Complications of Treatment
Risk of cardiac dysfunction with trastuzumab in breast cancer patients: A meta-analysis

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Abstract

Background

Trastuzumab is used widely for the treatment of early and advanced breast cancer. However, concerns have arisen regarding its cardiac toxicity. We did a systematic review and meta-analysis of published randomized controlled trials (RCTs) to assess the overall risk of cardiac dysfunction associated with trastuzumab treatment.

Methods

We searched PubMed and Web of Science (January 1966–July 2009) and American Society of Clinical Oncology conferences held (January 2000–July 2009) for relevant articles and abstracts. Summary incidence rates, relative risks (RRs), and 95% confident intervals (CIs) were calculated using a fixed-effects or random-effects model.

Results

11,882 patients from 10 RCTs were included for analysis. The incidences of LVEF decrease and congestive heart failure (CHF) were 7.5% (95% CI 4.2–13.1) and 1.9% (95% CI 1.0–3.8) among patients receiving trastuzumab. Trastuzumab significantly increased the risk of LVEF decrease (RR = 2.13, 95% CI, 1.31–3.49; p = 0.003). In addition, it significantly increased the risk of CHF (RR = 4.19, 95% CI 2.73–6.42; p < 0.00001). The increased risk of CHF was observed in patients with early stage (RR = 4.05, 95% CI 2.49–6.58; p < 0.00001) as well as metastatic disease (RR = 4.75, 95% CI 1.93–11.71; p = 0.0007). Furthermore, trastuzumab significantly increased the risk of CHF (RR = 4.27, 95% CI 2.75–6.61, p < 0.00001) in patients receiving anthracycline-based chemotherapy, but not in patients receiving non-anthracycline chemotherapy (RR = 2.42, 95% CI 0.36–16.19, p = 0.36).

Conclusion

The addition of trastuzumab to anthracycline-based chemotherapy significantly increase the risk of cardiac dysfunction in breast cancer patients. Further studies are recommended for non-anthracycline chemotherapy.

Introduction

Human epidermal growth factor receptor type 2 (HER-2) was found to be over-expressed in approximately 20% of breast cancer patients.1 It has been shown that the amplification of HER-2 was correlated with a short survival and a high risk of recurrence.[2], [3], [4] As a humanized anti-HER2 monoclonal antibody, trastuzumab (Herceptin Inc., South San Francisco, CA) was registered by the Food and Drug Administration (FDA) in 1998, and has been widely used in treating breast cancer patients all over the world. Earlier studies had established the efficacy of trastuzumab in patients with HER-2 overexpressing breast cancer when used alone.[5], [6] Further studies showed a significant survival benefit in the treatment of early stage and metastatic disease when used in combination with anthracyclines-based chemotherapy7, paclitaxel[8], [9], [10], or with fluorouracil-based chemotherapy.11 Trastuzumab is undergoing evaluation in the treatment of other types of HER-2 overexpressing cancer including non-small cell lung cancer (NSCLC)12, ovarian or primary peritoneal carcinoma13, and prostate carcinoma.14

Common serious adverse events with trastuzumab-based treatment included neutropenia, anemia, and myalgia.15 In recent years, trastuzumab was found to be associated with cardiac toxicity (congestive heart failure, decreased left ventricular ejection fraction and/or cardiac death). In a phase III study of metastatic breast cancer by Slamon and colleagues, 10% (22 of the 234) of patients who received trastuzumab developed heart failure.16 In one recent study involving 218 metastatic breast cancer patients who received trastuzumab, 49 (28%) patients experienced a cardiac event, and 19 (10.9%) patients had grade 3 cardiac toxicity within a median follow-up of 32.6 months.17 However, the risk may vary substantially among clinical studies. In another study carried out by Gasparini et al., no difference in cardiac toxicity was detected between patients received trastuzumab plus paclitaxel and those who received paclitaxel alone.10

The cardiac risk of trastuzumab-based chemotherapy in the adjuvant therapy has been explored by three meta-analyses.[18], [19], [20] However, these studies were limited to the analysis of early-stage breast cancer. Thus, it remains unclear the overall risk of cardiac toxicity in early and advanced breast cancer patients. Therefore, we performed a systematic review of published studies, and pooled relevant randomized controlled clinical trials for a meta-analysis to determine the overall risk of cardiac events associated with trastuzumab treatment.

