Changes in blood metabolomes as potential markers for severity and prognosis in doxorubicin-induced cardiotoxicity: a study in HER2-positive and HER2-negative breast cancer patients

Abstract

Background: We aimed to compare the changes in blood metabolomes and cardiac parameters following doxorubicin treatment in HER2-positive and HER2-negative breast cancer patients. Additionally, the potential roles of changes in blood metabolomes as severity and prognostic markers of doxorubicin-induced cardiotoxicity were determined.

Methods: HER2-positive (n = 37) and HER2-negative (n = 37) breast cancer patients were enrolled. Cardiac function assessment and blood collection were performed at baseline and 2 weeks after completion of doxorubicin treatment in all patients, as well as at three months after completion of doxorubicin treatment in HER2-negative breast cancer patients. Blood obtained at all three-time points was processed for measuring cardiac injury biomarkers. Blood obtained at baseline and 2 weeks after completion of doxorubicin treatment were also processed for measuring systemic oxidative stress and 85 metabolome levels.

Results: Cardiac injury and systolic dysfunction 2 weeks after completion of doxorubicin treatment were comparable between these two groups of patients. However, only HER2-negative breast cancer patients exhibited increased systemic oxidative stress and cardiac autonomic dysfunction at this time point. Moreover, 33 and 29 blood metabolomes were altered at 2 weeks after completion of doxorubicin treatment in HER2-positive and HER2-negative breast cancer patients, respectively. The changes in most of these metabolomes were correlated with the changes in cardiac parameters, both at 2 weeks and 3 months after completion of doxorubicin treatment.

Conclusions: The changes in blood metabolomes following doxorubicin treatment were dependent on HER2 status, and these changes might serve as severity and prognostic markers of doxorubicin-induced cardiotoxicity.

Trial registration: The study was conducted under ethical approval from the Institutional Review Board of the Faculty of Medicine, Chiang Mai University (Registration number: MED-2563-07001; Date: April 28, 2020). The study also complied with the Declaration of Helsinki.

Keywords: Breast cancer; Cardiotoxicity; Doxorubicin; HER2; Heart failure; Metabolomes.

Fig. 1

LVEF (A), E/e’ Ratio (B), LF/HF ratio (C), Plasma Troponin I (D), Plasma NT-proBNP (E), and Cellular Oxidative Stress in Peripheral Blood Mononuclear Cells (F) at Baseline in HER2-Positive Versus HER2-Negative Breast Cancer Patients. n = 37 per group. Data are reported as mean ± standard error of the mean (SEM). LVEF = Left ventricular ejection fraction; E/e’ ratio = Early mitral inflow velocity-to-mitral annular early diastolic velocity ratio; LF/HF ratio = Low frequency-to-high frequency ratio; NT-proBNP = N-terminal pro B-type natriuretic peptide; DCF = Dichlorofluorescein

Fig. 2

LVEF (A), E/e’ Ratio (B), LF/HF ratio (C), Plasma Troponin I (D), Plasma NT-proBNP (E), and Cellular Oxidative Stress in Peripheral Blood Mononuclear Cells (F) in HER2-Positive Breast Cancer Patients At Baseline Versus 2 Weeks After Completion of Doxorubicin Treatment. n = 37. Data are reported as mean ± standard error of the mean (SEM). *p < 0.05 when compared to baseline. LVEF = Left ventricular ejection fraction; E/e’ ratio = Early mitral inflow velocity-to-mitral annular early diastolic velocity ratio; LF/HF ratio = Low frequency-to-high frequency ratio; NT-proBNP = N-terminal pro B-type natriuretic peptide; DCF = Dichlorofluorescein

