Original Article

Evaluation of The Preventive Effects of Carvedilol on Trastuzumab-Induced Cardiotoxicity in Early-Stage and Locally Advanced HER2-Positive Breast Cancer Patients


Background: Trastuzumab is an efficient monoclonal antibody used in the treatment of Her2-positive breast cancer. Despite its prominent effect on Her2-positive patients’ disease-free Survival. Trastuzumab-induced cardiotoxicity is still one of the main challenges.  Angiotensin-converting enzyme inhibitors (ACE inhibitors) are one of the most potent agents used in heart failure, which also showed confirmed cardioprotective effects against anthracycline and doxorubicin. We aimed to assess the cardioprotective effects of Carvedilol in a randomized clinical trial study.

Materials and Methods: sixty non-metastatic Her-2 positive patients (30 cases; 30 controls) were entered to the study via a simple randomization method. Carvedilol was administered for the patients with the starting dose of 3.125 mg twice a day and started 7 days before trastuzumab administration. The dose has been increased in a three-week period to reach 12.5 mg twice a day and continued until the end of therapy. All the patients underwent an echocardiography after receiving Adriamycin and Cyclophosphamide in order to measure basal Ejection Fraction (EF) and Pulmonary Artery Pressure (PAP). Each patient underwent a follow-up echocardiography in 3,6,9 and 12 months after initiation of the treatment. Finally, all the patients went through the last episode of echocardiography 1 month after the end of treatment. All the Measured PAP and EF has been recorded and analyzed

Results: EF and PAP changes for both groups had no significant changes during the course of treatment with Trastuzmab (p-value = 0.628 and p-value = 0.723, respectively). 7 patients in the intervention group and 2 patients in the control group presented with EF decrease. Also, 8 patients in the intervention and 9 patients in the control groups showed PAP increase.

Conclusion: According to our results, in patients with HER2-positive breast cancer treated with trastuzumab, Carvedilol showed no significant protective effect on trastuzumab-induced cardiotoxicity.

