Cardiotoxicity of Targeted Cancer Drugs: Concerns, “The Cart Before the Horse,” and Lessons from Trastuzumab

  • Pierantonio Menna
  • Giorgio MinottiEmail author
  • Emanuela Salvatorelli
Myocardial Disease (A Abbate and G Sinagra, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Myocardial Disease


Purpose of Review

Modern oncology is witnessing a renaissance of its pharmacologic armamentarium. Old generation drugs, such as anthracyclines and other cytotoxic or cytostatic drugs, were plagued with a lack of specificity and with the possible occurrence of untoward effects in the cardiovascular system and other healthy tissues. The old drugs are now combined with, or replaced by, new agents that are more specific in attacking some unique moieties and vital functions of cancer cells, causing less noxious effects in healthy tissues. Regrettably, however, the new “targeted” drugs still cause varying levels of cardiac or vascular toxicity. Here, we describe the case of trastuzumab, a monoclonal antibody that dramatically improved the life expectancy of women with Erbb2-overexpressing breast tumor, while also raising concerns about a possible incidence of cardiac dysfunction.

Recent Findings

The scientific community counts experts that label trastuzumab as a “cardiotoxic agent” and other experts that maintain a more benign assessment. We describe the biologic foundations and clinical evidence for such controversy. We show that trastuzumab cardiotoxicity is probably overrated, leading some experts to raise unjustified overconcerns about the cardiotoxicity of trastuzumab as a single agent or in combination with anthracyclines or other old and new drugs. We analyze the biases that caused trastuzumab cardiotoxicity to be overrated.


Trastuzumab is a life-saving agent showing a moderate and clinically manageable cardiac dysfunction, and yet, it is portrayed as cardiotoxic. We take the trastuzumab lesson to reaffirm that cardio-oncologists should provide cancer patients with the best therapeutic opportunity, as is the case for trastuzumab, while also devising the necessary strategies of risk assessment and mitigation.


