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Originally published as JCO Early Release 10.1200/JCO.2006.09.1611 on July 23 2007 © 2007 American Society of Clinical Oncology. Trastuzumab-Associated Cardiac Adverse Effects in the Herceptin Adjuvant Trial
From the Swiss Cardiovascular Center, University Hospital Bern; F. Hoffmann-La Roche, Basel, Switzerland; Frontier Science, Kincraig, Kingussie, Scotland; Department of Cardiology, University of Groningen, Groningen; Department of Medical Oncology, Daniel den Hoed Cancer Center/Erasmus MC, Rotterdam, the Netherlands; Kardiologische Praxis, Munich; Cardiology Wilhelm-Marx-Haus and Krankenhaus Gerresheim, Duesseldorf; Department of Cardiology, University Hospital Hamburg-Eppendorf, Germany; Department of Oncology, Karolinska Institute and University Hospital, Stockholm, Sweden; Department of Molecular and Clinic Endocrinology and Oncology, Università Federico II, Napoli; Division of Medical Oncology, Istituti Ospitalieri, Cremona; Medical Oncology, National Cancer Institute, Genoa, Italy; Cancer Research UK Clinical Centre Leeds; St James's University Hospital, Leeds, United Kingdom; Cardiology Research Complex, Moscow, Russia; National Institute of Oncology, Budapest, Hungary; Aichi Cancer Center Hospital, Nagoya, Japan; Medical University of Vienna, Austria; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA; and the Department of Medicine and Breast International Group, Jules Bordet Institute, Université Libre de Bruxelles, Brussels, Belgium Address reprint requests to Thomas M. Suter, MD, Swiss Cardiovascular Center, University Hospital Bern, Inselspital, CH-3010 Bern, Switzerland; e-mail: thomas.suter{at}insel.ch
Purpose The purpose of this analysis was to investigate trastuzumab-associated cardiac adverse effects in breast cancer patients after completion of (neo)adjuvant chemotherapy with or without radiotherapy.
Patients and Methods The Herceptin Adjuvant (HERA) trial is a three-group, multicenter, open-label randomized trial that compared 1 or 2 years of trastuzumab given once every 3 weeks with observation in patients with HER-2–positive breast cancer. Only patients who after completion of (neo)adjuvant chemotherapy with or without radiotherapy had normal left ventricular ejection fraction (LVEF Results Data were available for 1,693 patients randomly assigned to 1 year trastuzumab and 1,693 patients randomly assigned to observation. The incidence of trastuzumab discontinuation due to cardiac disorders was low (4.3%). The incidence of cardiac end points was higher in the trastuzumab group compared with observation (severe congestive heart failure [CHF], 0.60% v 0.00%; symptomatic CHF, 2.15% v 0.12%; confirmed significant LVEF drops, 3.04% v 0.53%). Most patients with cardiac dysfunction recovered in fewer than 6 months. Patients with trastuzumab-associated cardiac dysfunction were treated with higher cumulative doses of doxorubicin (287 mg/m2 v 257 mg/m2) or epirubicin (480 mg/m2 v 422 mg/m2) and had a lower screening LVEF and a higher body mass index. Conclusion Given the clear benefit in disease-free survival, the low incidence of cardiac adverse events, and the suggestion that cardiac dysfunction might be reversible, adjuvant trastuzumab should be considered for treatment of breast cancer patients who fulfill the HERA trial eligibility criteria.
The human epidermal growth factor receptor 2 (HER-2/erbB2) is expressed in the adult myocardium and plays an important role in the modulation of anthracycline-associated cardiotoxicity.1-3 Trastuzumab benefits patients with metastatic breast cancer and improves disease-free and overall survival after adjuvant chemotherapy.4-6 However, trastuzumab treatment is also associated with congestive heart failure and cardiac dysfunction.7-9 In the Herceptin Adjuvant (HERA) trial, we therefore prospectively monitored cardiac function in all patients and report herein the cardiac safety data from this trial.