Fig. 3

LVEF (A), E/e’ Ratio (B), LF/HF ratio (C), Plasma Troponin I (D), Plasma NT-proBNP (E), and Cellular Oxidative Stress in Peripheral Blood Mononuclear Cells (F) in HER2-Negative Breast Cancer Patients at Baseline Versus 2 Weeks After Completion of Doxorubicin Treatment. n = 37. Data are reported as mean ± standard error of the mean (SEM). * p < 0.05 when compared to baseline. LVEF = Left ventricular ejection fraction; E/e’ ratio = Early mitral inflow velocity-to-mitral annular early diastolic velocity ratio; LF/HF ratio = Low frequency-to-high frequency ratio; NT-proBNP = N-terminal pro B-type natriuretic peptide; DCF = Dichlorofluorescein

Fig. 4

Correlations Between Absolute Changes in Altered Plasma Metabolome Levels 2 Weeks After Completion Of Doxorubicin Treatment Versus Absolute Changes in LVEF And Cardiac Injury Biomarkers 2 Weeks After Completion of Doxorubicin Treatment in HER2-Positive Breast Cancer Patients: (A) Metabolomes Involved in Amino Acid Metabolism, (B) Metabolomes Involved in Fatty Acid Metabolism, and (C) Phospholipids. n = 37. Data are reported as Pearson correlation coefficient value. * p < 0.05. LVEF = left ventricular ejection fraction; NT-proBNP = N-terminal pro B-type natriuretic peptide; LysoPC = Lysophosphatidylcholine; LysoPE = Lysophosphatidylethanolamine; LysoPI = Lysophosphatidylinositol; PA = Phosphatidic acid; PC = Phosphatidylcholine; PE = Phosphatidylethanolamine; PS = Phosphatidylserine

Fig. 5

Correlations Between Absolute Changes in Altered Plasma Metabolome Levels 2 Weeks After Completion of Doxorubicin Treatment Versus Absolute Changes in LVEF, LF/HF Ratio, and Cardiac Injury Biomarkers 2 Weeks After Completion of Doxorubicin Treatment in HER2-Negative Breast Cancer Patients: (A) Metabolomes Involved in Amino Acid Metabolism, (B) Metabolomes Involved in Fatty Acid Metabolism, and (C) Phospholipids. n = 37. Data are reported as Pearson correlation coefficient value. * p < 0.05. LVEF = Left ventricular ejection fraction; LF/HF ratio = Low frequency-to-high frequency ratio; NT-proBNP = N-terminal pro-B-type natriuretic peptide. LysoPC = Lysophosphatidylcholine; LysoPE = Lysophosphatidylethanolamine; PC = Phosphatidylcholine; PG = Phosphatidylglycerol; PS = Phosphatidylserine

Fig. 6

LVEF (A), E/e’ Ratio (B), LF/HF ratio (C), Plasma Troponin I (D), and Plasma NT-ProBNP (E) in HER2-Negative Breast Cancer Patients 2 Weeks After Completion of Doxorubicin Treatment Versus Three Months After Completion of Doxorubicin Treatment. n = 16. Data are reported as mean ± standard error of the mean (SEM). *p < 0.05 when compared with at 2 weeks after completion of doxorubicin treatment. LVEF = Left ventricular ejection fraction; E/e’ ratio = Early mitral inflow velocity-to-mitral annular early diastolic velocity ratio; LF/HF ratio = Low frequency-to-high frequency ratio; NT-proBNP = N-terminal pro B-type natriuretic peptide

Fig. 7

Correlations Between Absolute Changes in Altered Plasma Metabolome Levels 2 Weeks After Completion of Doxorubicin Treatment Versus Absolute Changes in LVEF, LF/HF Ratio, and Plasma Troponin I Three Months After Completion of Doxorubicin Treatment in HER2-Negative Breast Cancer Patients: (A) Metabolomes Involved in Amino Acid Metabolism, (B) Metabolomes Involved in Fatty Acid Metabolism, and (C) Phospholipids. n = 16. Data are reported as Pearson correlation coefficient value. * p < 0.05. LVEF = Left ventricular ejection fraction; LF/HF ratio = Low frequency-to-high frequency ratio. LysoPC = Lysophosphatidylcholine; LysoPE = Lysophosphatidylethanolamine; PC = Phosphatidylcholine; PG = Phosphatidylglycerol; PS = Phosphatidylserine