Targeted drugs Cardiotoxicity Trastuzumab 


Compliance with Ethical Standards

Conflict of Interest

Pierantonio Menna, Giorgio Minotti, and Emanuela Salvatorelli declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Minotti G, Salvatorelli E, Menna P. Pharmacological foundations of cardio-oncology. J Pharmacol Exp Ther. 2010;334:2–8.CrossRefPubMedGoogle Scholar
  2. 2.
    Armenian SH, Armstrong GT, Aune G, Chow EJ, Ehrhardt MJ, Ky B, et al. Cardiovascular disease in survivors of childhood cancer: insights into epidemiology, pathophysiology, and prevention. J Clin Oncol. 2018;36:2135–44.CrossRefPubMedGoogle Scholar
  3. 3.
    Armstrong GT, Joshi VM, Ness KK, Marwick TH, Zhang N, Srivastava D, et al. Comprehensive echocardiographic detection of treatment-related cardiac dysfunction in adult survivors of childhood cancer: results from the St Jude Lifetime Cohort Study. J Am Coll Cardiol. 2015;65:2511–22.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Carver JR, Shapiro CL, Ng A, Jacobs L, Schwartz C, Virgo KS, et al. American Society of Clinical Oncology clinical evidence review on the ongoing care of adult cancer survivors: cardiac and pulmonary late effects. J Clin Oncol. 2007;25:3991–4008.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev. 2004;56:185–229.CrossRefPubMedGoogle Scholar
  6. 6.
    Menna P, Salvatorelli E, Minotti G. Cardiotoxicity of antitumor drugs. Chem Res Toxicol. 2008;21:978–89.CrossRefPubMedGoogle Scholar
  7. 7.
    Menna P, Paz OG, Chello M, et al. Anthracycline cardiotoxicity. Expert Opin Drug Saf. 2012;11:S21–36.CrossRefPubMedGoogle Scholar
  8. 8.
    Babiker HM, McBride A, Newton M, Boehmer LM, Drucker AG, Gowan M, et al. Cardiotoxic effects of chemotherapy: a review of both cytotoxic and molecular targeted oncology therapies and their effect on the cardiovascular system. Crit Rev Oncol Hematol. 2018;126:186–200.CrossRefPubMedGoogle Scholar
  9. 9.
    Herrmann J, Yang EH, Iliescu CA, Cilingiroglu M, Charitakis K, Hakeem A, et al. Vascular toxicities of cancer therapies: the old and the new--an evolving avenue. Circulation. 2016;133:1272–89.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    • Moslehi JJ. Cardiovascular toxic effects of targeted cancer therapies. N Engl J Med. 2016;375:1457–67 A scholar review of new clinical phenotypes of cardiovascular toxicity induced by targeted drugs. CrossRefPubMedGoogle Scholar
  11. 11.
    Bellinger AM, Arteaga CL, Force T, Humphreys BD, Demetri GD, Druker BJ, et al. Cardio-oncology: how new targeted cancer therapies and precision medicine can inform cardiovascular discovery. Circulation. 2015;132:2248–58.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Menna P, Salvatorelli E. Primary prevention strategies for anthracycline cardiotoxicity: a brief overview. Chemother. 2017;62:159–68.CrossRefGoogle Scholar
  13. 13.
    Lemmens K, Segers VF, Demolder M, et al. Role of neuregulin-1/ErbB2 signaling in endothelium-cardiomyocyte cross-talk. J Biol Chem. 2006;281:19469–77.CrossRefPubMedGoogle Scholar
  14. 14.
    Chang HM, Moudgil R, Scarabelli T, Okwuosa TM, Yeh ETH. Cardiovascular complications of cancer therapy: best practices in diagnosis, prevention, and management: part 1. J Am Coll Cardiol. 2017;70:2536–51.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Dias A, Claudino W, Sinha R, Perez CA, Jain D. Human epidermal growth factor antagonists and cardiotoxicity-a short review of the problem and preventative measures. Crit Rev Oncol Hematol. 2016;104:42–51.CrossRefPubMedGoogle Scholar
  16. 16.
    Tagliabue E, Campiglio M, Pupa SM, Ménard S, Balsari A. Activity and resistance of trastuzumab according to different clinical settings. Cancer Treat Rev. 2012;38:212–7.CrossRefPubMedGoogle Scholar
  17. 17.
    Baselga J, Gelmon KA, Verma S, Wardley A, Conte PF, Miles D, et al. Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol. 2010;28:1138–44.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:783–92.CrossRefPubMedGoogle Scholar
  19. 19.
    Gassmann M, Casagranda F, Orioli D, et al. Aberrant neural and cardiac development in mice lacking the ERBB4 neuregulin receptor. Nature. 1995;378:39–94.CrossRefGoogle Scholar
  20. 20.