Study Design The HERA trial was a three-group, multicenter, open-label, phase III randomized trial involving women with HER-2–positive early-stage invasive breast cancer who completed locoregional therapy and a minimum of four cycles of a standard (neo)adjuvant chemotherapeutic regimen plus radiotherapy if indicated. The patients were randomly assigned to the following three groups: women who had observation only; those adjuvantly treated with trastuzumab (first dose 8 mg per kilogram of body weight, then 6 mg per kilogram every 3 weeks) for 1 year; and those treated with trastuzumab at the same dose and on the same schedule for 2 years. The primary end point was disease-free survival and secondary end points included cardiac safety, overall survival, time to recurrence, and time to distant recurrence. An interim efficacy analysis after 475 disease-free survival events showed a highly significant improvement of disease-free survival for patients who were randomly assigned to both 1 and 2 years of trastuzumab compared with the observation group. The independent data monitoring committee recommended release of the 1-year trastuzumab versus observation results. The detailed efficacy results for 1-year trastuzumab versus observation with a median follow-up period of 1 year were published.4 All patients adhered to the same schedule of follow-up visits. To ensure comparability in both groups, patients in whom trastuzumab treatment was stopped prematurely were asked to attend all planned remaining study visits, if possible.
Eligibility Criteria
Cardiac Eligibility Criteria
Cardiac Monitoring
Definitions
Discontinuation of Trastuzumab and Dose Modification
Statistical Analysis The clinical cutoff date for this analysis was March 29, 2005. Data were available for 3,386 patients randomly assigned between December 2001 and March 2005: 1,693 were randomly assigned to observation and 1,693 patients were randomly assigned to 1 year of trastuzumab. The safety population groups were defined by whether a patient received trastuzumab before disease recurrence. There were 19 patients randomly assigned to the 1-year trastuzumab group who did not receive any trastuzumab before disease recurrence and four patients randomly assigned to observation who received at least one dose of trastuzumab. Therefore, there were 1,678 patients in the trastuzumab safety analysis population group and 1,708 patients in the observation safety analysis population group. The difference in incidence of cardiac adverse events between safety analysis population groups was compared with an approximate 95% CI for the difference of two incidences using the Hauck-Anderson correction.10 The mean cumulative dose of chemotherapy agents was compared among patients with and without any cardiac end points in the trastuzumab safety analysis population group using a t-test assuming equal variances. The incidence of any cardiac end point was estimated for the trastuzumab safety analysis population group according to potential cardiac risk factors.
Patient Characteristics The demographic characteristics of patients in the two safety analysis population groups with respect to age, race (white, 84% v 83%), menopausal status (postmenopausal, 45% in both groups), smoking habits (smoker, 14% v 13%), previous or active cardiovascular diseases (22% v 23%), hypertension (17% in both groups), diabetes (3% in both groups), and previous radiotherapy (received radiotherapy, 77% v 76%) were balanced in both groups. The mean age (± standard deviation) of patients in the two groups was 49 ± 10 years. Patients received a minimum of four cycles of adjuvant (89%), neoadjuvant (5%), or both (6%) types of chemotherapy. The (neo)adjuvant chemotherapy was anthracycline based in 94% of patients, and in addition, 26% received taxanes. The median time between finishing any type of chemotherapy and start of trastuzumab treatment was 89 days.
Cardiac End Points
Recovery After a Cardiac End Point Of the 10 patients in the trastuzumab group with severe CHF, eight were asymptomatic at the last scheduled assessment on December 15, 2005 (Table 3). A patient's LVEF was considered recovered from a cardiac end point if the patient had an LVEF of  55% at any time after the cardiac end point until December 15, 2005. As presented in Table 3, six of 10 patients with severe CHF recovered their LVEF in a median of 124 days (range, 36 to 409 days). Among the 36 patients with symptomatic CHF, 24 patients recovered their LVEF in a median of 151 days (range, 26 to 831 days) and among the 51 patients with a confirmed significant LVEF drop, 35 patients recovered in a median of 191 days (range, 13 to 831 days).
