Skip to main content

Advertisement

SpringerLink
Log in

Anthracycline cardiotoxicity in breast cancer patients: synergism with trastuzumab and taxanes

  • Published:
Cardiovascular Toxicology Aims and scope Submit manuscript

Abstract

Doxorubicin is known to cause cardiomyopathy and congestive heart failure (CHF) upon chronic administration. A major obstacle to doxorubicin-containing multiagent therapies pertains to the possible development of cardiomyopathy and CHF at lower than expected cumulative doses of doxorubicin. For example, the cardiac toxicity of doxorubicin is aggravated by the anti-HER2 antibody Trastuzumab or by the tubulin-active taxane paclitaxel; however, the mechanisms by which Trastuzumab and paclitaxel aggravate doxorubicin-induced cardiotoxicity are mechanistically distinct: Trastuzumab interferes with cardiac-specific survival factors that help the heart to withstand stressor agents like anthracyclines, while paclitaxel acts by stimulating the formation of anthracycline metabolites that play a key role in the mechanism of cardiac failure. Here, we briefly review the molecular mechanisms of the cardiotoxic synergism of Trastuzumab or paclitaxel with doxorubicin, and we attempt to briefly outline how the mechanistic know-how translates into the clinical strategies for improving the safety of anthracycline-based multiagent therapies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Slamon, D. J., Leyland-Jones, B., Shak, S., Fuchs, H., Paton, V., Bajamonde, A., Fleming, T., Eiermann, W., Wolter, J., Pegram, M., Baselga, J., & Norton, L. (2001). Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. The New England journal of medicine, 344, 783–792.

    Article  PubMed  CAS  Google Scholar 

  2. Suter, T. M., Cook-Bruns, N., & Barton, C. (2004). Cardiotoxicity associated with trastuzumab (Herceptin®) therapy in the treatment of metastatic breast cancer. Breast, 13, 173–183.

    Article  PubMed  CAS  Google Scholar 

  3. Smith, I. E. (2001). Efficacy and safety of Herceptin® in women with metastatic breast cancer: Results from pivotal clinical studies. Anticancer Drugs, 12, 3–10.

    Google Scholar 

  4. Gianni, L. (2001). Tolerability in patients receiving trastuzumab with or without chemotherapy. Annals of Oncology, 12, 63–68.

    Article  Google Scholar 

  5. Perez, E. A., & Rodeheffer, R. (2004). Clinical cardiac tolerability of trastuzumab. Journal of Clinical Oncology, 22, 322–329.

    Article  PubMed  CAS  Google Scholar 

  6. Lee, K. F., Simon, H., Chen, H., Bates, B., Hung, M. C., & Hauser, C. (1995). Requirement for neuregulin receptor erbB2 in neural and cardiac development. Nature, 378, 394–398.

    Article  PubMed  CAS  Google Scholar 

  7. Crone, S. A., Zhao, Y. Y., Fan, L., Gu, Y., Minamisawa, S., Liu, Y., Peterson, K. L., Chen, J., Kahn, R., Condorelli, G., Ross, J. Jr., Chien, K. R., & Lee, K. F. (2002). ErbB2 is essential in the prevention of dilated cardiomyopathy. Nature Medicine, 8, 459–465.

    Article  PubMed  CAS  Google Scholar 

  8. Liu, F. F., Stone, J. R., Schuldt, A. J., Okoshi, K., Okoshi, M. P., Nakayama, M., Ho, K. K., Manning, W. J., Marchionni, M. A., Lorell, B. H., Morgan, J. P., & Yan, X. (2005). Heterozygous knockout of neuregulin-1 gene in mice exacerbates doxorubicin-induced heart failure. American journal of physiology. Heart and circulatory physiology, 289, H660–H666.

    Article  PubMed  CAS  Google Scholar 

  9. Sparano, J. A., & Winer, E. P. (2001). Liposomal anthracyclines for breast cancer. Seminars in Oncology, 28, 32–40.

    PubMed  CAS  Google Scholar 

  10. Harris, L., Batist, G., Belt, R., Rovira, D., Navari, R., Azarnia, N., Welles, L., Winer, E., & TLC D-99 Study Group. (2002). Liposome-encapsulated doxorubicin compared with conventional doxorubicin in a randomized multicenter trial as first-line therapy of metastatic breast carcinoma. Cancer, 94, 25–36.