    Meyer D, Birchmeier C. Multiple essential functions of neuregulin in development. Nature. 1995;378:386–90.CrossRefPubMedGoogle Scholar
  21. 21.
    Crone SA, Zhao YY, Fan L, Gu Y, Minamisawa S, Liu Y, et al. ERBB2 is essential in the prevention of dilated cardiomyopathy. Nat Med. 2002;8:459–65.CrossRefPubMedGoogle Scholar
  22. 22.
    Ozcelik C, Erdmann B, Pilz B, Wettschureck N, Britsch S, Hubner N, et al. Conditional mutation of the ErbB2 (Her2) receptor in cardiomyocytes leads to dilated cardiomyopathy. Proc Natl Acad Sci U S A. 2002;99:8880–5.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Sheng Z, Knowlton K, Chen J, Hoshijima M, Brown JH, Chien KR. Cardiotrophin 1 (CT-1) inhibition of cardiac myocyte apoptosis via a mitogen-activated protein kinase dependent pathway. Divergence from downstream CT-1 signals for myocardial cell hypertrophy. J Biol Chem. 1997;272:5783–91.CrossRefPubMedGoogle Scholar
  24. 24.
    Grant SL, Hammacher A, Douglas AM, Goss GA, Mansfield RK, Heath JK, et al. An unexpected biochemical and functional interaction between gp130 and the EGF receptor family in breast cancer cells. Oncogene. 2002;21:460–74.CrossRefPubMedGoogle Scholar
  25. 25.
    Pegram M, Ngo D. Application and potential limitations of animal models utilized in the development of trastuzumab (HerceptinR): a case study B. Adv Drug Deliv Rev. 2006;58:723–34.CrossRefPubMedGoogle Scholar
  26. 26.
    Peng X, Chen B, Lim CC, Sawyer DB. The cardiotoxicology of anthracycline chemotherapeutics: translating molecular mechanisms into preventative medicine. Mol Interv. 2005;5:163–71.CrossRefPubMedGoogle Scholar
  27. 27.
    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;116:954–60.CrossRefPubMedGoogle Scholar
  28. 28.
    Chien KR. Myocyte survival pathways and cardiomyopathy: implications for trastuzumab cardiotoxicity. Semin Oncol. 2000;27:9–14.PubMedGoogle Scholar
  29. 29.
    Pegram M, Hsu S, Lewis G, Pietras R, Beryt M, Sliwkowski M, et al. Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers. Oncogene. 1999;18:2241–51.CrossRefPubMedGoogle Scholar
  30. 30.
    Konecny G, Pegram MD, Beryt M, et al. Therapeutic advantage of chemotherapy drugs in combination with Herceptin against human breast cancer cells with HER-2/neu overexpression. Breast Cancer Res Treat. 1999;57:114.Google Scholar
  31. 31.
    Pietras RJ, Poen JC, Gallardo D, Wongvipat PN, Lee HJ, Slamon DJ. Monoclonal antibody to HER-2/neureceptor modulates repair of radiation-induced DNA damage and enhances radiosensitivity of human breast cancer cells overexpressing this oncogene. Cancer Res. 1999;59:1347–55.PubMedGoogle Scholar
  32. 32.
    Baselga J, Norton L, Albanell J, Kim YM, Mendelsohn J. Recombinant humanized anti-HER2 antibody (Herceptin) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts. Cancer Res. 1998;58:2825–31.PubMedGoogle Scholar
  33. 33.
    Baselga J, Tripathy D, Mendelsohn J, Baughman S, Benz CC, Dantis L, et al. Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol. 1996;14:737–44.CrossRefPubMedGoogle Scholar
  34. 34.
    Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, et al. Multinational study of the efficacy and safety of humanized anti-HER-2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol. 1999;17:2639–48.CrossRefPubMedGoogle Scholar
  35. 35.
    Pegram MD, Lipton A, Hayes DF, Weber BL, Baselga JM, Tripathy D, et al. Phase II study of receptor enhanced chemosensitivity using recombinant humanized antip185HER2/neu monoclonal antibody plus cisplatin in patients with HER-2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. J Clin Oncol. 1998;16:2659–71.CrossRefPubMedGoogle Scholar
  36. 36.
    Von Hoff DD, Layard MW, Basa P, et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med. 1979;91:710–7.CrossRefGoogle Scholar
  37. 37.
    Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer. 2003;97:2869–79.CrossRefPubMedGoogle Scholar
  38. 38.
    Salvatorelli E, Menna P, Chello M, Covino E, Minotti G. Low-dose anthracycline and risk of heart failure in a pharmacokinetic model of human myocardium exposure: analog specificity and role of secondary alcohol metabolites. J Pharmacol Exp Ther. 2018;364:323–31.CrossRefPubMedGoogle Scholar
