RESUMEN
Cardiovascular toxicity is the main adverse effect of Doxorubicin (DOX) in cancer patients. microRNAs (miRNAs) are promising biomarkers to identify cardiac injury induced by DOX in breast cancer patients during the subclinical phase. Using RT-qPCR, we compared the expression of circulating miR-208a5p, miR-133a, miR-499a5p, miR-15a, miR-133b, and miR-49a3p in serum samples from DOX-induced cardiotoxicity (case) compared to the non-cardiotoxicity group (control). To further explore the potential roles of these circulating miRNA in cardiotoxicity, we searched the miRTarBase for experimentally validated miRNA-target interactions and performed a functional enrichment analysis based on those interactions. miR-133a was significantly upregulated in case compared to control group. The most relevant pathway regulated by miR-133a was ErbB2 signaling, whose main genes involved are EGFR, ERBB2, and RHOA, which are possibly downregulated by miR133a. The other miRNAs did not show significant differential expression when compared on both groups. The data suggest that miR-133a is associated with DOX-based cardiotoxicity during chemotherapy in breast cancer patients through ErbB2 signaling pathway. Moreover, miR-133a may be a future marker of DOX-induced cardiotoxicity in women with breast cancer.
Asunto(s)
Neoplasias de la Mama , MicroARNs , Biomarcadores , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Cardiotoxicidad/genética , Doxorrubicina/efectos adversos , Femenino , Humanos , MicroARNs/metabolismo , Transducción de SeñalRESUMEN
BACKGROUND: Myocardial toxicity is a common side effect of doxorubicin (DOXO) therapy in breast cancer patients. We hypothesized that DOXO-induced cardiotoxicity may be related to the release of inflammatory cytokines in response to the treatment. This study aimed to assess changes in plasma levels of interleukin (IL)-1ß, IL-6, IL-10 and tumor necrosis factor (TNF) after chemotherapy and to correlate these levels with cardiac biomarkers and clinical data. METHODS: Sixty-four patients with breast cancer treated with DOXO were included. Twenty-two subjects (cases) developed cardiotoxicity until one year after the end of DOXO treatment. Cytokines and cardiac markers were evaluated before starting chemotherapy (T0), up to 7 days after the last infusion (T1) and 12 months after the last infusion (T2). RESULTS: Higher IL-10 levels were observed in the case group compared to controls at T1 (p = .006) and T2 (p = .046). The IL-1ß, IL-6 and TNF levels did not change during treatment in each group (p > .05), nor between the case and control groups. The IL-10 levels were higher at T1 than at T0 and T2 (p < .05 for both) in the cardiotoxicity group. A correlation between IL-10 and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels at T0 and T2 in the cardiotoxicity group was observed (p = .048 and p = .004, respectively). CONCLUSION: Our study demonstrated that DOXO induced an increase in plasma IL-10 levels in patients who presented cardiotoxicity after treatment, which correlated with NT-proBNP levels.
Asunto(s)
Neoplasias de la Mama , Cardiotoxicidad , Interleucina-10 , Biomarcadores , Neoplasias de la Mama/tratamiento farmacológico , Cardiotoxicidad/etiología , Doxorrubicina/efectos adversos , Femenino , Estudios de Seguimiento , Humanos , Interleucina-10/sangre , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangreRESUMEN
Cardiovascular adverse events in patients with breast cancer undergoing chemotherapy (CT) are frequent due to the high cardiotoxic potential of treatments, especially doxorubicin (DOXO). This study aimed to evaluate the association of plasma levels of various biomarkers with cardiotoxicity in women with breast cancer on DOXO-based chemotherapy. In this single center prospective cohort, 80 breast cancer patients who used DOXO as a first-line treatment for cancer were evaluated. Patients were assessed at three time points: before CT (T0), 1 week after (T1) and 12 months after DOXO treatment (T2). The predominant histological classification was ductal carcinoma, n = 72 (90.0%); the most frequent molecular classification was Human epidermal growth factor receptor-type 2 positive (HER2+), n = 34 (43.0%). In patients submitted to complementary treatment with trastuzumab (n = 23), there was no association with cardio-specific biomarkers. Evaluating the clinical variables and the laboratory parameters in T1 and T2 in relation to T0, the reduction any time of N-terminal-pro hormone B-type natriuretic peptide (NT-proBNP), triglycerides and hematocrit levels showed an association with higher cardiotoxicity risk. In addition, increased levels of troponin I (cTnI) and glycated hemoglobin (HbA1c) showed an independent association with the occurrence of cardiotoxicity. These results suggest that the evaluation of these laboratory tests should be included routinely to identify breast cancer patients under DOXO treatment at cardiotoxicity risk.