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Originally published as JCO Early Release 10.1200/JCO.2005.04.9551 on August 14 2006 © 2006 American Society of Clinical Oncology. Long-Term Cardiac Tolerability of Trastuzumab in Metastatic Breast Cancer: The M.D. Anderson Cancer Center Experience
From the Departments of Breast Medical Oncology, Cardiology, Biostatistics and Applied Mathematics, The University of Texas M.D. Anderson Cancer Center, Houston, TX Address reprint requests to Francisco J. Esteva, Department of Breast Medical Oncology, Unit 1354, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: festeva{at}mdanderson.org
Purpose: To evaluate the cardiac safety of long-term trastuzumab therapy in patients with human epidermal growth receptor 2 (HER2) –overexpressing metastatic breast cancer (MBC) treated at The University of Texas M.D. Anderson Cancer Center (Houston, TX). Patients and Methods: Among 218 MBC patients treated with trastuzumab-based therapy for at least 1 year, 173 patients were assessable for cardiac toxicity. Cardiac events (CEs) were defined as follows: asymptomatic decrease of left ventricular ejection fraction (LVEF) below 50%; decrease of 20 percentage points in LVEF compared with the baseline; or signs or symptoms of congestive heart failure (CHF). Results: The median cumulative time for trastuzumab administration was 21.3 months. The median follow-up was 32.6 months (range, 11.8 to 79.0 months). Forty-nine patients (28%) experienced a CE: three patients (1.7%) had an asymptomatic decrease in the LVEF of 20 percentage points, 27 patients (15.6%) experienced grade 2 cardiac toxicity, and 19 patients (10.9%) experienced grade 3 cardiac toxicity. All but three patients had improved LVEF or symptoms of CHF with trastuzumab discontinuation and appropriate therapy. There was one cardiac-related death (0.5%). Baseline LVEF was significantly associated with CE (hazard ratio, 0.94; P = .001). The hazard of a CE among patients taking concomitant taxanes was higher early in the follow-up period but declined during the course of follow-up. Conclusion: The risk of cardiac toxicity of long-term trastuzumab-based therapy is acceptable in this population, and this toxicity is reversible in the majority of the patients. In patients who have experienced a CE, additional treatment with trastuzumab can be considered after recovery of cardiac function.
Human epidermal growth receptor 2 (HER2) is a transmembrane tyrosine kinase that plays a critical role in cellular growth and differentiation. The HER2 gene is amplified in 20% to 25% of human breast cancers, and this feature is associated with poor clinical outcome.1,2 Trastuzumab (Herceptin; Genentech Inc, South San Francisco, CA), a humanized anti-HER2 monoclonal antibody, was developed as a specific targeted therapy against HER2-overexpressing invasive breast carcinomas, and it selectively binds the extracellular domain of HER2.3 Phase II and III trials have demonstrated efficacy of trastuzumab in patients with HER2-positive metastatic breast cancer, as a single agent as well as in combination with chemotherapy.4-7 In particular, when combined with chemotherapy, the use of trastuzumab is associated with an improvement in the overall response rate, time to progression, and overall survival compared with chemotherapy alone.6,8 Since the approval by the US Food and Drug Administration in September 1998, trastuzumab has become an essential part in the treatment of breast cancer patients whose tumors overexpress HER2 or exhibit HER2 gene amplification. Trastuzumab therapy is usually well tolerated. However, the use of trastuzumab, and in particular its combination with anthracyclines, resulted in an unexpected high incidence of cardiac toxicity.6 The exact pathogenesis of trastuzumab-induced cardiac damage is still unclear. In preclinical studies, it has been demonstrated that HER2 plays a crucial role in the embryonic cardiogenesis, and that HER2 signaling is essential for the prevention of dilated cardiomyopathy.9,10 The cardiac dysfunction associated with trastuzumab has several differences from the better characterized cardiac toxicity induced by anthracyclines. Generally, anthracycline cardiotoxicity is cumulative, dose dependent, predominantly irreversible, and associated with specific myocardial damage (vacuolization and loss of contractile elements) evidenced by light microscopy on cardiac biopsies.11-14 The cardiac damage induced by trastuzumab does not appear to be dose dependent and it is largely reversible.15,16 However, the cardiac safety of trastuzumab represents a relevant clinical issue not only for patients with metastatic breast cancer, but the long-term use of trastuzumab may have important implications in the adjuvant setting.