Section snippets

Data source

We did a comprehensive search of citations from PubMed between January, 1966, and July, 2009, using the keywords “trastuzumab”, “Herceptin”, “cancer” and “humans”. The search was limited to randomized clinical trials. Abstracts and virtual meeting presentations from the American Society of Clinical Oncology conferences (<http://www.asco.org/ASCO>) held between January 2000 and July, 2009 were also searched using the term “trastuzumab” or “herceptin” to identify relevant clinical trials. An

Search results

Our search yielded 240 clinical studies relevant to trastuzumab. After excluding review articles, phase I studies, single-arm phase II studies, case reports, meta-analyses, and observational studies (Fig. 1), we selected ten randomized clinical trials, including two phase II[9], [10] and eight phase III studies[8], [11], [16], [24], [25], [26], [27], [28], [29], [30], for the purpose of analysis (Table 1). For most studies, the patients’ number in tables and figures were extracted from the same

Discussion

The cardiac toxicity of trastuzumab had been concerned first in a retrospective analysis, the incidence of symptomatic heart failure to be approximately 9% among patients receiving trastuzumab plus paclitaxel.31 Piccart-Gebhardt et al. reported that asymptomatic LV dysfunction was found in 7.1% of patients receiving trastuzumab and 2.2% of controls, whereas CHF was encountered in 1.7% vs 0.1%, respectively. In the meta-analysis carried out by Bria et al.20, for people receiving trastuzumab more

Conflicts of interest

S.W. received honoraria from Onyx Pharmaceuticals, Novartis, and Wyeth, and a speaker for Onyx, Pfizer Inc. and Novartis.

The other authors declared no conflicts of interests.

Acknowledgement

S.W. is partially supported by the Research Foundation of SUNY. This work was also supported by the National Natural Science Foundation (No. 30973076) and Shanghai Rising-Star Program (No. 09QH1402900).

References (39)

  • D.J. Slamon et al.

    Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene

    Science

    (1987)
  • D.J. Slamon et al.

    Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer

    Science

    (1989)
  • P.M. Ravdin et al.

    The c-erbB-2 proto-oncogene as a prognostic and predictive marker in breast cancer: a paradigm for the development of other macromolecular markers – a review

    Gene

    (1995)
  • M.F. Press et al.

    HER-2/neu gene amplification characterized by fluorescence in situ hybridization: poor prognosis in node-negative breast carcinomas

    J Clin Oncol

    (1997)
  • J. Baselga et al.

    Phase II study of efficacy, safety, and pharmacokinetics of trastuzumab monotherapy administered on a 3-weekly schedule

    J Clin Oncol

    (2005)
  • C.L. Vogel et al.

    Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer

    J Clin Oncol

    (2002)
  • E.A. Perez et al.

    Effect of doxorubicin plus cyclophosphamide on left ventricular ejection fraction in patients with breast cancer in the North Central Cancer Treatment Group N9831 Intergroup Adjuvant Trial

    J Clin Oncol

    (2004)
  • H. Joensuu et al.

    Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer

    N Engl J Med

    (2006)
  • M. Marty et al.

    Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group

    J Clin Oncol

    (2005)
  • G. Gasparini et al.

    Randomized Phase II Trial of weekly paclitaxel alone versus trastuzumab plus weekly paclitaxel as first-line therapy of patients with Her-2 positive advanced breast cancer

    Breast Cancer Res Treat

    (2007)
  • A.U. Buzdar et al.

    Neoadjuvant therapy with paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide chemotherapy and concurrent trastuzumab in human epidermal growth factor receptor 2-positive operable breast cancer: an update of the initial randomized study population and data of additional patients treated with the same regimen

    Clin Cancer Res

    (2007)
  • U. Gatzemeier et al.

    Randomized phase II trial of gemcitabine–cisplatin with or without trastuzumab in HER2-positive non-small-cell lung cancer

    Ann Oncol

    (2004)
  • M.A. Bookman et al.

    Evaluation of monoclonal humanized anti-HER2 antibody, trastuzumab, in patients with recurrent or refractory ovarian or primary peritoneal carcinoma with overexpression of HER2: a phase II trial of the Gynecologic Oncology Group

    J Clin Oncol

    (2003)
  • P.N. Lara et al.

    Trastuzumab plus docetaxel in HER-2/neu-positive prostate carcinoma: final results from the California Cancer Consortium Screening and Phase II Trial

    Cancer

    (2004)
  • Genentech. Trastuzumab prescribing information. <http://www.gene.com/gene/products/information/oncology/herceptin/>...
  • D.J. Slamon et al.

    Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2

    N Engl J Med

    (2001)
  • V. Guarneri et al.

    Long-term cardiac tolerability of trastuzumab in metastatic breast cancer: the M.D. Anderson Cancer Center experience

    J Clin Oncol

    (2006)
  • I.J. Dahabreh et al.

    Trastuzumab in the adjuvant treatment of early-stage breast cancer: a systematic review and meta-analysis of randomized controlled trials

    Oncologist

    (2008)
  • G.A. Viani et al.

    Adjuvant trastuzumab in the treatment of her-2-positive early breast cancer: a meta-analysis of published randomized trials

    BMC Cancer

    (2007)

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