International Journal of Clinical Pharmacy

, Volume 37, Issue 2, pp 365–372 | Cite as

Trastuzumab induced cardiotoxicity in HER2 positive breast cancer patients attended in a tertiary hospital

  • Lorena Rocha AyresEmail author
  • Marília Silveira de Almeida Campos
  • Thais de Oliveira Gozzo
  • Edson Zangiacomi Martinez
  • Andrea Queiróz Ungari
  • Jurandyr Moreira de Andrade
  • Leonardo Régis Leira Pereira
Research Article


Background The use of trastuzumab is associated with an increased survival rate in HER2 positive breast cancer patients. However, it is related to different levels of cardiotoxicity leading to treatment discontinuation, which can deprive patients of the benefits of this therapy. Objective This study aimed to identify the incidence of trastuzumab induced cardiotoxicity (TIC) and the rate of discontinuation of trastuzumab in clinical practice. Possible factors associated with TIC were also investigated. Setting This study was conducted in the General Hospital of the School of Medicine of Ribeirão Preto, University of São Paulo. Methods We retrospectively reviewed the medical records of patients without distant metastasis that started trastuzumab between 2007 and 2011 in the tertiary hospital. TIC was defined as symptomatic heart failure or a decrease in left ventricular ejection fraction (LVEF) by ≥10 % compared to the first echocardiography measurement or to <50 % at any time. Logistic regression models were used to estimate odds ratios and their respective 95 % confidence intervals for TIC associated with variables such as age, body mass index, smoking history, cardiac risks, type of surgery, presence of positive lymph nodes, chemotherapy regimen and epirubicin cumulative dose. Main outcome measure The incidence and factors associated with TIC and the rate of discontinuation of trastuzumab in clinical practice. Results We analyzed the records of 79 patients. TIC developed in 26 (32.9 %) patients, being the LVEF decline by ≥10 % observed in 21 (26.6 %), a decreased to <50 % in four (5.1 %) and one (1.2 %) was symptomatic without LVEF decline. Thirteen (16.4 %) patients discontinued permanently the treatment, three (3.8 %) discontinued temporarily and 10 (12.6 %) finished it without interruption. None of the covariates influenced on the incidence of TIC in this population. Conclusion Although most patients finished their treatment, TIC led to trastuzumab discontinuation in a significant proportion of patients suggesting the need of a closer cardiac monitoring. None of the covariates influenced on the incidence of TIC, which can be due to the relatively small sample. Thus, larger scale studies should be conducted in order to establish which specific factors are associated with the development of TIC in order to avoid it.


Brazil Cardiotoxicity HER2 positive breast cancer Trastuzumab 



The authors would like to thank the School of Pharmaceutical Sciences of Ribeirão Preto—University of São Paulo for its support during the research and the General Hospital of the Faculty of Medicine of Ribeirão Preto of the University of São Paulo (HCFMRP-USP) for its support during data collection.


National Council for Scientific and Technological Development (CNPq).

