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