    Google Scholar 

  11. Baselga, J., Climent, M. A., & Lluch, A. (2004). Results of phase II of liposomal doxorubicin (Myocet®) in combination with weekly paclitaxel and trastuzumab (Herceptin®) in patients with Her2-positive locally advanced or metastatic breast cancer (LA/MBC). European Journal of Cancer, 2(3), 132A Suppl.

    Google Scholar 

  12. Romond, E. H., Perez, E. A., Bryant, J., Suman, V. J., Geyer, C. E. Jr., Davidson, N. E., Tan-Chiu, E., Martino, S., Paik, S., Kaufman, P. A., Swain, S. M., Pisansky, T. M., Fehrenbacher, L., Kutteh, L. A., Vogel, V. G., Visscher, D. W., Yothers, G., Jenkins, R. B., Brown, A. M., Dakhil, S. R., Mamounas, E. P., Lingle, W. L., Klein, P. M., Ingle, J. N., & Wolmark, N. (2005). Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. The New England Journal of Medicine, 353, 1673–1684.

    Article  PubMed  CAS  Google Scholar 

  13. Piccart-Gebhart, M. J., Procter, J., Leyland-Jones, B., Goldhirsch, A., Untch, M., Smith, I., Gianni, L., Baselga, J., Bell, R., Jackisch, C., Cameron, D., Dowsett, M., Barrios, C. H., Steger, G., Huang, C. S., Andersson, M., Inbar, M., Lichinitser, M., Lang, I., Nitz, U., Iwata, H., Thomssen, C., Lohrisch, C., Suter, T. M., Ruschoff, J., Suto, T., Greatorex, V., Ward, C., Straehle, C., McFadden, E., Dolci, M. S., Gelber, R. D. & Herceptin Adjuvant (HERA) Trial Study Team. (2005). Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. The New England Journal of Medicine, 353, 1659–1672.

  14. Slamon, D., Eiermann, W., Robert, N., Pienkowski, T., Martin, M., Pawlicki, M., Chan, M., Smylie, M., Liu, M., Falkson, C., Pinter, T., Fornander, T., Shiftan, T., Valero, V., Mackey, J., Tabah-Fisch, I., Buyse, M., Lindsay, M. A., Riva, A., Bee, V., Pegram, M., Press, M., & Crown, J. (2005). Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC→T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC→TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2 positive early breast cancer patients: BCIRG 006 study. Breast Cancer Research and Treatment, 94, S1.

    Article  Google Scholar 

  15. Joensuu, H., Kellokumpu-Lehtinen, P. L., Bono, P., Alanko, T., Kataja, V., Asola, R., Utriainen, T., Kokko, R., Hemminki, A., Tarkkanen, M., Turpeenniemi-Hujanen, T., Jyrkkio, S., Flander, M., Helle, L., Ingalsuo, S., Johansson, K., Jaaskelainen, A. S., Pajunen, M., Rauhala, M., Kaleva-Kerola, J., Salminen, T., Leinonen, M., Elomaa, I., & Isola, J. (2006). Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. The New England Journal of Medicine, 354, 809–820.

    Article  PubMed  CAS  Google Scholar 

  16. Perez, E. A., Suman, V. J., Nancy, E., & Davidson, N. E. (2005). Exploratory analysis from NCCTG N9831: Do clinical and laboratory characteristics predict cardiac toxicity of trastuzumab when administered as a component of adjuvant therapy? Breast Cancer Research and Treatment, 94, S2038.

    Google Scholar 

  17. Tan-Chiu, E., Yothers, G., Romond, E., Geyer, C. E. Jr., Ewer, M., Keefe, D., Shannon, R. P., Swain, S. M., Brown, A., Fehrenbacher, L., Vogel, V. G., Seay, T. E., Rastogi, P., Mamounas, E. P., Wolmark, N., & Bryant, J. (2005). Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31. Journal of Clinical Oncology, 23, 7811–7819.

    Article  PubMed  CAS  Google Scholar 

  18. Ewer, M. S., Vooletich, M. T., Durand, J. B., Woods, M. L., Davis, J. R., Valero, V., & Lenihan, D. J. (2005). Reversibility of trastuzumab-related cardiotoxicity: New insights based on clinical course and response to medical treatment. Journal of Clinical Oncology, 23, 7820–7826.

