Journal of Cancer Research and Clinical Oncology

, Volume 144, Issue 8, pp 1613–1621 | Cite as

Trastuzumab-induced cardiotoxicity and its risk factors in real-world setting of breast cancer patients

  • Tiina Moilanen
  • Anna Jokimäki
  • Olli Tenhunen
  • Jussi P. KoivunenEmail author
Original Article – Clinical Oncology



Cardiotoxicity is the most important side effect of trastuzumab treatment. Heart function monitoring is recommended during the treatment which has led to growing use of resources. The aim of this retrospective study was to determine the frequency and timing of trastuzumab cardiotoxicity and its risk factors in real-world setting.


Single institute, retrospective collection of data on HER2+ breast cancer patients (n = 246) was carried out through a pharmacy search for patients who had received trastuzumab in 2006–2014. Clinical and pathological factors, treatment history, EF measurements, cardiac medications, cardiovascular disease history, cardiac symptoms, and survival data were collected from patient records.


32 patients (13%) had EF decline ≥ 10%, eleven (4.5%) had EF decline ≥ 20% within 1 year after trastuzumab initiation, and trastuzumab was discontinued due to suspected cardiotoxicity in six patients (2.4%). 49 patients (19.9%) experienced symptoms related to cardiotoxicity during therapy, which accumulated among those with EF drop. Underlying cardiovascular diseases and multiple (≥ 2) cardiac medications were related to EF drop (≥ 20%) and trastuzumab discontinuation. Majority of EF drops (≥ 10%) and trastuzumab discontinuations were seen within 6months of trastuzumab initiation and recovery of EF drop to < 10% of the baseline was seen in most cases (62.5%). There was no statistically significant difference in the survival of patients according to EF drop.


Trastuzumab cardiotoxicity seems to accumulate among patients with underlying cardiac conditions. EF monitoring could be targeted to risk groups without compromising of the cardiac health or survival of HER2-positive breast cancer patients.


HER2 amplification Breast cancer Trastuzumab Cardiotoxicity 


Compliance with ethical standards

Conflict of interest

Authors declare no conflict of interest. The study was funded by Oulu University Hospital, University of Oulu, and Finnish Cancer Society. According to national legislation, informed consent is not needed due to retrospective and non-interventional nature of the study. The opinions expressed in this article are the personal views of the author (OT) and may not be understood or quoted as being behalf or reflect the position of the Finnish Medicines Agency or European Medicines Agency.