Cumulative Dose of Chemotherapy Agents The mean cumulative dose of chemotherapy agents cyclophosphamide, doxorubicin, epirubicin, docetaxel, and paclitaxel was calculated for patients who had reached a cardiac end point and patients who did not reach a cardiac end point (Table 4). The mean cumulative dose among patients with a cardiac end point was significantly higher for doxorubicin (287 mg/m2 v 257 mg/m2) and epirubicin (480 mg/m2 v 422 mg/m2). There were four patients treated with paclitaxel who developed a cardiac end point. The mean cumulative dose of paclitaxel showed a trend to a higher dose among patients with a cardiac end point that was not significant and was based on small numbers.
Potential Cardiac Risk Factors Several potential cardiac risk factors were analyzed, as presented in Table 5. The potential risk factors that were considered at baseline were screening LVEF, history of cardiac disease, CHF, coronary artery disease, previous radiotherapy, hypertension, high body mass index, low body mass index, current smoker, hyperlipidemia, diabetes mellitus, hyperthyroidism, hypothyroidism, and age. The incidence of any type of cardiac end point among patients with the risk factor was compared with the incidence of any type of cardiac end point among patients without the risk factor for the trastuzumab group. Patients with a screening LVEF of 55%  LVEF < 60% had a significantly higher incidence of cardiac end points than patients with a higher screening LVEF 60% (6.90% v 2.72%; 95% CI for the difference in incidence, 1.33% to 7.02%). Patients with a screening LVEF of 60% LVEF < 65% had significantly higher incidence of cardiac end points than patients with a higher screening LVEF 65% (3.89% v 1.88%; 95% CI for the difference in incidence, 0.02% to 4.01%). It is to be expected that patients with a lower screening LVEF have a higher incidence of cardiac end points. Patients with a high body mass index (> 25) had a significantly higher incidence of cardiac end points than patients with a body mass index in the normal range (20 BMI 25). Patients with a risk factor of hypertension, current smoker, diabetes, hypothyroidism, or age 60 showed a trend to a higher incidence of cardiac end points that was not significant. There are small numbers of patients (< 60) with the following risk factors: CHF, coronary artery disease, and diabetes mellitus, leading to wide CIs. It was not possible to consider metabolic syndrome as a potential risk factor as only one patient had been diagnosed with this condition.
Cumulative Incidence The cumulative incidence for cardiac death or severe CHF (Fig 1A), cardiac death, severe CHF or symptomatic CHF (Fig 1B), and any cardiac end point (Fig 1C) were calculated and are displayed along with the competing risk of a disease-free survival event.11 The median follow-up for patients was 12 months.
HER signaling plays an important role in modulating myocardial response to chemotherapy-induced injury and inhibition of the HER-2/erbB2 receptor worsens anthracycline-associated cardiotoxicity.1,12 Early clinical experience with trastuzumab in the pivotal trials indicated a high potential for cardiotoxicity.6 To ensure safety for patients in the HERA trial, we therefore applied an algorithm for discontinuation of trastuzumab in individual patients based on periodic LVEF assessment and we carefully monitored cardiac symptoms and function in all patients. Cardiac events were infrequent in the HERA trial. No cardiac deaths occurred in the trastuzumab group and the rate of severe heart failure was < 1%. Trastuzumab treatment was discontinued because of cardiac dysfunction for 4.3% of patients. The comparison with other trials is complicated by the fact that different definitions of cardiac end points, eligibility criteria, and treatment regimens were used. For example, the investigators of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial defined a cardiac event as a probable/definite cardiac death or NYHA III/IV CHF, confirmed by the cardiac review panel, which was blinded to treatment.9 In the HERA trial, to meet the definition of severe CHF, NYHA III/IV CHF was confirmed by a local, unblinded cardiologist and a significant LVEF drop was required. The eligibility criteria of the NSABP B-31 trial stated that a patient must not begin treatment with trastuzumab if the patient's LVEF was below the institution's lower limit of normal (which is most often an LVEF > 49%) or the patient's LVEF after anthracyclines or cyclophosphamide was at least 15% below baseline. Furthermore, the treatment regimen in the NSABP B-31 trial combined paclitaxel with weekly trastuzumab in the first 4 weeks after four cycles of anthracyclines or cyclophosphamide whereas in the HERA trial once every 3weeks trastuzumab was given after a median time of 89 days after completion of chemotherapy. However, despite these complications, comparing the incidence of severe CHF in the treatment groups, the incidence in the HERA trial (0.6%) appears noticeably lower than in the NSABP B-31 (3.6%). The percent of patients who prematurely discontinued trastuzumab because of cardiac dysfunction was 4.3% in HERA compared with 15.6% (133 of 850) in NSABP B-31.
