitude of change in citric acid at three months correlated with the change in left ventricular ejection fraction (LVEF) and absolute LVEF at nine months. Patients with cardiotoxicity also demonstrated more pronounced changes in purine and pyrimidine metabolism. Early metabolic changes may therefore provide insight into the mechanisms associated with the development of chemotherapy-associated cardiotoxicity.
KeywordsAnthracyclines Breast cancer Cardiotoxicity Chemotherapy Citric acid Heart failure HER2 Metabolism
Angiotensin converting enzyme
Body mass index
Citric acid cycle
Diastolic blood pressure
Liquid chromatography mass spectrometry
Left ventricular ejection fraction
Systolic blood pressure
AA was supported by a Scholar Award from the Sarnoff Cardiovascular Research Foundation (Great Falls, VA). The project was supported by an investigator-initiated grant from Susan G. Komen (Dallas, TX) and a SPARK grant initiated by Massachusetts General Hospital (Boston, MA), both to MSC.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
Human Subjects/Informed Consent Statement
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation at Massachusetts General Hospital, MD Anderson Cancer Center, and McGill University and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study.
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