1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424.
2. King CR, Kraus MH, Aaronson SA. Amplification of a novel v-erbB-related gene in a human mammary carcinoma. Science. 1985;229(4717):974-6.
3. Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235(4785):177-82.
4. Zhou P, Jiang YZ, Hu X, et al. Clinicopathological characteristics of patients with HER2-positive breast cancer and the efficacy of trastuzumab in the People's Republic of China. Onco Targets Ther. 2016;9:2287-95.
5. Killelea BK, Chagpar AB, Horowitz NR, et al. Characteristics and treatment of human epidermal growth factor receptor 2 positive breast cancer: 43,485 cases from the National Cancer Database treated in 2010 and 2011. Am J Surg. 2017;213(2):426-432.
6. Wolff AC, Hammond MEH, Allison KH, et al. Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. J Clin Oncol. 2018;36(20):2105-22.
7. Hudis CA. Trastuzumab--mechanism of action and use in clinical practice. N Engl J Med. 2007;357(1):39-51.
8. Gajria D, Chandarlapaty S. HER2-amplified breast cancer: mechanisms of trastuzumab resistance and novel targeted therapies. Expert Rev Anticancer Ther. 2011;11(2):263-75.
9. Barok M, Joensuu H, Isola J. Trastuzumab emtansine: mechanisms of action and drug resistance. Breast Cancer Res. 2014;16(2):209.
10. Nahta R. Molecular Mechanisms of Trastuzumab-Based Treatment in HER2-Overexpressing Breast Cancer. ISRN Oncol. 2012;2012:428062.
11. Buzatto IP, Ribeiro-Silva A, Andrade JM, et al. Neoadjuvant chemotherapy with trastuzumab in HER2-positive breast cancer: pathologic complete response rate, predictive and prognostic factors. Braz J Med Biol Res. 2017;50(2):e5674.
12. Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet Oncol. 2014;15(6):640-7.
13. de Korte MA, de Vries EG, Lub-de Hooge MN, et al. 111Indium-trastuzumab visualises myocardial human epidermal growth factor receptor 2 expression shortly after anthracycline treatment but not during heart failure: a clue to uncover the mechanisms of trastuzumab-related cardiotoxicity. Eur J Cancer. 2007;43(14):2046-51.
14. Lemmens K, Doggen K, De Keulenaer GW. Role of neuregulin-1/ErbB signaling in cardiovascular physiology and disease: implications for therapy of heart failure. Circulation. 2007;116(8):954-60.
15. Sengupta PP, Northfelt DW, Gentile F, et al. Trastuzumab-induced cardiotoxicity: heart failure at the crossroads. Mayo Clin Proc. 2008;83(2):197-203.
16. Farolfi A, Melegari E, Aquilina M, et al. Trastuzumab-induced cardiotoxicity in early breast cancer patients: a retrospective study of possible risk and protective factors. Heart. 2013;99(9):634-9.
17. Leyland-Jones B, Gelmon K, Ayoub JP, et al. Pharmacokinetics, safety, and efficacy of trastuzumab administered every three weeks in combination with paclitaxel. J Clin Oncol. 2003;21(21):3965-71.
18. Fried G, Regev T, Moskovitz M. Trastuzumab-related cardiac events in the treatment of early breast cancer. Breast Cancer Res Treat. 2013;142(1):1-7.
19. Nabati M, Janbabai G, Baghyari S, et al. Cardioprotective Effects of Carvedilol in Inhibiting Doxorubicin-induced Cardiotoxicity. J Cardiovasc Pharmacol. 2017;69(5):279-285.
20. Pituskin E, Mackey JR, Koshman S, et al. Multidisciplinary Approach to Novel Therapies in Cardio-Oncology Research (MANTICORE 101-Breast): A Randomized Trial for the Prevention of Trastuzumab-Associated Cardiotoxicity. J Clin Oncol. 2017;35(8):870-877.
21. Guglin M, Krischer J, Tamura R, et al. Randomized Trial of Lisinopril Versus Carvedilol to Prevent Trastuzumab Cardiotoxicity in Patients With Breast Cancer. J Am Coll Cardiol. 2019;73(22):2859-2868.
22. Avila MS, Ayub-Ferreira SM, de Barros Wanderley Jr MR, et al. Carvedilol for Prevention of Chemotherapy-Related Cardiotoxicity: The CECCY Trial. J Am Coll Cardiol. 2018;71(20):2281-2290.
23. Jawa Z, Perez RM, Garlie L, et al. Risk factors of trastuzumab-induced cardiotoxicity in breast cancer: A meta-analysis. Medicine (Baltimore). 2016;95(44):e5195.
24. Russell SD, Blackwell KL, Lawrence J, et al. Independent adjudication of symptomatic heart failure with the use of doxorubicin and cyclophosphamide followed by trastuzumab adjuvant therapy: a combined review of cardiac data from the National Surgical Adjuvant breast and Bowel Project B-31 and the North Central Cancer Treatment Group N9831 clinical trials. J Clin Oncol. 2010;28(21):3416-21.
25. Floyd JD, Nguyen DT, Lobins RL, et al. Cardiotoxicity of cancer therapy. J Clin Oncol. 2005;23(30):7685-96.
26. Ewer MS, Vooletich MT, Durand JB, et al. Reversibility of trastuzumab-related cardiotoxicity: new insights based on clinical course and response to medical treatment. J Clin Oncol. 2005;23(31):7820-6.
27. Guglin M, Hartlage G, Reynolds C, et al. Trastuzumab-induced cardiomyopathy: not as benign as it looks? A retrospective study. J Card Fail. 2009;15(8):651-7.
28. Seidman A, Hudis C, Pierri MK, et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol. 2002;20(5):1215-21.
29.Guarneri V, Lenihan DJ, Valero V, et al. Long-term cardiac tolerability of trastuzumab in metastatic breast cancer: the M.D. Anderson Cancer Center experience. J Clin Oncol. 2006;24(25):4107-15.
30. Chavez-MacGregor M, Niu J, Zhang N, et al. Cardiac Monitoring During Adjuvant Trastuzumab-Based Chemotherapy Among Older Patients With Breast Cancer. J Clin Oncol. 2015;33(19):2176-83.
31. Plana JC, Galderisi M, Barac A, et al. Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2014;27(9):911-39.
32. Santos DL, Moreno AJ, Leino RL, et al. Carvedilol protects against doxorubicin-induced mitochondrial cardiomyopathy. Toxicol Appl Pharmacol. 2002;185(3):218-27.
33. Oliveira PJ, Bjork JA, Santos MS, et al. Carvedilol-mediated antioxidant protection against doxorubicin-induced cardiac mitochondrial toxicity. Toxicol Appl Pharmacol. 2004;200(2):159-68.
IssueVol 15, No 4 (2021) QRcode
SectionOriginal Article(s)
DOI https://doi.org/10.18502/ijhoscr.v15i4.7475
Trastuzumab-induced cardiotoxicity; Carvedilol; Human epidermal growth factor receptor-2 (HER-2); Ejection fraction; Pulmonary artery pressure

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
Esfandbod M, Naderi M, Naseri AS, Ahmadi A, Noroozi M, Sadeghi Joni S. Evaluation of The Preventive Effects of Carvedilol on Trastuzumab-Induced Cardiotoxicity in Early-Stage and Locally Advanced HER2-Positive Breast Cancer Patients. Int J Hematol Oncol Stem Cell Res. 2021;15(4):206-212.