It may also be possible to compare the incidence of left ventricular (LV) dysfunction in the two trials. The NSABP B-31 reports the cumulative incidence of asymptomatic cardiac dysfunction, defined as at least once a drop in LVEF An important feature of trastuzumab-associated cardiotoxicity might be reversibility of symptoms and LV dysfunction.13,14 As of the last scheduled visit in December 15, 2005, 80% of patients with severe CHF were asymptomatic. Sixty percent had a recovery of their LV dysfunction to at least 55% as of December 15, 2005. For patients with severe CHF whose LV dysfunction recovered, the median time to recovery was fewer than 6 months. A similar percentage of patients with symptomatic CHF or confirmed significant LVEF drops had a recovery of the LV function. It remains possible that with longer follow-up time a higher incidence of LV dysfunction recovery would be observed. Continued follow-up is required to determine long-time cardiac prognosis in these patients. In the HERA trial, the patients who had a cardiac end point received a significantly higher dose of epirubicin and doxorubicin than the patients without. As in other trials, we found that patients with a lower screening LVEF had a significantly higher incidence of a cardiac end point. However, unlike the investigators in the NSABP B-31, we found no evidence of older patients being at greater risk for trastuzumab-associated cardiac dysfunction.8 In contrast to the retrospective analysis of the pivotal trials in metastatic breast cancer, we found no evidence that previous cardiac disease, hyperlipidemia, or hypertension was a risk factor for a cardiac end point. Of interest is that patients with a high body mass index have a significantly higher incidence of a cardiac end point. However, it is important to remember that analysis of potential risk factors are exploratory based on a small number of cardiac end points. The cumulative incidence functions shown in Figure 1 illustrate that the benefit of trastuzumab in terms of reducing the risk of a disease-free survival event is greater than the increased risk of cardiac adverse effects even within the first year of follow-up. In addition, the benefit appears to increase into the second year of follow-up while the cumulative incidence of any type of cardiac end point appears stable after completion of trastuzumab at 12 months.
Limitations In conclusion, given the clear benefit in disease-free survival of 1-year trastuzumab, the low incidence of cardiac end points, and the suggestion that cardiac dysfunction may be reversible, adjuvant trastuzumab should be considered a standard treatment option for patients who fulfill the HERA trial eligibility criteria.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. 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: Susanne Muehlbauer, F. Hoffmann-La Roche Ltd Leadership: N/A Consultant: Thomas M. Suter, F. Hoffmann-La Roche, Basel, Switzerland; Jonas Bergh, Roche; Timothy Perren, F. Hoffmann-La Roche; Martine J. Piccart, GlaxoSmithKline Stock: N/A Honoraria: Thomas M. Suter, F. Hoffmann-La Roche, Basel, Switzerland; Jonas Bergh, Roche; Timothy Perren, F. Hoffmann-La Roche; Claudia Bighin, Novartis, Dompè Bioetich; Michael Gnant, AstraZeneca, Novartis, Sanofi-Aventis, Roche, Pfizer; Martine J. Piccart, F. Hoffman LaRoche Research Funds: Thomas M. Suter, F. Hoffmann-La Roche, Basel, Switzerland; Jonas Bergh, Roche; Timothy Perren, F. Hoffmann-La Roche; Juergen Groetz, Pfizer; Michael Gnant, AstraZeneca, Novartis, Sanofi-Aventis; Richard D. Gelber, Roche; Martine J. Piccart, Pfizer Testimony: N/A Other: N/A
