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Trastuzumab (Herceptin®) is a humanized monoclonal antibody that binds to the extracellular domain of human epidermal growth factor receptor (EGFR) 2 (HER-2), which is overexpressed and/or amplified in 20–30% of breast cancers.These tumors, without systemic treatment, show a more aggressive behaviour. In the metastatic breast cancer setting, in the subgroup of patients with tumors that overexpress HER-2, trastuzumab has proven to be an active drug both as a single agent and in combination with chemotherapy, modifying the natural history of these tumors even if approximately one out of two patients obtains a clinical response. Based on these results trastuzumab has been utilized in adjuvant trials. Recently, the results of five adjuvant trials have been reported, showing a 50% reduction of the relative risk of recurrence.The design of these trials is shown in Table 1.
Two of these trials have been carried out in the USA and are the North American Surgical Adjuvant Breast and Bowel Project (NSABP) B31 and the North Central Cancer Treatment Group (NCCTG) N9831 trials. The first one is a two-arm trial comparing four courses of doxorubicin and cyclophosphamide (AC) followed by four courses of three weekly paclitaxel with or without trastuzumab. The second is a three-arm trial exploring two different modalities of trastuzumab administration with weekly paclitaxel (concurrent versus sequential at the end of chemotherapy) after four courses of AC.The National Cancer Institute (NCI) and the US Food and Drug Administration (FDA) approved a joint analysis of the two similar arms in the two studies whose results have been reported. Two other large trials have enrolled patients from different countries and are the Herceptin Adjuvant (HERA) trial, where trastuzumab was administered for 0, one or two years every three weeks at the end of chemotherapy (any) and radiotherapy if required and the Breast Cancer International Research Group (BCIRG) 006 trial, which is a three-arm trial evaluating 4 courses of AC followed by four courses of docetaxel with or without trastuzumab and a regimen not containing anthracyclines with carboplatin and docetaxel for six courses given concurrently with trastuzumab.
The fifth trial is a small Finnish trial (FinHer), where trastuzumab is randomly administered concurrently with docetaxel or vinorelbine for only nine weeks and before three courses of fluorouracil, epirubicin, and cyclophosphamide (FEC).A total of 13,352 patients have been enrolled; however, about 3,000 patients (those enrolled in the two-year arm of trastuzumab in the HERA trial and those in the sequential arm in the NCCTG N9831 trial) have not been included in this analysis.There are several differences among the five trials: the definition of high-risk node-negative patients that were eligible in all trials except in the NSABP B31; the definition of HER-2 status; the modalities of administering chemotherapy and trastuzumab (concurrent or sequential) and radiation therapy and trastuzumab (concurrent or at the end); the type of chemotherapy (i.e. only 26% of patients in the HERA trial received taxane-based regimens); the duration (from nine weeks to two years) and the schedule (weekly or three-weekly) of trastuzumab administration. In all trials half of the enrolled patients were younger than 50 years and had hormonal receptor-positive tumors. The proportion of node-negative patients was low in the NCCTG N9831 trial (5.7%) and in the FinHer trial (16%), while it represented about a third of patients in the HERA and BCIRG 006 trials.