Effects of metformin and donepezil on the prevention of doxorubicin-induced cardiotoxicity in breast cancer: a randomized controlled trial

Abstract Doxorubicin (DOX) causes deleterious cardiotoxicity. We aimed to investigate the protective roles of metformin and donepezil against DOX-induced cardiotoxicity. In this randomized-controlled trial, 143 female breast cancer patients were enrolled. Metformin (n = 43), donepezil (n = 52), or placebo (n = 48) were prescribed during DOX treatment. The primary endpoint was a proportion of patients with high sensitivity troponin-I (hsTnI) more than the 99th percentile value (> 15.6 ng/L) after DOX treatment. The secondary outcomes were the changes in the hsTnI, N-terminal pro-B-type natriuretic peptide (NT-proBNP), left ventricular ejection fraction (LVEF), global longitudinal strain (GLS) and peripheral blood mononuclear cells analysis for mitochondrial respiration. Baseline characteristics were similar between the groups. The primary endpoint occurred in 58.54% of metformin group, 76.92% in donepezil group, and 69.77% in placebo group (p = 0.215). The level of hsTnI increased after receiving DOX with subsequent decline in LVEF and GLS. Metformin and donepezil did not attenuate hsTnI elevation, LVEF or GLS reduction. There was no significant change in NT-proBNP level. Mitochondrial respiratory dysfunction was observed in the placebo and donepezil groups. However, metformin preserved mitochondrial respiration during DOX therapy. In conclusion, co-treatment with metformin or donepezil did not prevent myocardial injury. Metformin had a favorable mitochondrial outcome and warranted future studies

Real-life clinical pattern, management, and survival in Thai patients with early-stage or metastatic triple-negative breast cancer.

OBJECTIVES:To characterize the clinical pattern and evaluate real-life practices in the management of patients with triple-negative breast cancer (TNBC) in Thailand. METHODS:In this multicenter, prospective, observational cohort, females (aged ≥18 years) with histologically and immunohistochemically confirmed TNBC were enrolled. Patient data was collected at four study visits-an inclusion visit (for enrollment), and three subsequent follow-up visits at 12±1, 24±1, and 36±1 months after completion of first day of any planned chemotherapy. RESULTS:Of the 293 enrolled patients, 262 (89.4%) had early-stage TNBC (Stage I: 46 patients, Stage II: 151 patients, and Stage III: 65 patients) and 31 (10.6%) had metastatic TNBC (mTNBC). Chemotherapy was prescribed to 95.4% of the early-stage patients and to 100.0% of the mTNBC patients; most commonly as anthracycline-based in combination with cyclophosphamide and other agents. Patients' performance status and consensus guidelines were the major factors affecting choice of treatment. In early-stage patients, median disease-free survival (DFS) and overall survival (OS) had not been reached for Stage I and II patients, and were calculated to be 37.0 months and 40.0 months, respectively, in Stage III patients. In mTNBC patients, progression-free survival (PFS) and OS were found to be 10.0 months and 14.0 months, respectively. In Stage III patients, anthracycline-based regimens were found to be associated with increase in DFS (p = 0.0181) and OS (p = 0.0027) compared to non-anthracycline-based regimens. In mTNBC patients, non-taxane-based regimens were associated with an increase in PFS (p = 0.0025). The 3-year survival rates in early-stage and mTNBC patients were 85.0% and 21.0%, respectively. CONCLUSION:Clinical management of TNBC in Thailand follows the general guidelines for treatment of TNBC. However, prognosis and survival outcomes are suboptimal, especially in progressive disease. This study is the first assessment in the existing practices in which the results could pave to way to improve the treatment outcome of TNBC in Thailand

Additional file 1 of 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

Additional file 1: Fig. S1. Study protocol. Fig. S2. Absolute changes in LVEF (A), LF/HF ratio (B), plasma troponin I (C), plasma NT-proBNP (D), and cellular oxidative stress in peripheral blood mononuclear cells (E) at 2 weeks after completion of doxorubicin treatment in HER2-positive versus HER2-negative breast cancer patients. Table S1. Lists of eighty-five targeted plasma metabolomes and the chromatographic technique for each metabolome. Table S2. Patients’ characteristics at baseline. Table S3: Baseline plasma metabolome levels in HER2-positive versus HER2-negative breast cancer patients. Table S4. Plasma metabolome levels in HER2-positive breast cancer patients at baseline versus at 2 weeks after completion of doxorubicin treatment. Table S5. Plasma metabolome levels in HER2-negative breast cancer patients at baseline versus at 2 weeks after completion of doxorubicin treatment. Table S6. The top five plasma metabolomes that their alterations were significantly correlated with the changes in each cardiac parameter of HER2-positive and HER2-negative breast cancer patients at 2 weeks after completion of doxorubicin treatment