Efficacy of high-dose alkylating chemotherapy in the adjuvant treatment of HER2/neu-negative primary breast cancer: update of the Dutch randomized trial

Introduction

The role of high-dose chemotherapy in the adjuvant treatment of high-dose breast cancer has not been established. Results have been reported from six randomized studies with a symmetrical study design (Table 1). All show a lower relapse rate in the high-dose arm, but in only one study was this result statistically significant.

Table 1 Randomized studies evaluating the role of high-dose chemotherapy in high-risk breast cancer

Methods

Patients below 56 years of age who had undergone surgery for stage II or III breast cancer were eligible if they had at least four tumor-positive axillary lymph nodes. Patients in the conventional dose (CD) arm received five courses of FEC (fluorouracil 500 mg/m², epirubicin 90 mg/m² and cyclophosphamide 500 mg/m²; every 3 weeks) followed by radiation therapy and tamoxifen. The high-dose (HD) arm was identical, except that high-dose chemotherapy (CTC [cyclophosphamide 6 g/m², thiotepa 480 mg/m² and carboplatin 1600 mg/m²]) with peripheral blood progenitor cell reinfusion was given instead of the fifth FEC course.

Results

Between August 1993 and July 1999, 885 patients with primary breast cancer and four or more tumor-positive lymph nodes were randomized in 10 Dutch centers in a study of high-dose chemotherapy. The results of this study at 57 months of follow-up have now been updated at 87 months. In a pathology review, 621 tumor samples were shown to be HER2/neu-negative (either 0+ at immunohistochemistry or negative at in situ hybridization). Patients with HER2/neu-negative disease had a 5-year RFS of 72% following HD and of 59% after CD (P = 0.002). Overall survival in the HD group was 78% at 5 years versus 71% for the CD group (P = 0.02). Young age and low malignancy grade were associated with a relative benefit for HD (tests for interactions: P = 0.04 and P = 0.0057, respectively). The treatment-related mortality in the high-dose chemotherapy arm was 1%. An equal number of second malignancies were observed in both arms.

Conclusion

Although the subgroup analysis of HER2/neu-negative disease was not planned in the original protocol, these findings are consistent with findings from other studies [4]. The marked efficacy of HD therapy in HER2/neu-negative breast cancer may have been masked in this and in other studies by its disadvantage in the HER2/neu-positive group, which may have benefited from a higher dose of anthracycline-dose in the control arm. High-dose alkylating chemotherapy is a viable option for high-risk breast cancer patients with HER2/neu-negative disease.