Patient Selection Patients were selected through a search of two databases maintained by the Department of Pharmaceutical Policy and Outcomes Research (Division of Pharmacy) and the Department of Breast Medical Oncology at The University of Texas M.D. Anderson Cancer Center (MDACC; Houston, TX). We identified 548 metastatic breast cancer patients treated with trastuzumab from 1998 to December 2003. Among this group, 218 patients received trastuzumab at MDACC for 1 year or longer. The Institutional Review Board approved the retrospective review of the medical records for this analysis.
Cardiac Evaluation Patients who experienced a significant decrease in their LVEF and patients who developed cardiac symptoms were evaluated by a cardiologist. Trastuzumab was discontinued in patients who developed CHF or asymptomatic decrease in LVEF below 40%. In the other cases, the decision of continuing trastuzumab was considered carefully on a patient-by-patient basis, and the risks and potential benefits of trastuzumab therapy were discussed accurately with the patient and with the cardiologist. For patients who recovered their cardiac function after discontinuation of trastuzumab (and appropriate cardiac therapy), the risks and benefits of re-treatment with trastuzumab were evaluated carefully with the cardiologist and discussed with the patients.
Statistical Analysis Time to CE was measured from the start of trastuzumab use to the date of first CE or the date of last follow-up. Median follow-up was calculated as the median observation time among assessable patients. Time to CE was described by a Kaplan-Meier curve and the 95% CI. The association between each parameter and CE was estimated with a Cox proportional hazards model. We conducted an additional analysis to describe the hazard (ie, instantaneous risk) of CEs among patients who received concomitant taxanes and trastuzumab, and in particular to discriminate between paclitaxel and docetaxel. Hazard rates were smoothed using standard kernel methods that were modified to deal with multistate data. To estimate the variance of the hazard rates we generated 1,000 bootstrap samples and calculated the 2.5%, 50%, and 97.5% quantiles of the hazard rate at each time.21 Hazards relative to trastuzumab alone were estimated for each bootstrap sample by dividing the estimated hazard of each state by the estimated hazard of trastuzumab alone.
One hundred seventy-three patients were assessable. Median age at the start of trastuzumab use was 50 years (range, 26 to 79 years) and median cumulative time receiving trastuzumab was 21.3 months (range, 11.6 to 77.6 months). Approximately 62% of patients received trastuzumab consecutively during only one period throughout the course of their treatment; however, the remaining patients received trastuzumab at up to four different times. Median time from the last anthracycline administration to the start of trastuzumab use was 14.5 months (range, 0 to 181.9 months). Patient characteristics overall and by CE group are summarized in Table 1. Sixty-three percent of patients received concomitant vinorelbine and 84% received concomitant taxanes (Table 2). The median number of LVEF measurements was five (range, two to 22 measurements). Median follow-up was 33.6 months (range, 11.8 to 79.0 months); 49 patients (28%) experienced a CE.
According to the criteria adopted by Seidman et al,19 53 patients experienced a CE: New York Heart Association class I, 44 patients; class II, three patients; class III, four patients; and class IV, two patients. No substantial differences in the distribution of patient characteristics were seen as compared with patients with a CE according to the criteria used in the clinical practice in our institution. In addition, inference regarding risk factors for CE was not appreciably different using the Seidman's criteria19 (data not shown). Because an important part of this study is related to the clinical management of cardiac toxicity, we present the data obtained by classifying CE according to the clinical practice of the MDACC. Figure 1 shows the Kaplan-Meier curve of time to first CE and the 95% CIs. CE-free survival was 87.3% (95% CI, 82.5% to 92.4%), 71.5% (95% CI, 64.6% to 79.2%), and 63.0% (95% CI, 53.2% to 74.7%) at 1, 3, and 5 years, respectively. Three patients (1.7%) experienced an asymptomatic decrease in the LVEF of 20 percentage points, 27 patients (15.6%) experienced a grade 2 cardiac toxicity (LVEF range, 40% to 50%) in absence of cardiac symptoms), and 19 patients (10.9%) experienced a grade 3 cardiac toxicity (symptoms of CHF; or LVEF range, 20% to 40%). Among patients with grade 3 toxicity, 13 patients had asymptomatic decrease of LVEF below 40%, four patients had symptoms of CHF with LVEF more than 40%, and two patients were diagnosed with CHF despite normal LVEF. One of these patients died with CHF (Table 3). Overall, only 15 patients of the 49 diagnosed with cardiac toxicity were symptomatic at the time of diagnosis.