  39. 39.
    Seidman A, Hudis C, Pierri MK, Shak S, Paton V, Ashby M, et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol. 2002;20:1215–21.CrossRefPubMedGoogle Scholar
  40. 40.
    Ewer MS, Gibbs HR, Swafford J, Benjamin RS. Cardiotoxicity in patients receiving trastuzumab (Herceptin): primary toxicity, synergistic or sequential stress, or surveillance artifact? Semin Oncol. 1999;26:96–101.PubMedGoogle Scholar
  41. 41.
    Tripathy D, Seidman A, Keefe D, Hudis C, Paton V, Lieberman G. Effect of cardiac dysfunction on treatment outcomes in women receiving trastuzumab for HER2-overexpressing metastatic breast cancer. Clin Breast Cancer. 2004;5:293–8.CrossRefPubMedGoogle Scholar
  42. 42.
    Suter TM, Procter M, van Veldhuisen DJ, Muscholl M, Bergh J, Carlomagno C, et al. Trastuzumab-associated cardiac adverse effects in the Herceptin adjuvant trial. J Clin Oncol. 2007;25:3859–65.CrossRefPubMedGoogle Scholar
  43. 43.
    •• de Azambuja E, Procter MJ, van Veldhuisen DJ, et al. Trastuzumab-associated cardiac events at 8 years of median follow-up in the Herceptin adjuvant trial (BIG 1-01). J Clin Oncol. 2014;32:2159–65 Contains remarkably important information on the long-term safety of trastuzumab in survivors of the HERA trial in which trastuzumab was given after (neo)adjuvant anthracycline. CrossRefPubMedGoogle Scholar
  44. 44.
    Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353:1659–72.CrossRefPubMedGoogle Scholar
  45. 45.
    Gombos A, Metzger-Filho O, Dal Lago L, Awada-Hussein A. Clinical development of insulin-like growth factor receptor--1 (IGF-1R) inhibitors: at the crossroad? Investig New Drugs. 2012;30:2433–42.CrossRefGoogle Scholar
  46. 46.
    Kümler I, Tuxen MK, Nielsen DL. A systematic review of dual targeting in HER2-positive breast cancer. Cancer Treat Rev. 2014;40:259–70.CrossRefPubMedGoogle Scholar
  47. 47.
    Swain SM, Ewer MS, Cortés J, et al. Cardiac tolerability of pertuzumab plus trastuzumab plus docetaxel in patients with HER2-positive metastatic breast cancer in CLEOPATRA: a randomized, double-blind, placebo-controlled phase III study. Oncologist. 2013;18:257–64.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Swain SM, Ewer MS, Viale G, Delaloge S, Ferrero JM, Verrill M, et al. Pertuzumab, trastuzumab, and standard anthracycline- and taxane-based chemotherapy for the neoadjuvant treatment of patients with HER2-positive localized breast cancer (BERENICE): a phase II, open-label, multicenter, multinational cardiac safety study. Ann Oncol. 2018;29:646–53.CrossRefPubMedGoogle Scholar
  49. 49.
    Yu AF, Singh JC, Wang R, Liu JE, Eaton A, Oeffinger KC, et al. Cardiac safety of dual anti-HER2 therapy in the neoadjuvant setting for treatment of HER2-positive breast cancer. Oncologist. 2017;22:642–7.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Baron JM, Boster BL, Barnett CM. Ado-trastuzumab emtansine (T-DM1): a novel antibody-drug conjugate for the treatment of HER2-positive metastatic breast cancer. J Oncol Pharm Pract. 2015;21:132–42.CrossRefPubMedGoogle Scholar
  51. 51.
    Krop IE, Suter TM, Dang CT. Feasibility and cardiac safety of trastuzumab emtansine after anthracycline-based chemotherapy as (neo)adjuvant therapy for human epidermal growth factor receptor 2-positive early-stage breast cancer. J Clin Oncol. 2015;33:1136–42.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Voigtlaender M, Schneider-Merck T, Trepel M. Lapatinib. Recent Results Cancer Res. 2018;211:19–44.CrossRefPubMedGoogle Scholar
  53. 53.
    Perez EA, Koehler M, Byrne J. Cardiac safety of lapatinib: pooled analysis of 3689 patients enrolled in clinical trials. Mayo Clin Proc. 2008;83:679–86.CrossRefPubMedGoogle Scholar
  54. 54.
    Ewer MS, Lippman SM. Type II chemotherapy-related cardiac dysfunction: time to recognize a new entity. J Clin Oncol. 2005;23:2900–2.CrossRefPubMedGoogle Scholar
  55. 55.
