Elsevier

Clinical Breast Cancer

Volume 10, Issue 1, February 2010, Pages 40-45
Clinical Breast Cancer

Original Study
Pathologic Complete Response to Preoperative Sequential Doxorubicin/Cyclophosphamide and Single-Agent Taxane With or Without Trastuzumab in Stage II/III HER2-Positive Breast Cancer

https://doi.org/10.3816/CBC.2010.n.005Get rights and content

Abstract

Background

Four major clinical trials have established that trastuzumab added to adjuvant systemic chemotherapy for women with HER2+ breast cancer significantly improves disease-free and overall survival compared with chemotherapy alone. We evaluated pathologic complete response (pCR) rate and cardiac safety of preoperative doxorubicin and cyclophosphamide followed by a taxane with or without trastuzumab.

Patients and Methods

We reviewed pCR rate and change in left ventricular ejection fraction in women with operable HER2+ breast cancer (defined as immunohistochemical 3+ or fluorescence in situ hybridization ratio ≥ 2.2) who were treated between 2002 and 2008 with doxorubicin and cyclophosphamide followed by a taxane with or without trastuzumab before definitive breast surgery.

Results

We identified 33 patients, of whom 42.4% received preoperative chemotherapy without trastuzumab and 57.6% of whom received trastuzumab with chemotherapy. The pCR rates were 28.6% and 52.6% in the group that received chemotherapy alone or with trastuzumab, respectively (odds ratio, 2.78; 95% CI, 0.64-12.1; P = .173). Severe cardiac events or treatment delays as a result of cardiac toxicity were not observed. With a median follow-up time of 14 months, 21.4% of patients in the non-trastuzumab group and 10.5% in the trastuzumab group had disease recurrence.

Conclusion

Sequential administration of preoperative doxorubicin and cyclophosphamide followed by a taxane and trastuzumab combination is safe in women with primary operable HER2+ breast cancer and is associated with a high pCR rate. Large randomized phase III clinical trials are evaluating the role of preoperative trastuzumab when added to anthracycline- and/or taxane-based regimens.

Introduction

HER2 (also known as HER2/neu and ErbB2) is a 185-kD transmembrane tyrosine kinase receptor that regulates cell growth, survival, adhesion, migration, differentiation, and other cellular responses.1, 2 HER2 signaling promotes cell proliferation through the mitogen-activated protein kinase pathway and enhances cell survival via the phosphatidylinositol 3-kinase/AKT (PI3K/AKT) pathway.3 Overexpression or amplification of HER2 is reported in 20%–30% of invasive breast cancers. It is historically associated with aggressive disease and poor overall survival (OS). Trastuzumab is a recombinant humanized monoclonal antibody directed against HER2. The emergence of trastuzumab has drastically revolutionized therapy for women with HER2-positive (HER2+) breast cancer. The initial phase II trials that investigated single-agent trastuzumab in metastatic breast cancer demonstrated response rates of 12% and 35% in the pretreated and first-line settings, respectively.4, 5, 6 The pivotal randomized clinical trial of trastuzumab in combination with chemotherapy demonstrated an improvement in time to disease progression (7.4 months vs. 4.6 months; P < .001), objective response rate (50% vs. 32%; P < .001), and median survival (25.1 months vs. 20.3 months; P = .046) compared with chemotherapy alone.7 Several subsequent studies have confirmed the efficacy and relative safety of trastuzumab in combination with most chemotherapy agents.8, 9, 10, 11, 12, 13, 14, 15 Cardiac dysfunction, which is the foremost concerning toxicity of trastuzumab, has been reported in ≤ 27% of patients treated concurrently with anthracyclines and 0.4%–1% of women on taxane-based regimens.16, 17, 18

Based on its robust activity in the advanced setting, 4 major international studies of adjuvant trastuzumab were initiated: the Herceptin Adjuvant (HERA) trial, the National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-31, the North Central Cancer Treatment Group (NCCTG) trial N9831, and the Breast Cancer International Research Group (BCIRG) 006 trial. All 4 studies demonstrated a marked improvement in disease- or recurrence-free and overall survival favoring the trastuzumab-containing regimens compared with chemotherapy alone.19, 20, 21, 22 Therefore, the incorporation of trastuzumab in the adjuvant therapy of women with early-stage HER2+ breast cancer should always be considered. A cardiac toxicity rate of ≤ 4.1% was reported in the trastuzumab-containing arms of these adjuvant studies.23

Neoadjuvant or preoperative chemotherapy has been used in women with stage II or III breast cancer to downstage the tumor and increase the opportunity for breast-conserving surgeries. Moreover, the administration of preoperative chemotherapy can serve as an in vivo test of treatment sensitivity17 as indicated by determining the pathologic complete response (pCR), a surrogate marker for long-term disease-free survival.24

Although several studies have evaluated concurrent chemotherapy and trastuzumab in the preoperative setting, none evaluated a sequential doxorubicin and cyclophosphamide regimen followed by paclitaxel and trastuzumab.25, 26, 27, 28 The purposes of this retrospective review of data were to evaluate the pCR rate in women with HER2+ breast cancer who received doxorubicin and cyclophosphamide followed by a taxane with or without trastuzumab in the preoperative setting and to assess the incidence of cardiac toxicity in this setting.