Cardiac Recovery Among the 15 symptomatic patients, 14 discontinued trastuzumab, and 11 recovered with specific cardiac therapy (beta blockers with or without angiotensin-converting enzyme inhibitors); one patient recovered quickly with specific cardiac therapy, and trastuzumab was not discontinued. Three patients did not recover despite standard therapy for CHF, and among these patients there was the one patient who died with CHF. Among the 34 asymptomatic patients, trastuzumab was discontinued in 17 patients: 15 patients recovered completely after trastuzumab discontinuation, with or without specific cardiac therapy. In two of 17 patients, additional assessment of LVEF was not available; however, they did not experience any cardiac symptoms. Trastuzumab was not discontinued in 17 of 34 asymptomatic patients: 13 patients recovered completely without specific cardiac therapy, and two patients recovered completely with specific cardiac therapy. In two patients, additional assessment of LVEF was not available; however, they did not experience any cardiac symptoms while receiving trastuzumab therapy. After complete recovery of cardiac function, and after careful evaluation of potential risks and benefits, 26 patients were re-treated with trastuzumab; 16 patients did not experience additional cardiac toxicity, whereas 10 patients experienced subsequent CEs. Among these 10 patients, five recovered completely after trastuzumab discontinuation; five patients maintained a slightly reduced LVEF without symptoms, and trastuzumab was continued along with careful periodic cardiac evaluations. Endomyocardial biopsy was performed in three patients who experienced a CE. On light microscopy evaluation there was no evidence of structural damage, including loss of contractile elements or necrosis. However, additional evaluation using electron microscopy showed evidence of focal vacuolar changes, pleomorphic mitochondria, myocardial cell hypertrophy, and mild interstitial fibrosis (Fig 2). These ultrastructural changes are consistent with a reversible cardiomyopathy.
Risk Factors Among the 49 patients who experienced a CE, 44 experienced their CE while receiving trastuzumab. Thirty-six patients experienced a CE during their first treatment period of trastuzumab, after a median time on trastuzumab of 7.8 months (range, 1.3 to 40.9 months). Another eight patients experienced a CE during their second treatment period of trastuzumab, after a median cumulative time receiving trastuzumab (including the first period) of 16.0 months (range, 6.1 to 29.9 months). Median time between the first and second interval among these eight patients was 8.9 months (range, 3.6 to 40.0 months). Five patients experienced their CEs after their first treatment period with trastuzumab had ended. Among these patients, the median duration of their first period of trastuzumab use had been 13.8 months (range, 9.2 to 23.4 months), and the median time without trastuzumab was 7.7 months (range, 0.2 to 11.4 months). Among these five patients, one developed the CE after receiving additional subsequent chemotherapy with capecitabine, gemcitabine, and liposomal doxorubicin, and one developed the CE after receiving high-dose chemotherapy with peripheral stem-cell transplantation. Table 4 shows the estimated hazard ratios of a CE for other prognostic variables after adjustment for trastuzumab use. The time from the last anthracycline administration was marginally significantly associated with risk of CE (P = .051). However, the estimated effect was close to 1, suggesting a small decrease in the hazard of CE for every month increase in the interval.
