Cardiac safety of trastuzumab in combination with epirubicin and cyclophosphamide in women with metastatic breast cancer

Abstract

This prospective, parallel-group, dose-escalation study evaluated the cardiac safety of trastuzumab (Herceptin®) plus epirubicin/cyclophosphamide (EC) in women with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer (MBC) and determined an epirubicin dose for further evaluation. HER2-positive patients received standard-dose trastuzumab plus epirubicin (60 or 90 mg/m²)/cyclophosphamide (600 mg/m²) 3-weekly (EC60+H, n=26; EC90+H, n=25), for four to six cycles; 23 HER2-negative patients received EC alone (90/600 mg/m²) 3-weekly for six cycles (EC90). All patients underwent thorough cardiac evaluation. Two EC90+H-treated patients experienced symptomatic congestive heart failure 4.5 and 6 months after the end of chemotherapy. One EC60+H-treated patient experienced an asymptomatic decrease in left ventricular ejection fraction (LVEF) to <50% 6 months after the end of chemotherapy. No such events occurred in control patients. Asymptomatic LVEF decreases of >10% points were detected in 12 (48%), 14 (56%) and 5 (24%) patients treated with EC60+H, EC90+H, and EC90. Objective response rates with EC60+H and EC90+H were >60%, and 26% for EC90 alone. These results indicate that trastuzumab may be combined with EC with manageable cardiotoxicity and promising efficacy.

Introduction

The gene encoding the human epidermal growth factor receptor-2 (HER2, also know as c-erbB-2 or neu) is amplified and the protein overexpressed in 20–25% of breast cancers 1, 2, 3. This abnormality is associated with aggressive disease and poor prognosis 4, 5, 6. In addition to its prognostic significance, HER2 positivity may have predictive value for the likelihood of response to cyclophosphamide, methotrexate and fluorouracil, hormonal therapy, anthracyclines and taxanes 7, 8, 9.

The occurrence of HER2 amplification early in the course of breast cancer [10] and evidence that it causes malignant transformation [8] led to the development of the humanised anti-HER2 monoclonal antibody trastuzumab (Herceptin®) [11]. Trastuzumab monotherapy is active and well tolerated in women with HER2-positive metastatic breast cancer (MBC), both as first-line therapy [12] and in patients whose disease has progressed after receiving chemotherapy for MBC [13]. Treatment with trastuzumab has been shown to prolong survival from a median of 20.3–25.1 months when used in combination with chemotherapy. Furthermore, it increases the objective response rate (from 32% to 50%) and extends time to progression (4.6–7.4 months) when used first line in combination with an anthracycline plus cyclophosphamide (AC) or paclitaxel in women with HER2-positive MBC [14]. Response rate and survival duration (56% and 26.8 months, respectively) were greatest in patients treated with trastuzumab plus AC, most of whom received doxorubicin.

Based on a retrospective analysis, the combination of trastuzumab with AC was associated with a greater risk of cardiotoxicity than AC alone in this trial (27% versus 8% of patients, respectively) 14, 15. Cardiotoxicity was manifest as decreases in left ventricular ejection fraction (LVEF), with or without signs and symptoms of congestive heart failure (CHF). Cardiotoxicity was usually reversible using standard medication, and often with continued trastuzumab therapy. Prior or concomitant anthracycline exposure has been identified as the most significant risk factor for cardiotoxicity in patients receiving trastuzumab [15]. Therefore, the combination of trastuzumab with anthracyclines is not currently approved for use outside clinical trials.

Anthracyclines are very active in the treatment of breast cancer and preclinical data show that trastuzumab has additive, or even synergistic, activity in combination with a number of chemotherapeutic agents, including anthracyclines [16]. Clinical data also showed that the addition of trastuzumab to AC produced an overall survival benefit even when cardiac events are taken into account, and that most deaths were due to progressive breast cancer and not cardiac failure [17]. Patients who received doxorubicin and epirubicin in this trial were not differentiated, although it is known that the majority of patients received doxorubicin rather than epirubicin. Therefore, the combination of trastuzumab and anthracyclines, and particularly the less cardiotoxic anthracycline, epirubicin, is worthy of further investigation. Trastuzumab plus anthracyclines may potentially have a role as first-, second-, or third-line therapy, following prior adjuvant treatment with taxanes, or even in patients who relapse after a long disease-free interval following anthracycline treatment. To this end, studies exploring the use of trastuzumab with anthracyclines other than doxorubicin are in progress [18].

Epirubicin is active in primary and MBC, with similar efficacy to doxorubicin but less cardiotoxicity [19]. The aim of the present phase I/II study was to evaluate the cardiac safety of trastuzumab plus epirubicin/cyclophosphamide (EC) in patients with HER2-positive disease and to compare it with that of EC alone in a parallel cohort of patients with HER2-negative breast cancer. Results of the phase I part of this study are presented here.