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

Abstract

Purpose: Findings from our previously published phase III randomized trial showed a high pathologic complete remission (CR) rate in patients with human epidermal growth factor receptor 2^positive breast cancer after the concurrent administration of trastuzumab and paclitaxel, followed by concurrent trastuzumab and 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) preoperative chemotherapy. The safety and efficacy data of initial population were updated, with inclusion of additional experience with the same therapy. Study Design: The initial randomized study population of 42 patients were randomly assigned to either four cycles of paclitaxel followed by four cycles of FEC or to the same chemotherapy with simultaneous weekly trastuzumab for 24 weeks. All data were updated through November 2005. Results: Pretreatment characteristics of the initial patients and of the second cohort were similar. In the second cohort, pathologic CR rate was 54.5% (95% confidence interval, 32.2-75.6%) and the pathologic CR rate among all patients treated with chemotherapy plus trastuzumab was 60% (95% confidence interval, 44.3-74.3%). Three patients in the chemotherapy only group have recurred, and one has died. There has been no recurrences in the patients randomized to chemotherapy plus trastuzumab, and the estimated disease-free survival at 1 and 3 years was 100% (P = 0.041). In additional cohort treated with chemotherapy and trastuzumab at the median followup of16.3 months, no patients had recurred. No new safety concerns were observed in this study. Conclusion: Our expanded cardiac safety data and the updated efficacy data showed that the natural history of this subset of breast cancer patients can be substantially modified by this treatment approach.Findings from our previously published phase III randomized trial showed a high pathologic complete remission (CR) rate in patients with human epidermal growth factor receptor 2 (HER2) -positive breast cancer after the concurrent administration of trastuzumab and paclitaxel, followed by concurrent 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) preoperative chemotherapy (1).Since these findings were published, the efficacy of trastuzumab as adjuvant therapy has been well established (2 -4). In the adjuvant setting, trastuzumab has reduced the risk for recurrence and has favorably affected the survival rate in patients with HER2-positive breast cancer. In addition, findings in patients with metastatic disease and other experimental findings have suggested that the concomitant administration of trastuzumab and chemotherapy is superior to the sequential administration of these therapies (5 -7). Preliminary unplanned data analyses of one prospective clinical trial (NCCTG-N9831) addressing the optimal timing of trastuzumab, in relation to chemotherapy, suggest the superiority of concomitant chemotherapy and trastuzumab over sequential use of the same therapies.1 However, the optimal time to

Trastuzumab‐based neoadjuvant therapy in patients with HER2‐positive breast cancer

“…A third, open-label, nonrandomized cohort (n ¼ 22) was added to the study, and all of those patients were assigned to the trastuzumab arm. 31 The combined pCR rate for the randomized and open-label trastuzumab arms was 60%, which was considerably greater than the rate in the chemotherapy-alone arm (26.3%). Both the 1-year DFS rate (100% vs 94.7% in the chemotherapy with trastuzumab and chemotherapy-alone arms, respectively) and the 3-year DFS rate (100% vs 85.3%, respectively) improved with the addition of trastuzumab.…”

“…27 The Role of Trastuzumab in Neoadjuvant Therapy Several trials have examined the potential benefits of neoadjuvant trastuzumab combined with chemotherapeutic agents in patients with HER2-positive tumors and have reported pCR rates of up to 67%. [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44] The encouraging data published from clinical trials to date resulted in a recommendation by the National Comprehensive Cancer Network for the use of neoadjuvant paclitaxel plus trastuzumab followed by 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) plus trastuzumab 45 based on data reported by Buzdar et al 23 Phase 3 Studies Three phase 3 neoadjuvant studies have investigated the use of trastuzumab with various chemotherapy regimens.…”

“…Both the 1-year DFS rate (100% vs 94.7% in the chemotherapy with trastuzumab and chemotherapy-alone arms, respectively) and the 3-year DFS rate (100% vs 85.3%, respectively) improved with the addition of trastuzumab. 31 The addition of trastuzumab to neoadjuvant therapy had a minimal effect on the rate of breast-conserving therapy (BCT) performed (52.6% and 56.5% of patients in the chemotherapy alone and chemotherapy with trastuzumab arms, respectively). 23 Trastuzumab-based therapies have been associated with an increased incidence of cardiac dysfunction (CD).…”

“…In the extended study with longer follow-up in the original cohort (36.1 months; range, 12.3-54.8 months), no patients who received trastuzumab plus chemotherapy experienced CD. 31 In the initial study, a decrease in left ventricular (LV) ejection fraction (LVEF) !10 percentage points was observed in 5 patients (26%) in the chemotherapy-alone arm and in 7 patients (30%) in the chemotherapy plus trastuzumab arm. The LVEF returned to baseline levels for all but 1 of these patients, whose LVEF remained in the low normal range.…”

Cardiotoxicity From Human Epidermal Growth Factor Receptor‐2 (HER2) Targeted Therapies

“…In the HERA and PHARE (Protocol for Herceptin as Adjuvant therapy with Reduced Exposure) trials, longer duration of therapy was associated with higher rates of cardiotoxicity 12, 38, 39. Rates of cardiotoxicity appear to be similar when trastuzumab is added to chemotherapy containing epirubicin as opposed to doxorubicin 40, 41, 42, 43. In a meta‐analysis of adjuvant trastuzumab trials published by the Cochrane group in 2012, there were 135 cases (2.5%) of HF of 5471 patients in the trastuzumab groups compared with 20 cases (0.4%) of 4810 in the control groups, yielding a statistically significant relative risk of 5.1 for development of HF in patients treated with the monoclonal antibody.…”