Dataset Information

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.

SUBMITTER: Rigaud VO

PROVIDER: S-EPMC5351685 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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

Rigaud Vagner Oliveira-Carvalho VO Ferreira Ludmila R P LR Ayub-Ferreira Silvia M SM Ávila Mônica S MS Brandão Sara M G SM Cruz Fátima D FD Santos Marília H H MH Cruz Cecilia B B V CB Alves Marco S L MS Issa Victor S VS Guimarães Guilherme V GV Cunha-Neto Edécio E Bocchi Edimar A EA

Oncotarget 20170101 4

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), whi ...[more]

PMID: 28052002

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Project description:Cancer treatment with doxorubicin (DOX) can induce cumulative dose-dependent cardiotoxicity. Currently, there are no specific biomarkers that can identify patients at risk during the initial doses of chemotherapy. The aim of this study was to examine plasma cytokines/chemokines and potential cardiovascular biomarkers for the prediction of DOX-induced cardiotoxicity. Plasma samples were collected before (T0), and after the first (T1) and the second (T2) cycles of DOX-based chemotherapy of 27 breast cancer patients, including five patients who presented with >10% decline of left ventricular ejection fraction (LVEF), five patients with LVEF decline of 5-10%, and 17 patients who maintained normal LVEF at the end of chemotherapy (240 mg/m2 cumulative dose of DOX from four cycles of treatment). Multiplex immunoassays were used to screen plasma samples for 40 distinct chemokines, nine matrix metalloproteinases, 33 potential markers of cardiovascular diseases, and the fourth-generation cardiac troponin T assay. The results showed that the patients with abnormal decline of LVEF (>10%) had lower levels of CXCL6 and sICAM-1 and higher levels of CCL23 and CCL27 at T0; higher levels of CCL23 and lower levels of CXCL5, CCL26, CXCL6, GM-CSF, CXCL1, IFN-?, IL-2, IL-8, CXCL11, CXCL9, CCL17, and CCL25 at T1; and higher levels of MIF and CCL23 at T2 than the patients who maintained normal LVEF. Patients with LVEF decline of 5-10% had lower plasma levels of CXCL1, CCL3, GDF-15, and haptoglobin at T0; lower levels of IL-16, FABP3, and myoglobin at T1; and lower levels of myoglobin and CCL23 at T2 as compared to the patients who maintained normal LVEF. This pilot study identified potential biomarkers that may help predict which patients are vulnerable to DOX-induced cardiotoxicity although further validation is needed in a larger cohort of patients. Impact statement Drug-induced cardiotoxicity is one of the major concerns in drug development and clinical practice. It is critical to detect potential cardiotoxicity early before onset of symptomatic cardiac dysfunction or heart failure. Currently there are no qualified clinical biomarkers for the prediction of cardiotoxicity caused by cancer treatment such as doxorubicin (DOX). By using multiplex immunoassays, we identified proteins with significantly changed plasma levels in a group of breast cancer patients who were treated with DOX-based chemotherapy and produced cardiotoxicity. These proteins were associated with immune response and were identified before DOX treatment or at early doses of treatment, thus they could be potential predictive biomarkers of cardiotoxicity although further validation is required to warrant their clinical values.

Project description:Based on a few studies, heart failure patients with breast cancer were assessed to find potential biomarkers for doxorubicin-induced cardiotoxicity. However, key immune-related transcriptional markers linked to doxorubicin-induced cardiotoxicity in breast cancer patients have not been thoroughly investigated. We used GSE40447, GSE76314, and TCGA BRCA cohorts to perform this study. Then, we performed various bioinformatics approaches to identify the key immune-related transcriptional markers and their association with doxorubicin-induced cardiotoxicity in patients with breast cancer. We found 255 upregulated genes and 286 downregulated genes in patients with doxorubicin-induced heart failure in breast cancer. We discovered that in patients with breast cancer comorbidity doxorubicin-induced cardiotoxicity, the 58 immunological genes are elevated (such as CPA3, VSIG4, GATA2, RFX2, IL3RA, and LRP1), and the 60 genes are significantly suppressed (such as MS4A1, FCRL1, CD200, FCRLA, FCRL2, and CD79A). Furthermore, we revealed that the immune-related differentially expressed genes (DEGs) are substantially associated with the enrichment of KEGG pathways, including B-cell receptor signaling pathway, primary immunodeficiency, chemokine signaling pathway, hematopoietic cell lineage, cytokine-cytokine receptor interaction, Toll-like receptor signaling pathway, MAPK signaling pathway, focal adhesion, dilated cardiomyopathy, cell adhesion molecule, etc. Moreover, we discovered that the doxorubicin-induced immune-related genes are crucially involved in the protein-protein interaction and gene clusters. The immune-related genes, including IFIT5, XCL1, SPIB, BTLA, MS4A1, CD19, TCL1A, CD83, CD200, FCRLA, CD79A, BIRC3, and IGF2R are significantly associated with a poor survival prognosis of breast cancer patients and showed diagnostic efficacy in patients with breast cancer and heart failure. Molecular docking revealed that the survival-associated genes interact with the doxorubicin with appreciable binding affinity. Finally, we validated the expression level of immune-related genes in breast cancer patients-derived cardiomyocytes with doxorubicin-induced cardiotoxicity and found that the level of RAD9A, HSPA1B, GATA2, IGF2R, CD200, ERCC8, and BCL11A genes are consistently dysregulated. Our findings offered a basis for understanding the mechanism and pathogenesis of the cardiotoxicity caused by doxorubicin in breast cancer patients and predicted the interaction of immune-related potential biomarkers with doxorubicin.

Dataset Information

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

Publications

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

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