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Journal of Clinical Oncology, Vol 26, No 12 (April 20), 2008: pp. 2053-2054 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.5838
In ReplyDepartment of Cardiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
Frontier Science, Kincraig, Kingussie, Scotland
Department of Medicine and Breast International Group, Jules Bordet Institute, Université Libre de Bruxelles, Brussels, Belgium Montemurro et al report their experience of trastuzumab-associated early cardiac adverse effects in the adjuvant and metastatic setting, and we await the full report of the cardiac events observed in these patients. The presently available data from the different adjuvant breast cancer trials indicate that several factors increase the likelihood of trastuzumab-associated early cardiac dysfunction.1,2 However, as discussed in our paper, the comparison of the incidence of these adverse effects across trials is difficult. The comparison to cardiac safety among patients treated with trastuzumab outside clinical trials is complicated by the fact that patients receiving trastuzumab outside clinical trials may not meet the cardiac eligibility criteria for a clinical trial.
Regardless of these limitations, the careful analysis of the design and definitions used in the adjuvant trastuzumab trials might help to further shed some light on the issue. Focusing on the two trials that have published their cardiac adverse effects so far,1,2 there are significant differences in the design of the trials (Table 1). We agree with Montemurro et al that the cardiovascular risk of trastuzumab in National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial appears to be higher than in the Herceptin Adjuvant (HERA) trial. Factors which might explain this finding include (1) a lower left ventricular ejection fraction (LVEF) before trastuzumab treatment in NSABP B-31, (2) a shorter time between chemotherapy and initiation of trastuzumab in NSABP B-31, (3) the combination of paclitaxel and trastuzumab in NSABP B-31, and (4) the different definition used for cardiac dysfunction. A lower LVEF before trastuzumab treatment already has been identified as a risk factor for treatment-associated cardiac dysfunction in the individual trials.1,2 The NSABP B-31 used an LVEF of greater than the lower limit of normal for the institution (which usually is
In summary, multiple factors affect the rate of cardiac dysfunction in patients with breast cancer treated with trastuzumab. The differences in discontinuation between the adjuvant and metastatic group of patients reported by Montemurro et al may be related to prior anthracycline exposure. Other investigators found that an anthracycline-based chemotherapeutic regimen increases the risk of trastuzumab-associated cardiac dysfunction8 and evidence from preclinical data offer an explanation for this finding.5 However, for physicians treating patients with trastuzumab, it is important to understand that not only chemotherapeutic choices but also timing of the drugs used may affect the cardiovascular adverse effects. Montemurro et al also suggest that efforts should be made to maximize the group of patients who are able to complete the intended adjuvant trastuzumab treatment safely, and we agree that this is vitally important. In order to accomplish this, the cardiologic and oncologic communities will need further understanding of the mechanisms of cancer drug associated cardiovascular adverse effects, as well as a consensus of how we should recognize and define such events. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Thomas M. Suter, Hoffmann-La Roche Ltd (C); Martine J. Piccart, GlaxoSmithKline (C) Stock Ownership: None Honoraria: Thomas M. Suter, Hoffmann-La Roche Ltd; Martine J. Piccart, GlaxoSmithKline Research Funding: Thomas M. Suter, Hoffmann-La Roche Ltd Expert Testimony: None Other Remuneration: None
REFERENCES
1. Suter TM, Procter M, van Veldhuisen DJ, et al: Trastuzumab-associated cardiac adverse effects in the herceptin adjuvant trial. J Clin Oncol 25:3859-3865, 2007 2. Tan-Chiu E, Yothers G, Romond E, et al: 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. J Clin Oncol 23:7811-7819, 2005 3. Hess OM, Carroll JD: Assessment of normal and abnormal cardiac function, in Libby P, Bonow RO, Mann DL, et al (eds): Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine (ed 8). Philadelphia, PA, Saunders, Elsevier, 2008, pp 561-581 4. Chien KR: Herceptin and the heart–a molecular modifier of cardiac failure. N Engl J Med 354:789-790, 2006 5. Timolati F, Ott D, Pentassuglia L, et al: Neuregulin-1 beta attenuates doxorubicin-induced alterations of excitation-contraction coupling and reduces oxidative stress in adult rat cardiomyocytes. J Mol Cell Cardiol 41:845-854, 2006[CrossRef][Medline] 6. Sharma AB, Sun J, Howard LL, et al: Oxidative stress reversibly inactivates myocardial enzymes during cardiac arrest. Am J Physiol Heart Circ Physiol 292:H198-206, 2007 7. Pentassuglia L, Timolati F, Seifriz F, et al: Inhibition of ErbB2/neuregulin signaling augments paclitaxel-induced cardiotoxicity in adult ventricular myocytes. Exp Cell Res 313:1588-1601, 2007[CrossRef][Medline] 8. Slamon D, Eiermann W, Robert N, et al: BCIRG 006: 2nd interim analysis phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (ACT) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (ACTH) with docetaxel, carboplatin and trastuzumab (TCH) in Her-2/neu positive early breast cancer patients. 29th San Antonio Breast Cancer Symposium San Antonio, TX, 2006
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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50%) and a drop of less than 15 percentage points after anthracyclines as an eligibility criterion prior for trastuzumab treatment. It is important to realize that an LVEF of less than 55%, at least when measured by echocardiography, is slightly reduced (normal range for LVEF, 55% to 75%).
