Dynamic circulating microRNA signatures associated with cancer therapy-related cardiotoxicity in breast cancer patients

Background Cancer therapy-related cardiotoxicity (CTRCD) remains a major complication of breast cancer treatment. Circulating microRNAs (miRs) regulate pathways involved in myocardial injury, fibrosis, and remodeling and may serve as early biomarkers of cardiotoxicity. However, longitudinal data linking miR alterations to CTRCD are limited. Purpose To investigate longitudinal changes in circulating miRs during cancer therapy and identify miRs differentially modulated in patients who develop cardiotoxicity. Methods We prospectively enrolled women with breast cancer undergoing cancer therapy. Circulating miRs were quantified at baseline and after completion of therapy. Cardiotoxicity was defined according to standard echocardiographic criteria. Fold-change analysis assessed overall therapy-induced modulation. Repeated-measures analysis evaluated interaction between time and cardiotoxicity status to identify miRs with differential longitudinal trajectories. Results A total of 47 patients with breast cancer were included, of whom 14 (29.8%) developed CTRCD. Cancer therapy induced alterations in several circulating miRs, including significant downregulation of miR-30c-5p (-4.07-fold, p<0.001), miR-31-5p (-2.98-fold, p<0.001), miR-423-3p (-1.99-fold, p<0.001), miR-124-3p (-1.89-fold, p=0.005), and miR-29b-3p (-1.52-fold, p=0.03), as well as upregulation of miR-23a-3p (2.27-fold, p=0.001) and miR-144-3p (2.46-fold, p=0.01). In repeated-measures interaction analysis, three miRs demonstrated cardiotoxicity-specific longitudinal patterns. miR-124-3p showed a relative increase in patients who developed CTRCD compared with a decrease in those without cardiotoxicity (Figure 1, Panel A). miR-29b-3p exhibited a more pronounced downregulation in the cardiotoxicity group (Figure 1, Panel B). In contrast, miR-423-3p displayed a considerable increase in patients with CTRCD compared with non-cardiotoxic patients (Figure 1, Panel C). Conclusions Cancer therapy induces significant alterations in circulating microRNA profiles. Importantly, miR-124-3p, miR-29b-3p, and miR-423-3p demonstrate cardiotoxicity-specific longitudinal modulation, identifying a potential early molecular signature of CTRCD. These findings support further evaluation of circulating miRs as dynamic biomarkers for early detection and risk stratification of cancer therapy-related cardiac dysfunction.