Research Papers:

Plasma biomarkers reflecting high oxidative stress in the prediction of myocardial injury due to anthracycline chemotherapy and the effect of carvedilol: insights from the CECCY Trial

Mauro Rogério de Barros Wanderley Jr. _, Mônica Samuel Ávila, Miguel Morita Fernandes-Silva, Fátima das Dores Cruz, Sara Michelly Gonçalves Brandão, Vagner Oliveira Carvalho Rigaud, Ludhmila Abrahão Hajjar, Roberto Kalil Filho, Edécio Cunha-Neto, Edimar Alcides Bocchi and Silvia Moreira Ayub-Ferreira

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Oncotarget. 2022; 13:214-223. https://doi.org/10.18632/oncotarget.28182

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Mauro Rogério de Barros Wanderley Jr.1, Mônica Samuel Ávila1, Miguel Morita Fernandes-Silva2, Fátima das Dores Cruz1, Sara Michelly Gonçalves Brandão1, Vagner Oliveira Carvalho Rigaud1, Ludhmila Abrahão Hajjar3,4, Roberto Kalil Filho3,4, Edécio Cunha-Neto3, Edimar Alcides Bocchi1 and Silvia Moreira Ayub-Ferreira1

1 Heart Failure Department, Heart Institute (InCor) do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

2 School of Medicine, Universidade Federal do Paraná, Curitiba, Paraná, Brazil

3 Heart Institute (InCor) do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

4 Instituto do Câncer do Estado de São Paulo-Universidade de São Paulo, São Paulo, Brazil

Correspondence to:

Mauro Rogério de Barros Wanderley Jr., email: maurowanderley@gmail.com

Keywords: cardiotoxicity; biomarkers; myeloperoxidase; galectin-3; anthracyclines

Received: August 18, 2021     Accepted: January 17, 2022     Published: January 25, 2022

Copyright: © 2022 Wanderley Jr. et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Background: Anthracycline (ANT) is often used for breast cancer treatment but its clinical use is limited by cardiotoxicity (CTX). CECCY trial demonstrated that the β-blocker carvedilol (CVD) could attenuate myocardial injury secondary to ANT. Mieloperoxydase (MPO) is a biomarker of oxidative stress and galectin-3 (Gal-3) is a biomarker of fibrosis and cardiac remodeling. We evaluated the correlation between MPO and Gal-3 behavior with CTX.

Materials and Methods: A post hoc analysis was performed in the patients who were included in the CECCY trial. A total of 192 women had her blood samples stored during the study at –80°C until the time of assay in a single batch. Stored blood samples were obtained at baseline, 3 and 6 months after randomization. We excluded samples from 18 patients because of hemolysis. MPO and Gal-3 were measured using Luminex xMAP technology through MILLIPLEX MAP KIT (Merck Laboratories).

Results: 26 patients (14.9%) had a decrease of at least 10% in LVEF at 6 months after the initiation of chemotherapy. Among these, there was no significant difference in the MPO and Gal-3 when compared to the group without drop in LVEF (p = 0.85 for both MPO and Gal-3). Blood levels of MPO [baseline: 13.2 (7.9, 24.8), 3 months: 17.7 (11.1, 31.1), 6 months: 19.2 (11.1, 37.8) ng/mL] and Gal-3 [baseline: 6.3 (5.2, 9.6), 3 months: 12.3 (9.8, 16.0), 6 months: 10.3 (8.2, 13.1) ng/mL] increased after ANT chemotherapy, and the longitudinal changes were similar between the placebo and CVD groups (p for interaction: 0.28 and 0.32, respectively). In an exploratory analysis, as there is no normal cutoff value established for Gal-3 and MPO in the literature, the MPO and Gal-3 results were splited in two groups: above and below median. In the placebo group, women with high (above median) baseline MPO blood levels demonstrated a greater increase in TnI blood levels than those with low baseline MPO blood levels (p = 0.041). Compared with placebo, CVD significantly reduced TnI blood levels in women with high MPO blood levels (p < 0.001), but did not reduce the TnI levels in women with low baseline MPO blood levels (p = 0.97; p for interaction = 0.009). There was no significant interaction between CVD treatment and baseline Gal-3 blood levels (p for interaction = 0.99).

Conclusions: In this subanalysis of the CECCY trial, MPO and Gal-3 biomarkers did not predict the development of CTX. However, MPO blood levels above median was associated with more severe myocardial injury and identified women who were most likely to benefit from carvedilol for primary prevention (NCT01724450).

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