    Article  PubMed  CAS  Google Scholar 

  19. Chien, K. R. (2006). Herceptin and the heart—a molecular modifier of cardiac failure. The New England Journal of Medicine, 354, 789–790.

    Article  PubMed  CAS  Google Scholar 

  20. Gianni, L., Munzone, E., Capri, G., Fulfaro, F., Tarenzi, E., Villani, F., Spreafico, C., Laffranchi, A., Caraceni, A., Martini, C., Stefanelli, M., Valagussa, P., & Bonadonna, G. (1995). Paclitaxel by 3-hour infusion in combination with bolus doxorubicin in women with untreated metastatic breast cancer: High antitumor efficacy and cardiac effects in a dose-finding and sequence-finding study. Journal of Clinical Oncology, 13, 2688–2699.

    PubMed  CAS  Google Scholar 

  21. Gianni, L., Vigano, L., Locatelli, A., Capri, G., Giani, A., Tarenzi, E., & Bonadonna, G. (1997). Human pharmacokinetic characterization and in vitro study of the interaction between doxorubicin and paclitaxel in patients with breast cancer. Journal of Clinical Oncology, 15, 1906–1915.

    PubMed  CAS  Google Scholar 

  22. D’ Incalci, M., Schuller, J., Colombo, T., Zucchetti, M., & Riva, A. (1998). Taxoids in combination with anthracyclines and other agents: Pharmacokinetic considerations. Seminars in Oncology, 25(Suppl. 13), 16–20.

    CAS  Google Scholar 

  23. Nabholtz, J. M., Falkson, C., Campos, D., Szanto, J., Martin, M., Chan, S., Pienkowski, T., Zaluski, J., Pinter, T., Krzakowski, M., Vorobiof, D., Leonard, R., Kennedy, I., Azli, N., Murawsky, M., Riva, A., & Pouillart, P. (2003). Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer: Results of a randomized, multicenter, phase III trial. Journal of Clinical Oncology, 21, 968–975.

    Article  PubMed  CAS  Google Scholar 

  24. Olson, R. D., & Mushlin, P. S. (1990). Doxorubicin cardiotoxicity: Analysis of prevailing hypotheses. The FASEB journal, 4, 3076–3086.

    PubMed  CAS  Google Scholar 

  25. Salvatorelli, E., Menna, P., Cascegna, S., Liberi, G., Calafiore, A., Gianni, L., & Minotti, G. (2006). Paclitaxel and docetaxel stimulation of doxorubicinol formation in the human heart: Implications for cardiotoxicity of doxorubicin-taxane chemotherapies. The Journal of Pharmacology and Experimental Therapeutics, 318, 424–433.

    Article  PubMed  CAS  Google Scholar 

  26. Minotti, G., Saponiero, A., Licata, S., Menna, A., Calafiore, A. M., Teodori, G., & Gianni, L. (2001). Paclitaxel and docetaxel enhance the metabolism of doxorubicin to toxic species in human myocardium. Clinical Cancer Research, 7, 1511–1515.

    PubMed  CAS  Google Scholar 

  27. Gianni, L., Baselga, J., Eiermann, W., Guillem Porta, V., Semiglazov, V., Lluch, A., Zambetti, M., Sabadell, D., Raab, G., Llombart Cussac, A., Bozhok, A., Martinez-Agullo, A., Greco, M., Byakhov, M., Lopez Lopez, J. J., Mansutti, M., Valagussa, P., & Bonadonna, G. (European Cooperative Trial in Operable Breast Cancer Study Group). (2005). Feasibility and tolerability of sequential doxorubicin/paclitaxel followed by cyclophosphamide, methotrexate, and fluorouracil and its effects on tumor response as preoperative therapy. Clinical Cancer Research, 11, 8715–8721.