Concomitant Taxanes Thirty-one patients experienced their CEs while receiving trastuzumab alone, 10 patients experienced their CEs while receiving concomitant trastuzumab and paclitaxel, three patients experienced their CEs while receiving concomitant trastuzumab and docetaxel, and five patients experienced their CEs while receiving neither trastuzumab nor a taxane. Because no patients experienced a CE while receiving a taxane alone, the hazard of CE is not presented for these two states. Estimates are presented out to only 25 months because data beyond this point, especially in the concomitant states, were scarce. At the start of follow-up, 62 patients were receiving trastuzumab alone, 58 patients were receiving concomitant trastuzumab and paclitaxel, and 53 patients were receiving concomitant trastuzumab and docetaxel. Figure 3 shows the 2.5%, 50%, and 97.5% quantiles of the hazard rates from the bootstrap samples. Figure 4 shows the hazard ratios of concomitant trastuzumab and taxanes, and neither trastuzumab nor a taxane versus trastuzumab alone.
Relative to trastuzumab alone, the hazard of CE among patients receiving concomitant taxanes is higher early in the follow-up period and declines during the course of follow-up. The hazard of CE for trastuzumab alone increases during the course of follow-up. Because no patients experienced a CE while receiving a taxane alone, we cannot estimate the hazard of concomitant trastuzumab and taxanes relative to taxanes alone, and therefore, we cannot address whether the combination is safe compared with a taxane alone.
Trastuzumab represents the standard of care for HER2-positive metastatic breast cancer patients.6 In response to the exciting results reported recently in the neoadjuvant and adjuvant settings,22-25 the large majority of patients with HER2-positive tumors will receive trastuzumab therapy. In the metastatic setting, the risk of developing cardiac impairment is largely counterbalanced by the benefit of trastuzumab26,27; however, this toxicity might represent a major concern for patients with early-stage breast cancer.28,29 Therefore, it is important to define the long-term risk of cardiac toxicity and the impact of other risk factors on the cardiac safety of trastuzumab therapy. After a median follow-up of 33.6 months, and a median time receiving trastuzumab of 21.3 months, the overall incidence of cardiac dysfunction was 28% (grade 3, 10.9%). This figure is as high as that reported in the pivotal trial in association with anthracycline6; however, in our opinion this is not surprising, in view of the significant percentage of patients with a known positive history for cardiac disease (4% to 5%), prior exposure to anthracyclines (85%), the prolonged exposure to trastuzumab (median, 21.3 months), and the overall exposure to multiple regimens of chemotherapy and hormonal therapy. This is an accurate representation of clinical practice in that patients have other important comorbidities placing them at risk for cardiotoxicity. Furthermore, as the treated population ages, these considerations will be more relevant. Identifying and treating cardiac risk factors will become a paramount treatment paradigm. Another important issue, which is still a matter of debate, is the optimal method to evaluate treatment-induced cardiac toxicity.15 Interestingly, two patients in our analysis developed CHF (in one case with radiographic evidence of pulmonary edema) with normal LVEF. These data suggest that the evaluation of systolic function may not be sufficient for predicting or diagnosing cardiac impairment in this population. The clinical utility of other tests is under investigation; for example, the evaluation of the cardiac troponin or B-type natriuretic peptide certainly seems promising as an easy, reproducible noninvasive screening tool.30-32 Three patients with evidence of cardiac dysfunction underwent endomyocardial biopsy. As reported previously, we found no evidence of myocardial damage on light microscopy.15,16 However, electron microscopy evaluation revealed evidence of a toxic cardiomyopathy. These patients were treated with beta blockers and angiotensin-converting enzyme inhibitors on trastuzumab discontinuation and fully recovered their LVEF, suggesting that the pathologic changes induced by trastuzumab are reversible with medical therapy. Although the number of patients studied is small, light microscopy may not be sensitive enough to detect myocardial damage. Additional ultrastructural changes associated with trastuzumab-induced cardiac toxicity can be identified using electron microscopy. The baseline value of LVEF was significantly associated with the hazard ratio for CE, and this finding is in line with that already described in the National Surgical Adjuvant Breast and Bowel Project B-31 trial, and