Safety and Efficacy of Neo-adjuvant Sequential Dose-Dense Chemotherapy Doublets Combined with Trastuzumab in Patients with HER-2-Positive Early Stage Breast Cancer

Abstract

the management of early breast cancer. This strategy is indicated in patients with locally advanced breast cancer and has shown to increase the rate of breastconserving surgery. Neo-adjuvant chemotherapy is also an excellent in vivo chemosensitivity test that enables the rapid and direct assessment of tumor response, allowing the testing of new drug treatments for patients with early stages of the disease. Likewise, pathologic complete response (pCR) is a powerful predictor of both prolonged disease-free and overall survival (1-4).The aim of the present study was to evaluate the efficacy, measured as pCR rate and safety of dose-dense chemotherapy doublets (sequential treatment of cyclophosphamide and epirubicin followed by paclitaxel and gemcitabine) combined with the targeted agent trastuzumab as neo-adjuvant treatment in patients diagnosed with stage II and III breast cancer, including inflammatory disease, with HER-2 overexpression (3+ by immunohistochemistry or fluorescence in situ hybridization-positive). pCR was defined as the absence of invasive tumor in the breast. Patients with only carcinoma in situ were also considered to have pCR.Treatment consisted of a first sequence with epirubicin 90 mg ⁄ m 2 (15-minute infusion) and cyclophosphamide 600 mg ⁄ m 2 (30-minute infusion) for a total of three cycles and a second sequence with paclitaxel 150 mg ⁄ m 2 (3-hour infusion) and gemcitabine 2,500 mg ⁄ m 2 (60-minute infusion) to a total of six cycles. All drugs were administered intravenously on day one every 2 weeks with prophylactic growth factor support (5 days of subcutaneous injections per course). Weekly trastuzumab was administered at a dose of 2 mg ⁄ kg (infusion 60 minutes) (loading dose of 4 mg ⁄ kg, 90-minute infusion), concomitantly with paclitaxel and gemcitabine to a total of 12 doses. Subsequently, they underwent surgery and received radiotherapy and ⁄ or adjuvant hormonal therapy according to physician criteria. A tru-cut biopsy was performed before treatment for the assessment of biologic markers (hormone receptors, HER2 status, Ki-67 labeling index, and p53 levels).A total of 20 patients with early stage breast cancer were enrolled in the study. Baseline patient characteristics are summarized in Table 1. All patients achieved clinical response after treatment and 50% (95% CI: 28.1-71.8%) had a pCR that is in agreement with other reports of preoperative treatment in similar groups of patients with HER2-positive breast cancer (range of pCR rates: 47-65%) although none of the previous studies included patients with T4 lesions, including inflammatory disease (5,6). It should be noted, however, that three of these patients had in situ residual disease in the breast. After a median followup of 18.2 months, three patients had progressed. Patients with less differentiated tumors and high proliferative index were more likely to achieve a pathologically complete response (Table 2). Despite the high rate of pCR, a high proportion of patients underwent radical surgery (55%) because of the initial large t...