  28. Martin, M., Pienkowski, T., Mackey, J., Pawlicki, M., Guastalla, J. P., Weaver, C., Tomiak, E., Al-Tweigeri, T., Chap, L., Juhos, E., Guevin, R., Howell, A., Fornander, T., Hainsworth, J., Coleman, R., Vinholes, J., Modiano, M., Pinter, T., Tang, S. C., Colwell, B., Prady, C., Provencher, L., Walde, D., Rodriguez-Lescure, A., Hugh, J., Loret, C., Rupin, M., Blitz, S., Jacobs, P., Murawsky, M., Riva, A., Vogel, C., & Breast Cancer International Research Group 001 Investigators (2005). Adjuvant docetaxel for node-positive breast cancer. The New England Journal of Medicine, 352, 2302–2313.

  29. Nabholtz, J. M., Pienkowski, T., Mackey, J., Pawlicki, M., Guastalla, J. P., Vogel, C., Weaver, C., Walley, B., Martin, M., Chap, L., Tomiak, E., Juhos, E., Guevin, R., Howell, A., Hainsworth, J., Fornander, T., Blitz, S., Gazel, S., Loret, C., & Riva, A. (2002). Phase III trial comparing TAC (docetaxel, doxorubicin, cyclophosphamide) with FAC (5-fluorouracil, doxorubicin, cyclophosphamide) in the adjuvant treatment of node positive breast cancer (BC) patients: Interim analysis of the BCIRG 001 study. Proceedings of the American Society of Clinical Oncology, 21, 141A.

    Google Scholar 

  30. Perotti, S., Cresta, G., Grasselli, G., Capri, G., Minotti, G., & Gianni, L. (2003). Cardiotoxic effects of anthracycline-taxane combinations. Expert Opinion on Drug Safety, 2, 59–71.

    Article  PubMed  CAS  Google Scholar 

  31. Gennari, A., Salvadori, B., Donati, S., Bengala, C., Orlandini, C., Danesi, R., Del Tacca, M., Bruzzi, P., & Conte, P. F. (1999). Cardiotoxicity of epirubicin/paclitaxel-containing regimens: Role of cardiac risk factors. Journal of Clinical Oncology, 17, 3596–3602.

    PubMed  CAS  Google Scholar 

  32. Pagani, O., Sessa, C., Nole, F., Crivellari, D., Lombardi, D., Thurlimann, B., Hess, D., Corner, M., Bauer, J., Martinelli, G., Graffeo, R., Zucchetti, M., D’Incalci, M., & Goldhirsch, A. (2000). Epidoxorubicin and docetaxel as first-line chemotherapy in patients with advanced breast cancer: A multicentric phase I-II study. Annals of Oncology, 11, 985–991.

    Article  PubMed  CAS  Google Scholar 

  33. Salvatorelli, E., Menna, P., Gianni, L., & Minotti, G. (2007). Defective taxane stimulation of epirubicinol formation in the human heart: Insights into the cardiac tolerability of epirubicin-taxane chemotherapies. The Journal of pharmacology and experimental therapeutics, 320, 790–800.

    Article  PubMed  CAS  Google Scholar 

  34. Sessa, C., Perotti, A., Salvatorelli, E., Minotti, G., Vigano, L., Lladò, A., Capri, G., Locatelli, A., Colombini, S., Peccatori, F., Voi, M., Marsoni, S., & Gianni, L. (2004). Phase IB and pharmacological study of the novel taxane BMS-184476 in combination with doxorubicin. European Journal of Cancer, 40, 560–570.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by Associazione Italiana Ricerca sul Cancro and Ministero dell’ Universita’ e Ricerca Scientifica e Tecnologica (MIUR) (Center of Excellence on Aging at the University of Chieti).

Author information

Authors and Affiliations

  1. Division of Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, ViaVenezian 1, Milan, 20133, Italy

    Luca Gianni

  2. Department of Drug Sciences and Center of Excellence on Aging, G. d’Annunzio University School of Medicine, Chieti, Italy

    Emanuela Salvatorelli & Giorgio Minotti

Authors
  1. Luca Gianni
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Emanuela Salvatorelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Giorgio Minotti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Luca Gianni.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gianni, L., Salvatorelli, E. & Minotti, G. Anthracycline cardiotoxicity in breast cancer patients: synergism with trastuzumab and taxanes. Cardiovasc Toxicol 7, 67–71 (2007). https://doi.org/10.1007/s12012-007-0013-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12012-007-0013-5

Keywords

Search

Navigation