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Journal of Clinical Oncology, Vol 23, No 31 (November 1), 2005: pp. 7775-7776 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.1558
Trastuzumab Cardiac Side Effects: Only Time Will TellJurevinski Cancer Centre and McMaster University, Hamilton, Ontario, Canada Trastuzumab, a drug targeted against the product of the Her2 neu gene, has recently become an important agent in the treatment of women with metastatic breast cancer. Subsequently, trials were then initiated with trastuzumab in the adjuvant setting, with the oncology community eagerly awaiting their results. The positive early results of three of these trials were presented in a special symposium at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005. In the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial and the North Central Cancer Treatment Group (NCCTG) 9831 trial, patients received either doxorubicin and cyclophosphamide (AC) for four cycles followed by four cycles of paclitaxel, or the same chemotherapy with weekly trastuzumab starting concurrently with paclitaxel. In a joint analysis of the two trials, the three-year disease-free survival was 87% in the trastuzumab arm compared to 75% in the control arm (hazard ratio = 0.48, P < .0001).1 There was an accompanying 33% relative risk reduction in mortality (hazard ratio = 0.67, P = .015). In the third study, the HERA trial, patients received trastuzumab every three weeks for one or two years or observation following any approved adjuvant chemotherapy regimen. The two-year disease-free survival was 86% in the trastuzumab patients who received one year of therapy compared to 77% in the control group (hazard ratio = 0.54, P < .0001).2 In the brief period of time since these results were reported, there has been rapid adoption of the drug into clinical practice and, in some instances, change in the design of existing adjuvant chemotherapy trials to permit the addition of trastuzumab. Even in Canada, which often lags behind the United States in the adoption of new anticancer drugs, adjuvant trastuzumab has already been approved for funding by provincial governments. Compared to cytotoxic chemotherapy, trastuzumab has relatively few side effects. However, it is not without any toxicity. We learned from the pivotal trial in metastatic breast cancer that there is the potential for cardiac toxicity.3 The rate of cardiac dysfunction (mainly congestive heart failure) was 27% in women who received doxorubicin plus trastuzumab and 13% (2.2% New York Heart Criteria Class III/IV) in women who received paclitaxel and trastuzumab. In this issue of the Journal of Clinical Oncology, Tan-Chiu et al report the cardiac toxicity from the adjuvant B-31 trial.4 The mechanism of cardiac toxicity due to trastuzumab is unclear. Neuregulin, a member of the epidermal growth factor family can transmit signals in cells through ErbB receptor tyrosine kinases, including ErbB2.5 The neuregulin-ErbB system is important for cardiac development. The absence of either the entire neuregulin family or the ErbB2 receptor in gene-targeted mice resulted in embryonic lethality due to cardiac defects.6 In a recent study in adult mice, ErbB2 was found to be localized at the T-tubule in cardiac muscle.7 Based on this finding, one can speculate that ErbB2 receptor signaling plays a physiologic role in cardiac function. However, how this occurs remains to be elucidated. The NSABP should be congratulated on their careful monitoring and documentation of cardiac side effects. The cardiac outcomes were established before commencing the trial and adjudicated by an independent panel. Strict eligibility criteria were applied, such that patients with a cardiac history or those with a low left ventricular ejection fraction (LVEF) after AC or an LVEF that had decreased by more than 15% from baseline could not receive trastuzumab. Serial cardiac scans were performed throughout the trial and trastuzumab was stopped if the LVEF dropped significantly according to prespecified guidelines. In reading this report, it should be kept in mind that the trial follow-up is relatively short: 27 months. The cumulative incidence of a cardiac event defined by New York Heart Criteria Class III or IV dysfunction or cardiac death was 4.1% at 3 years. In addition, 14% of patients who started trastuzumab stopped it because of an asymptomatic drop in LVEF. Hence, almost one in five patients in the trastuzumab arm of the trial experienced a cardiac-related problem. For many of the patients who developed a cardiac event, it would appear that the congestive heart failure was well controlled with medication. This may be reassuring, but their long-term clinical cardiac course is unknown and they will need close follow-up. Similarly, the clinical significance of an asymptomatic drop in LVEF is unclear. It is likely that in many patients the LVEF will return to normal, but only further follow-up will clarify this. In