Study of circulating levels of microRNAs as biomarkers of doxorubicin-induced cardiotoxicity in breast cancer patients

D (DOX) is the first-line drug in the treatment of breast cancer. Despite its beneficial therapeutic effects, cardiomyopathy and heart failure are observed when DOX is chronically administered for several weeks. Therefore, the development of new approaches to detect the cardiotoxic effects of DOX in earlier stages is still required. In this study, we evaluated circulating levels of miR-1, miR-133b, miR-146a, miR-208a/b and miR-423-5p in 59 female patients with breast cancer along 3, 6, 9 and 12 weeks of chemotherapy with cumulative dose of 60 mg/m2 DOX. As result, miR-208a/b were undetectable in plasma from all samples even at the maximum dose of DOX (12 weeks). Circulating levels of miR-1, miR-133b, miR-146a and miR-423-5p increased along the treatment reaching its peak at 9 weeks with a an increase of 18.9-fold, 11.51-fold, 10.56-fold and 12.09-fold respectively (P<0.01 for all miRNAs). Seven patients (11.86%) developed cardiotoxicity showing a cTnI increase from 8.3 (±1.9) to 123.4 pg/ml (±10.0) whereas from 6.3 (±0.2) to 31 pg/ml (±3.2) in the non-cardiotoxicity patients (P<0.001). A decrease in the LVEF from 65.71 (±1.97) to 56.80 (±6.59) was also observed in cardiotoxicity patients whereas it was preserved in non-cardiotoxicity patients (P<0.001). Despite all miRNAs analyzed had been up-regulated along the treatment, only miR-1 and miR-133b were differentially expressed between the two groups (10.25-fold and 3.73-fold respectively; P<0.05) showing a positive correlation with cTnI (P<0.05). These findings may lead to the development of biomarkers of earlier events in DOX-induced cardiotoxicity that occur before the release of cardiac troponins.