Conflicts of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917.CrossRefPubMedGoogle Scholar
  2. 2.
    Instituto Nacional do Câncer. Estimativa 2012: Incidência de Câncer no Brasil. Rio de Janeiro: Ministério da Saúde; 2011.Google Scholar
  3. 3.
    Lee BL, Liedke PE, Barrios CH, et al. Breast cancer in Brazil: present status and future goals. Lancet Oncol. 2012;13:e95–102.CrossRefPubMedGoogle Scholar
  4. 4.
    Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER2-2/neu oncogene. Science. 1987;235:177–82.CrossRefPubMedGoogle Scholar
  5. 5.
    Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:789–92.CrossRefGoogle Scholar
  6. 6.
    Murphy CG, Modi S. HER2 breast cancer therapies: a review. Biologics. 2009;3:289–301.PubMedCentralPubMedGoogle Scholar
  7. 7.
    Yarden Y. The EGFR family and its ligands in human cancer: signalling mechanisms and therapeutic opportunities. Eur J Cancer. 2001;37(Suppl 4):S3–8.CrossRefPubMedGoogle Scholar
  8. 8.
    Wolff AC, Hammond ME, Schwartz JN, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 2007;25:118–45.CrossRefPubMedGoogle Scholar
  9. 9.
    Ross JS, Slodkowska EA, Symmans WF, et al. The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine. Oncologist. 2009;14:320–68.CrossRefPubMedGoogle Scholar
  10. 10.
    Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353:1659–72.CrossRefPubMedGoogle Scholar
  11. 11.
    Procter M, Suter TM, de Azambuja E, et al. Longer-term assessment of trastuzumab-related cardiac adverse events in the Herceptin Adjuvant (HERA) trial. J Clin Oncol. 2010;28:3422–8.CrossRefPubMedGoogle Scholar
  12. 12.
    de Azambuja E, Bedard PL, Suter T, Piccart-Gebhart M. Cardiac toxicity with anti-HER-2 therapies: what have we learned so far? Target Oncol. 2009;4:77–88.CrossRefPubMedGoogle Scholar
  13. 13.
    Guglin M, Hartlage G, Reynolds C, et al. Trastuzumab-induced cardiomyopathy: not as benign as it looks? A retrospective study. J Card Fail. 2009;15:651–7.CrossRefPubMedGoogle Scholar
  14. 14.
    Wadhwa D, Fallah-Rad N, Grenier D, et al. Trastuzumab mediated cardiotoxicity in the setting of adjuvant chemotherapy for breast cancer: a retrospective study. Breast Cancer Res Treat. 2009;117:357–64.CrossRefPubMedGoogle Scholar
  15. 15.
    Tarantini L, Cioffi G, Gori S, et al. Trastuzumab adjuvant chemotherapy and cardiotoxicity in real-world women with breast cancer. J Card Fail. 2012;18:113–19.CrossRefPubMedGoogle Scholar
  16. 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;99:634–9.CrossRefPubMedGoogle Scholar
  17. 17.
    Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (HCFMRP/USP). Last accessed 26 May 2013.
  18. 18.
    Brasil. Portaria nº 741 de 19 de dezembro de 2005. Last accessed 26 May 2013.
  19. 19.
  20. 20.
    Allison PD. Logistic regression using the SAS system: theory and application. Cary: SAS Books; 2001.Google Scholar
  21. 21.
    Guarneri V, Lenihan DJ, Valero V, et al. Long-term cardiac tolerability of trastuzumab in metastatic breast cancer: the MD Anderson Cancer Center experience. J Clin Oncol. 2006;24:4107–15.CrossRefPubMedGoogle Scholar
  22. 22.
    Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 1995;353:1673–84.CrossRefGoogle Scholar
  23. 23.
    Aogi K, Saeki T, Nakamura S, et al. A multicenter, phase II study of epirubicin/cyclophosphamide followed by docetaxel and concurrent trastuzumab as primary systemic therapy for HER-2 positive advanced breast cancer (the HER2NAT study). Int J Clin Oncol. 2012;. doi: 10.1007/s10147-012-0437-1.Google Scholar
  24. 24.
    Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Peto R, Davies C, et al. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trial. Lancet. 2012;379:432–44.CrossRefGoogle Scholar
  25. 25.
    Roca-Alonso L, Pellegrino L, Castellano L, et al. Breast cancer treatment and adverse cardiac events: what are the molecular mechanisms? Cardiology 2012;122:253–59.Google Scholar
  26. 26.
    Singal PK, Iliskovic N. Doxorubicin-induced cardiomyopathy. N Engl J Med. 1998;339:900–5.CrossRefPubMedGoogle Scholar
  27. 27.
    Di Cosimo S. Heart to heart with trastuzumab: a review on cardiac toxicity. Target Oncol. 2011;6:189–95.CrossRefPubMedGoogle Scholar
  28. 28.
    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;23:7820–6.CrossRefPubMedGoogle Scholar
  29. 29.
    Chen T, Xu T, Li Y, et al. Risk of cardiac dysfunction with trastuzumab in breast cancer patients: a meta-analysis. Cancer Treat Rev. 2011;37:312–20.CrossRefPubMedGoogle Scholar
  30. 30.
    Dent S, Hopkins S, Graham N. The experience of a multidisciplinary clinic in the management of early-stage breast cancer patients receiving trastuzumab therapy: an observational study. Cardiol Res Pract. 2012;2012:135819. doi: 10.1155/2012/135819.
  31. 31.
    Serrano C, Cortés J, De Mattos-Arruda L, et al. Trastuzumab-related cardiotoxicity in the elderly: a role for cardiovascular risk factors. Ann Oncol. 2012;23:897–902.CrossRefPubMedGoogle Scholar
  32. 32.
    van Hasselt JG, Boekhout AH, Beijnen JH, et al. Population pharmacokinetic-pharmacodynamic analysis of trastuzumab-associated cardiotoxicity. Clin Pharmacol Ther. 2011;90:126–32.CrossRefPubMedGoogle Scholar
  33. 33.
    Fox KF. The evaluation of left ventricular function for patients being considered for, or receiving trastuzumab (Herceptin) therapy. Br J Cancer. 2006;95:1454.CrossRefPubMedCentralPubMedGoogle Scholar
  34. 34.

Copyright information

© Koninklijke Nederlandse Maatschappij ter bevordering der Pharmacie 2015

Authors and Affiliations

  • Lorena Rocha Ayres
    • 1
    Email author
  • Marília Silveira de Almeida Campos
    • 1
  • Thais de Oliveira Gozzo
    • 2
  • Edson Zangiacomi Martinez
    • 3
  • Andrea Queiróz Ungari
    • 4
  • Jurandyr Moreira de Andrade
    • 3
  • Leonardo Régis Leira Pereira
    • 1
  1. 1.Departamento de Ciências Farmacêuticas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Centro de Pesquisa em Assistência Farmacêutica e Farmácia Clínica (CPAFF)Universidade de São PauloRibeirão PretoBrazil
  2. 2.Escola de Enfermagem de Ribeirão PretoUniversidade de São PauloRibeirão PretoBrazil
  3. 3.Faculdade de Medicina de Ribeirão PretoUniversidade de São PauloRibeirão PretoBrazil
  4. 4.Hospital das Clínicas da Faculdade de Medicina de Ribeirão PretoUniversidade de São PauloRibeirão PretoBrazil

Personalised recommendations