    Bowles EJ, Wellman R, Feigelson HS. Risk of heart failure in breast cancer patients after anthracycline and trastuzumab treatment: a retrospective cohort study. J Natl Cancer Inst. 2012;104:1293–305.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Yu AF, Manrique C, Pun S. Cardiac safety of paclitaxel plus trastuzumab and pertuzumab in patients with HER2-positive metastatic breast cancer. Oncologist. 2016;21:418–24.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Truong SR, Barry WT, Moslehi JJ. Evaluating the utility of baseline cardiac function screening in early-stage breast cancer treatment. Oncologist. 2016;21:666–70.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    de Azambuja E, Ameye L, Diaz M. Cardiac assessment of early breast cancer patients 18 years after treatment with cyclophosphamide-, methotrexate-, fluorouracil- or epirubicin-based chemotherapy. Eur J Cancer. 2015;51:2517–24.CrossRefPubMedGoogle Scholar
  59. 59.
    Pinder MC, Duan Z, Goodwin JS, Hortobagyi GN, Giordano SH. Congestive heart failure in older women treated with adjuvant anthracycline chemotherapy for breast cancer. J Clin Oncol. 2007;25:3808–15.CrossRefPubMedGoogle Scholar
  60. 60.
    Cardinale D, Colombo A, Torrisi R, Sandri MT, Civelli M, Salvatici M, et al. Trastuzumab-induced cardiotoxicity: clinical and prognostic implications of troponin I evaluation. J Clin Oncol. 2010;28:3910–6.CrossRefPubMedGoogle Scholar
  61. 61.
    Guarneri V, Lenihan DJ, Valero V, Durand JB, Broglio K, Hess KR, et al. Long-term cardiac tolerability of trastuzumab in metastatic breast cancer: the M.D. Anderson Cancer Center experience. J Clin Oncol. 2006;24:4107–15.CrossRefPubMedGoogle Scholar
  62. 62.
    •• Thavendiranathan P, Abdel-Qadir H, Fischer HD, et al. Risk-imaging mismatch in cardiac imaging practices for women receiving systemic therapy for early-stage breast cancer: a population-based cohort study. J Clin Oncol. 2018;23:2018779736 Important metanalysis showing that baseline cardiac imaging is driven primarily by chemotherapy regimen rather than heart failure risk. It may help to reconcile conflicting reports on the cardiac safety or toxicity of trastuzumab and other agents in cancer patients. Google Scholar
  63. 63.
    Riccio G, Coppola C, Piscopo G, Capasso I, Maurea C, Esposito E, et al. Trastuzumab and target-therapy side effects: is still valid to differentiate anthracycline type I from type II cardiomyopathies? Hum Vaccin Immunother. 2016;12:1124–31.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Buzdar AU, Valero V, Ibrahim NK, Francis D, Broglio KR, Theriault RL, et al. Neoadjuvant therapy with paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide chemotherapy and concurrent trastuzumab in human epidermal growth factor receptor 2-positive operable breast cancer: an update of the initial randomized study population and data of additional patients treated with the same regimen. Clin Cancer Res. 2007;13:228–33.CrossRefPubMedGoogle Scholar
  65. 65.
    Ewer MS, Suter TM, Lenihan DJ, Niculescu L, Breazna A, Demetri GD, et al. Cardiovascular events among 1090 cancer patients treated with sunitinib, interferon, or placebo: a comprehensive adjudicated database analysis demonstrating clinically meaningful reversibility of cardiac events. Eur J Cancer. 2014;50:2162–70.CrossRefPubMedGoogle Scholar
  66. 66.
    Salvatorelli E, Menna P, Minotti G. Pharmacology of cardio-oncology. In: Ewer MS, Yeh ET, editors. Cancer and the Heart. Shelton: People’s Medical Publishing House, CT; 2018. (in press).Google Scholar
  67. 67.
    Menna P, Salvatorelli E, Minotti G. Cancer drugs and QT prolongation: weighing risk against benefit. Expert Opin on Drug Saf. 2017;16:1099–102.CrossRefGoogle Scholar
  68. 68.
    Moslehi JJ, Salem JE, Sosman JA, Lebrun-Vignes B, Johnson DB. Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis. Lancet. 2018;391:933.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019
corrected publication 2019

Authors and Affiliations

  • Pierantonio Menna
    • 1
  • Giorgio Minotti
    • 1
    • 2
    • 3
    Email author
  • Emanuela Salvatorelli
    • 2
  1. 1.Clinical Pharmacology UnitCampus Bio-Medico University HospitalRomeItaly
  2. 2.Department of Medicine, Unit of Drug Sciences and Center for Integrated ResearchUniversity Campus Bio-MedicoRomeItaly
  3. 3.Department of Medicine and Units of Drug Sciences and Clinical PharmacologyUniversity Campus Bio-MedicoRomeItaly

Personalised recommendations