Section snippets

Patients and Methods

In 2001, we initiated an algorithm for the multidisciplinary management of preoperative therapy at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins for women with clinical stage II and III breast cancer in concordance with recommendations from an International Expert Panel (Figure 1).29 From May 2002 to May 2005, women with HER2+ disease who were candidates for preoperative chemotherapy received doxorubicin and cyclophosphamide and a single-agent taxane. Following the publication

Patient Characteristics

Between May 2002 and August 2008, we identified a total of 39 women who received preoperative therapy for stage II or III HER2+ breast cancer. Six women who did not receive sequential AC and taxane–based therapy were not included in the analysis. Of the 33 patients who we included in this analysis, 14 women (42.4%) received preoperative chemotherapy without trastuzumab, and 19 women (57.6%) received therapy that included AC and concurrent taxane and trastuzumab. Patient characteristics are

Discussion

The purpose of this retrospective study was to determine the efficacy by means of pCR rate and cardiac safety of incorporating trastuzumab with taxanes following AC in the preoperative setting. In this study, we observed a trend toward a higher pCR rate among patients who received trastuzumab-containing therapy compared with patients receiving chemotherapy alone (52.6% vs. 28.6%, respectively; P = .173). The administration of trastuzumab with taxane after AC was well tolerated without

Conclusion

Our study suggests that trastuzumab should be incorporated in the preoperative treatment of women with HER2+ disease. A larger randomized phase III clinical trial, NSABP-B41, is currently ongoing to evaluate pCR rate with the administration of AC followed by weekly paclitaxel in combination with either trastuzumab plus lapatinib, trastuzumab, or lapatinib in the preoperative setting for patients with palpable and operable HER2+ breast cancer (NCT00486668). Several key questions need to be

Disclosures

Antonio C. Wolff and Leisha A. Emens have received research funding from Genentech, Inc. All other authors report no conflicts of interest.

References (37)

  • I Smith et al.

    2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomized controlled trial

    Lancet

    (2007)
  • V Guarneri et al.

    Preoperative chemotherapy plus lapatinib or trastuzumab or both in HER2-positive operable breast cancer (CHERLOB Trial)

    Clin Breast Cancer

    (2008)
  • AL Schechter et al.

    The neu oncogene: an erb-B-related gene encoding a 185,000-Mr tumour antigen

    Nature

    (1984)
  • Y Yarden

    The EGFR family and its ligands in human cancer. signalling mechanisms and therapeutic opportunities

    Eur J Cancer

    (2001)
  • Y Yarden et al.

    Untangling the ErbB signalling network

    Nat Rev Mol Cell Biol

    (2001)
  • MA Cobleigh et al.

    Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease

    J Clin Oncol

    (1999)
  • J Baselga et al.

    Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer

    J Clin Oncol

    (1996)
  • CL 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)
  • DJ Slamon et al.

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

    N Engl J Med

    (2001)
  • HJ Burstein et al.

    Trastuzumab and vinorelbine as first-line therapy for HER2-overexpressing metastatic breast cancer: multicenter phase II trial with clinical outcomes, analysis of serum tumor markers as predictive factors, and cardiac surveillance algorithm

    J Clin Oncol

    (2003)
  • S Chia et al.

    Pegylated liposomal doxorubicin and trastuzumab in HER-2 overexpressing metastatic breast cancer: a multicenter phase II trial

    J Clin Oncol

    (2006)
  • FJ Esteva et al.

    Phase II study of weekly docetaxel and trastuzumab for patients with HER-2-overexpressing metastatic breast cancer

    J Clin Oncol

    (2002)
  • M Jahanzeb et al.

    Phase II trial of weekly vinorelbine and trastuzumab as first-line therapy in patients with HER2(+) metastatic breast cancer

    Oncologist

    (2002)
  • 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)
  • J O'Shaughnessy et al.

    Phase II trial of gemcitabine plus trastuzumab in metastatic breast cancer patients previously treated with chemotherapy: preliminary results

    Clin Breast Cancer

    (2002)
  • MD Pegram et al.

    Combination therapy with trastuzumab (Herceptin) and cisplatin for chemoresistant metastatic breast cancer: evidence for receptor-enhanced chemosensitivity

    Semin Oncol

    (1999)
  • N Robert et al.

    Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer

    J Clin Oncol

    (2006)
  • CA Hudis

    Trastuzumab–mechanism of action and use in clinical practice

    N Engl J Med

    (2007)
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