emphasizes the importance of an assessment of cardiac function before beginning therapy with trastuzumab, particularly after anthracycline exposure.29 Our analysis failed to show any association between age, prior exposure to radiation therapy, exposure to anthracycline, or exposure to high-dose chemotherapy with peripheral stem-cell transplantation and increased risk of developing cardiac toxicity with trastuzumab. However, the lack of association might be the result of the limited sample size of this analysis. Eighty-five percent of the patients had received doxorubicin before trastuzumab; however, the median cumulative dose of doxorubicin was 300 mg/m2, suggesting that the use of trastuzumab after exposure to a cumulative dose of doxorubicin below 300 to 400 mg/m2 was not associated with an increase in cardiac risk. In the pivotal phase III trial of chemotherapy with and without trastuzumab,6 the incidence of cardiac dysfunction was 13% for patients receiving paclitaxel and trastuzumab and 1% for patients receiving paclitaxel alone. However, it should be noted that these patients had received anthracyclines in the adjuvant setting before treatment with paclitaxel and trastuzumab. In our analysis, the hazard of CE among patients receiving concomitant taxanes was higher early in the follow-up period and declined during the course of follow-up, whereas the hazard of CE for trastuzumab alone increased during the course of follow-up. However, a potential limitation of our analysis is that when the estimates approach zero, the quantiles of the bootstrapped estimates also approach zero, and therefore underestimate the true variance. Therefore, the risk of cardiotoxicity associated with concomitant trastuzumab and taxanes administration needs to be investigated further. We acknowledge the potential selection bias derived from evaluating patients treated for at least 1 year, thus excluding those patents with early events or patients who were unable to tolerate trastuzumab for at least 1 year. However, although retrospective in nature, we believe our data can be useful in daily practice. Patients included in clinical trials evaluating the safety and efficacy of trastuzumab-based therapies often are not representative of the population commonly seen in clinical practice because many patients do not meet the eligibility criteria of the protocol. Furthermore, clinical trials adhere to strict rules for treatment discontinuation in the setting of cardiac toxicity. This analysis offers an overview of the cardiac effects of prolonged trastuzumab therapy in actual practice of treating a metastatic breast cancer population. Furthermore, all of the patients were evaluated carefully by the same group of cardiologists, and all evaluations (clinical assessment, echocardiography, and/or multiple-gated acquisition scans) were performed at a single institution. This ensures uniformity in the evaluation and management of these patients. Finally, it offers a suggestion for the possible management of trastuzumab-related cardiac dysfunction that does not exclude the possibility of maintaining or re-treating with trastuzumab if no other acceptable therapeutic options are available.
The authors indicated no potential conflicts of interest.
Conception and design: Valentina Guarneri, Gabriel N. Hortobagyi, Francisco J. Esteva Collection and assembly of data: Valentina Guarneri, Daniel J. Lenihan, Kenneth R. Hess, Laura Boehnke Michaud, Gabriel N. Hortobagyi, Francisco J. Esteva Data analysis and interpretation: Valentina Guarneri, Daniel J. Lenihan, Vicente Valero, Jean-Bernard Durand, Kristine Broglio, Laura Boehnke Michaud, Ana M. Gonzalez-Angulo, Gabriel N. Hortobagyi, Francisco J. Esteva Manuscript writing: Valentina Guarneri, Daniel J. Lenihan, Vicente Valero, Jean-Bernard Durand, Laura Boehnke Michaud, Ana M. Gonzalez-Angulo, Gabriel N. Hortobagyi, Francisco J. Esteva Final approval of manuscript: Daniel J. Lenihan, Ana M. Gonzalez-Angulo, Gabriel N. Hortobagyi, Francisco J. Esteva
We thank Shu-Wan Kau for assistance with data management.
published online ahead of print at www.jco.org on August 14, 2006 Supported in part by the Nellie B. Connally Breast Cancer Research Fund. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Ann Oncol 13:710-715, 2002 31. Snowden JA, Hill GR, Hunt P, et al: Assessment of cardiotoxicity during haemopoietic stem cell transplantation with plasma brain natriuretic peptide. Bone Marrow Transplant 26:309-313, 2000[CrossRef][Medline] 32. Auner HW, Tinchon C, Linkesch W, et al: Prolonged monitoring of troponin T for the detection of anthracycline cardiotoxicity in adults with hematological malignancies. Ann Hematol 82:218-222, 2003[Medline] Submitted November 16, 2005; accepted May 25, 2006. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
