Circulating miR-1 as a potential biomarker of doxorubicin-induced cardiotoxicity in breast cancer patients

Abstract

Cardiotoxicity is associated with the chronic use of doxorubicin leading to cardiomyopathy and heart failure. Identification of cardiotoxicity-specific miRNA biomarkers could provide clinicians with a valuable prognostic tool. The aim of the study was to evaluate circulating levels of miRNAs in breast cancer patients receiving doxorubicin treatment and to correlate with cardiac function. This is an ancillary study from “Carvedilol Effect on Chemotherapy-induced Cardiotoxicity” (CECCY trial), which included 56 female patients (49.9±3.3 years of age) from the placebo arm. Enrolled patients were treated with doxorubicin followed by taxanes. cTnI, LVEF, and miRNAs were measured periodically. Circulating levels of miR-1, -133b, -146a, and -423-5p increased during the treatment whereas miR-208a and -208b were undetectable. cTnI increased from 6.6±0.3 to 46.7±5.5 pg/mL (p<0.001), while overall LVEF tended to decrease from 65.3±0.5 to 63.8±0.9 (p=0.053) over 12 months. Ten patients (17.9%) developed cardiotoxicity showing a decrease in LVEF from 67.2±1.0 to 58.8±2.7 (p=0.005). miR-1 was associated with changes in LVEF (r=-0.531, p<0.001). In a ROC curve analysis miR-1 showed an AUC greater than cTnI to discriminate between patients who did and did not develop cardiotoxicity (AUC = 0.851 and 0.544, p= 0.0016). Our data suggest that circulating miR-1 might be a potential new biomarker of doxorubicin-induced cardiotoxicity in breast cancer patients.

Clinical Relevance of Circulating, Cell-Free and Exosomal microRNAs in Plasma and Serum of Breast Cancer Patients

“…For example, plasma miR-1 is associated with the doxorubicin-induced cardiotoxicity in BC patients. Thus, this miRNA, which influences cardiac functions, may provide clinicians with a valuable prognostic tool for avoiding cardiomyopathy and heart failure in BC patients [33]. Moreover, a genome-wide expression assay identified a signature of 4 serum miRNAs (miR-18b, miR-103, miR-107 and miR-652) that predicted tumor relapse and reduced overall survival in triple-negative BC patients [34].…”

MicroRNAs in Cancer Treatment-Induced Cardiotoxicity

“…Circulating miR-1 was found up-regulated in DOX-treated rats and in breast cancer patients treated with DOX [137,138].…”

“…miR-1 levels were associated with changes in LVEF, and its levels were useful to discriminate patients affected by cardiotoxicity from unaffected subjects better than cTnI levels [138].…”

Potential Clinical Implications of miR-1 and miR-21 in Heart Disease and Cardioprotection

“…↑miR-1 in blood plasma of rats after doxorubicin treatment [105] ↑miR-1 in blood plasma of cancer patients after doxorubicin treatment [106] ↓miR-1 in blood plasma of rats after doxorubicin-induced injury [107] ↑miR-1 in heart tissue of rats after doxorubicin treatment [108] ↓miR-1 in blood plasma of cancer child and young adult patients after anthracycline treatment [109] ↓miR-1 in blood plasma of breast cancer patients after doxorubicin treatment [110] miR-21 ↑miR-21 in mice hearts after doxorubicin treatment [108,111,112] Abbreviations…”

“…Several studies also focused on the investigation of the role of miRs in doxorubicin-induced cardiotoxicity in cancer patients. Rigaud et al [106] evaluated circulating levels of miRs in breast cancer patients receiving doxorubicin treatment. They found that circulating levels of miR-1, as well as cTnI, increased during the treatment while overall left ventricular ejection fraction (LVEF) tended to decrease over 12 months.…”