  1. Baron KB, Brown JR, Heiss BL, Marshall J, Tait N, Tkaczuk KHR et al (2014) Trastuzumab-induced cardiomyopathy: Incidence and associated risk factors in an inner-city population. J Card Fail 20(8):555–559. CrossRefPubMedGoogle Scholar
  2. Baselga J, Cortés J, Kim S, Im S, Hegg R, Im Y et al (2012) Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366(2):109–119. CrossRefPubMedGoogle Scholar
  3. Bowles EJA, Wellman R, Feigelson HS, Onitilo AA, Freedman AN, Delate T et al (2012) Risk of heart failure in breast cancer patients after anthracycline and trastuzumab treatment: a retrospective cohort study. J Natl Cancer Inst 104(17):1293–1305. CrossRefPubMedPubMedCentralGoogle Scholar
  4. Burstein HJ, Kuter I, Campos SM, Gelman RS, Tribou L, Parker LM et al (2001) Clinical activity of trastuzumab and vinorelbine in women with HER2-overexpressing metastatic breast cancer. J Clin Oncol 19(10):2722–2730. CrossRefPubMedGoogle Scholar
  5. Cardinale D, Colombo A, Torrisi R, Sandri MT, Civelli M, Salvatici M et al (2010) Trastuzumab-induced cardiotoxicity: clinical and prognostic implications of troponin I evaluation. J Clin Oncol 28(25):3910–3916. CrossRefPubMedGoogle Scholar
  6. Crone SA, Zhao Y, Fan L, Gu Y, Minamisawa S, Liu Y et al (2002) ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat Med 8(5):459–465. CrossRefPubMedGoogle Scholar
  7. ElZarrad MK, Mukhopadhyay P, Mohan N, Hao E, Dokmanovic M, Hirsch DS et al (2013) Trastuzumab alters the expression of genes essential for cardiac function and induces ultrastructural changes of cardiomyocytes in mice. PLOS One 8(11):e79543. CrossRefPubMedPubMedCentralGoogle Scholar
  8. FDA (2017) Trastuzumab prescribing information. Accessed 5 June 2018
  9. Florido R, Smith KL, Cuomo KK, Russell SD (2017) Cardiotoxicity from human epidermal growth factor receptor-2 (HER2) targeted therapies. J Am Heart Assoc. PubMedPubMedCentralCrossRefGoogle Scholar
  10. Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T et al (2006) Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355(26):2733–2743. CrossRefPubMedGoogle Scholar
  11. Goldhirsch A, Gelber RD, Piccart-Gebhart M, de Azambuja E, Procter M, Suter TM et al (2013) 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet 382(9897):1021–1028. CrossRefPubMedGoogle Scholar
  12. Guarneri V, Lenihan DJ, Valero V, Durand J, Broglio K, Hess KR et al (2006) Long-term cardiac tolerability of trastuzumab in metastatic breast cancer: the M.D. anderson cancer center experience. J Clin Oncol 24(25):4107–4115. CrossRefPubMedGoogle Scholar
  13. Guenancia C, Lefebvre A, Cardinale D, Yu AF, Ladoire S, Ghiringhelli F et al (2016) Obesity as a risk factor for anthracyclines and trastuzumab cardiotoxicity in breast cancer: a systematic review and meta-analysis. J Clin Oncol 34(26):3157–3165. CrossRefPubMedPubMedCentralGoogle Scholar
  14. Joensuu H, Kellokumpu-Lehtinen P, Bono P, Alanko T, Kataja V, Asola R et al (2006) Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 354(8):809–820. CrossRefPubMedGoogle Scholar
  15. Kaufman B, Mackey JR, Clemens MR, Bapsy PP, Vaid A, Wardley A et al (2009) Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2–Positive, hormone Receptor–Positive metastatic breast cancer: Results from the randomized phase III TAnDEM study. 27(33):5529–5537.
  16. Lee KF, Simon H, Chen H, Bates B, Hung MC, Hauser C (1995) Requirement for neuregulin receptor erbB2 in neural and cardiac development. Nature 378(6555):394–398. CrossRefPubMedGoogle Scholar
  17. Moja L, Tagliabue L, Balduzzi S, Parmelli E, Pistotti V, Guarneri V et al (2012) Trastuzumab containing regimens for early breast cancer. Cochrane Database Syst Rev. CrossRefPubMedGoogle Scholar
  18. Nemeth BT, Varga ZV, Wu WJ, Pacher P (2017) Trastuzumab cardiotoxicity: from clinical trials to experimental studies. Br J Pharmacol 174(21):3727–3748. CrossRefPubMedGoogle Scholar
  19. Piccart-Gebhart M, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I et al (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353(16):1659–1672. CrossRefPubMedGoogle Scholar
  20. Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE, Davidson NE et al (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353(16):1673–1684. CrossRefPubMedGoogle Scholar
  21. Seferina SC, de Boer M, Derksen MW, van dB, van Kampen R,JW, van de Wouw A,J et al (2016) Cardiotoxicity and cardiac monitoring during adjuvant trastuzumab in daily dutch practice: a study of the southeast Netherlands breast cancer consortium. Oncologist 21(5):555–562. CrossRefPubMedPubMedCentralGoogle Scholar
  22. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235(4785):177–182CrossRefPubMedGoogle Scholar
  23. Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE et al (1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244(4905):707–712CrossRefPubMedGoogle Scholar
  24. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A et al (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344(11):783–792. CrossRefPubMedGoogle Scholar
  25. Swain SM, Baselga J, Kim S, Ro J, Semiglazov V, Campone M et al (2015) Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 372(8):724–734. CrossRefPubMedPubMedCentralGoogle Scholar
  26. Telli ML, Hunt SA, Carlson RW, Guardino AE (2007) Trastuzumab-related cardiotoxicity: calling into question the concept of reversibility. 25(23):3525–3533.
  27. Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J et al (2012) Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 367(19):1783–1791. CrossRefPubMedPubMedCentralGoogle Scholar
  28. von Minckwitz G, du Bois A, Schmidt M, Maass N, Cufer T, de Jongh FE et al (2009) Trastuzumab beyond progression in human epidermal growth factor receptor 2–Positive advanced breast cancer: A german breast group 26/breast international group 03–05 study. 27(12):1999–2006.
  29. Yu AF, Yadav NU, Lung BY, Eaton AA, Thaler HT, Hudis CA et al (2015) Trastuzumab interruption and treatment-induced cardiotoxicity in early HER2-positive breast cancer. Breast Cancer Res Treat 149(2):489–495. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Medical Oncology and RadiotherapyOulu University Hospital, University of Oulu, and MRC OuluOuluFinland
  2. 2.Finnish Medicines AgencyHelsinkiFinland

Personalised recommendations