Circulating MicroRNAs as Potential Predictors of Anthracycline-Induced Troponin Elevation in Breast Cancer Patients: Diverging Effects of Doxorubicin and Epirubicin

Figure 1. Flow chart of the study. CT: chemotherapy; LV, left ventricle; HF, heart failure; EKG: electrocardiogram.

Figure 2. Experimental design. Eighty-eight breast cancer patients were enrolled and treated with doxorubicin (DOX) or epirubicin (EPI). Thick black vertical bars indicate experimental time-points when echocardiography was performed and blood samples collected.

Figure 3. Differential expression of DOX plasma miRNAs. (A) Three miRNAs, miR-122-5p, -499a-5p and -885-5p, showed modulated expression in DOX cTn+ vs. DOX cTn− patients at baseline. Data are depicted as box-and-whisker plots and expressed as max, median and min. (n = 14 DOX cTn−; n = 18 DOX cTn+; n = 44 EPI cTn−; n = 12 EPI cTn+). (B) Time course of miR-122-5p, -499a-5p and -885-5p, showing modulated expression in cTn+ vs. cTn− DOX patients at baseline but not at T1 and T2. Vertical bars represent the mean of −ΔΔCT ± SEM. Blue, cTn− DOX; Red, cTn+ DOX. (n = 14 DOX cTn−; n = 18 DOX cTn+). DOX, doxorubicin; miRNAs, microRNAs; EPI, epirubicin; cTn−, negative troponin levels; cTn+, positive troponin levels; −ΔΔCT, –delta-delta Ct; SEM, standard error of the mean.

Figure 4. Baseline plasma miRNA-based identification of DOX-cTn+ and DOX-cTn− patients. 3D scatterplots (left) and ROC analyses (right) were used to investigate whether the DOX-related plasma miRNA expression at baseline could be used to correctly separate cTn+ from cTn− patients. The AUC assesses the performance of the logistic model built, taking into account miR-499a-5p, miR-885-5p and miR-122-5p. Blue: cTn−. Red: cTn+. AUC: area under the curve.

Figure 5. Circulating miRNAs modulated upon anthracycline treatment. Time course for miR-34a-5p, -122-5p and -885-5p showing modulated expression in DOX (red) and EPI (green) patients. Vertical bars represent mean –ΔΔCT ± SEM. Green, DOX; Orange, EPI. * p < 0.05; ** p < 0.01; *** p < 0.001.

Figure 6. Circulating miRNAs as Anthracyclines Chemotherapy decision-makers. Flow chart of the possible use of plasma miRNA assessment at baseline to help clinicians in selecting drugs with the lowest cardiotoxicity risk and/or deciding whether to start cardioprotective preventive therapies.