Conception and design: Thomas M. Suter, Jonas Bergh, Rodolfo Passalacqua, Jan GM Klijn, Richard D. Gelber, Martine J. Piccart Provision of study materials or patients: Jonas Bergh, Chiara Carlomagno, Timothy Perren, Claudia Bighin, Jan GM Klijn, Fail T. Ageev, Erika Hitre, Hiroji Iwata, Michael Gnant, Martine J. Piccart Collection and assembly of data: Claudia Bighin, Jan GM Klijn, Fail T. Ageev, Erika Hitre, Juergen Groetz, Hiroji Iwata, Malgorzata Knap, Susanne Muehlbauer, Alison Spence Data analysis and interpretation: Thomas M. Suter, Marion Procter, Dirk J. van Veldhuisen, Michael Muscholl, Susanne Muehlbauer, Richard D. Gelber, Martine J. Piccart Manuscript writing: Thomas M. Suter, Marion Procter, Richard D. Gelber Final approval of manuscript: Thomas M. Suter, Dirk J. van Veldhuisen, Michael Muscholl, Jonas Bergh, Chiara Carlomagno, Timothy Perren, Rodolfo Passalacqua, Claudia Bighin, Jan GM Klijn, Fail T. Ageev, Erika Hitre, Juergen Groetz, Hiroji Iwata, Malgorzata Knap, Michael Gnant, Alison Spence, Richard D. Gelber, Martine J. Piccart Other: Thomas M. Suter [Chair of the Cardiac Advisory Board], Timothy Perren [Coordination of United Kingdom Yorkshire Breast Cancer Group contribution to the HERA trial]
We thank the women who participated in the HERA study. Participating groups and investigators and further acknowledgments are listed in Piccart-Gebhart MJ et al: N Engl J Med 353:1659-1672, 2005.
published online ahead of print at www.jco.org on July 23, 2007. Supported by F. Hoffmann-La Roche (Roche), Basel, Switzerland. Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Sawyer DB, Zuppinger C, Miller TA, et al: Modulation of anthracycline-induced myofibrillar disarray in rat ventricular myocytes by neuregulin-1beta and anti-erbB2: Potential mechanism for trastuzumab-induced cardiotoxicity. Circulation 105:1551-1554, 2002 2. Zhao YY, Sawyer DR, Baliga RR, et al: Neuregulins promote survival and growth of cardiac myocytes: Persistence of ErbB2 and ErbB4 expression in neonatal and adult ventricular myocytes. J Biol Chem 273:10261-10269, 1998 3. 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] 4. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al: Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353:1659-1672, 2005 5. Romond EH, Perez EA, Bryant J, et al: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673-1684, 2005 6. 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 7. Cook-Bruns N: Retrospective analysis of the safety of Herceptin immunotherapy in metastatic breast cancer. Oncology 61:58-66, 2001 (suppl 2)[CrossRef][Medline] 8. Suter TM, Cook-Bruns N, Barton C: Cardiotoxicity associated with trastuzumab (Herceptin) therapy in the treatment of metastatic breast cancer. Breast 13:173-183, 2004[CrossRef][Medline] 9. 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 10. Hauck W, Anderson S: A comparison of large-sample confidence interval methods for the difference of two binomial probabilities. American Statistician 4:318-322, 1986 11. Gray RJ: A class of K-sample tests for comparing the cumulative incidence of a competing risk. Annals of Statistics 16:1141-1154, 1988[CrossRef] 12. Crone SA, Zhao YY, Fan L, et al: ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat Med 8:459-465, 2002[CrossRef][Medline] 13. Ewer MS, Vooletich MT, Durand J-B, et al: Reversibility of trastuzumab-related cardiotoxicity: new insights based on clinical course and response to medical treatment. J Clin Oncol 23:7820-7826, 2005 14. Ewer MS, Lippman SM: Type II chemotherapy-related cardiac dysfunction: Time to recognize a new entity. J Clin Oncol 23:2900-2902, 2005 Submitted October 17, 2006; accepted May 1, 2007.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