the analysis for factors that predicted for congestive heart failure, only post AC LVEF and age were statistically significant in the multivariate analysis. It is somewhat surprising that breast irradiation, particularly local regional radiation, did not increase the risk of cardiac dysfunction.8 However, it is possible that the follow-up is too short for any additive effects of cardiac irradiation to be manifest. The reported rate of cardiotoxicity in the HERA trial was much lower than in the B-31 trial, at less than 1%. One can only speculate on reasons for this. Perhaps the cardiac monitoring was less stringent, or perhaps the sequential administration of trastuzumab in the HERA trial—as opposed to the concurrent administration of trastuzumab with chemotherapy in the NSABP B-31 trial—played a role in the lower reported rate of cardiotoxicity. Undoubtedly, the use of trastuzumab in the adjuvant setting is a major advance in the treatment of early breast cancer. Despite the observed cardiac toxicity, overall survival was improved in these adjuvant trials. The goal of this editorialist is not to temper the excitement and enthusiasm for trastuzumab, but to pause, reflect, and perhaps introduce a note of caution. The follow-up of these trials is relatively short. Outside of clinical trials there is a tendency for there to be less stringent patient selection, management, and follow-up. So it is possible that when trastuzumab is used widely in clinical practice, the rate of cardiac dysfunction could be higher than that observed in these trials. It is unclear whether, in the long-term, cardiac dysfunction will be increased when trastuzumab is used following more intensive chemotherapy regimens than doxorubicin and cyclophosphamide followed by paclitaxel (ACT) or in association with regional radiation. Should all patients whose tumors overexpress Her2 neu be offered adjuvant trastuzumab? The NSABP B-31 trial only included node-positive patients and the North Central Cancer Treatment Group predominantly node-positive patients, with only 10% being node-negative. Her2 neu has been shown to be an independent prognostic factor in node-negative breast cancer, but the increase in risk is modest.9,10 However, one wonders whether in a node-negative patient with a small grade 1 tumor, whether the potential reduction in breast cancer recurrence would be offset by the risk of cardiac dysfunction. In the adjuvant setting, where all patients are exposed to risks of treatment, but many do not require or benefit from treatment, the introduction of new agents into general practice requires both the enthusiasm for the positive results and the watchfulness for unwanted early and late toxicities of our successes, as we have seen in the management of Hodgkin's disease and testicular cancer. It is important that women be presented with not only the benefits of trastuzumab, but also the potential risks. Until there is more long-term data on the cardiac risks of trastuzumab, it is imperative in practice to follow the stringent criteria for eligibility and cardiac monitoring used by the NSABP. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. REFERENCES 1. Romond E: Joint analysis of NSABP B-31 and NCCTG N-9831. Meetings and Education, Virtual Meeting Advances in Monoclonal Antibody Therapy for Breast Cancer (Scientific Symposium, 2005).www.asco.org 2. Piccart-Gebhart MN: HERA Trial. Meetings and Education, Virtual Meeting Advances in Monoclonal Antibody Therapy for Breast Cancer (Scientific Symposium, 2005). www.asco.org
3. 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 344:783-792, 2001
4. TanChiu E, Yothers G, Romond E, et al: Assessment of cardiac dysfunction in NSABP B-31, a randomized trial comparing doxorubicin and cyclophosphamide (AC) followed by paclitaxel to AC followed by paclitaxel plus trastuzumab as adjuvant therapy for patients with node-positive, HER2-overexpressive breast cancer. J Clin Oncol 23:7811-7819, 2005 5. Garratt AN, Ozcelik C, Birchmeier C: ErbB2 pathways in heart and neural diseases. Trends Cardiovasc Med 13:80-86, 2003[CrossRef][Medline]
6. Negro A, Brar BK, Lee KF: Essential roles of HER2/erbB2 in cardiac development and function. Recent Prog Horm Res 59:1-12, 2004
7. Ueda H, Oikawa A, Nakamura A, et al: Neuregulin receptor ErbB2 localization at T-tubule in cardiac and skeletal muscle. J Histochem Cytochem 53:87-91, 2005
8. Pierce LJ: The use of radiotherapy after mastectomy: A review of the literature. J Clin Oncol 23:1706-1717, 2005 9. Trudeau ME, Pritchard KI, Chapman J-AW, et al: Prognostic factors affecting the natural history of node-negative breast cancer. Breast Cancer Res Trt 89:35-45, 2005
10. Bull SB, Ozcelik H, Pinnaduwage D, et al: The combination of p53 mutation and neu/erbB-2 amplification is associated with poor survival in node-negative breast cancer. J Clin Oncol 22:86-96, 2004
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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