HER2 Overexpression as a Predictive Marker in a Randomized Trial Comparing Adjuvant Cyclophosphamide/Methotrexate/5-Fluorouracil with Epirubicin in Patients with Stage I/II Breast Cancer: Long-Term Results

HER2 overexpression/amplification has been reported to be a predictor of prognosis in breast cancer and a potential marker for selecting the optimal adjuvant chemotherapy. HER2 expression and its interaction with treatment were retrospectively evaluated in 266 of 348 patients in a trial comparing adjuvant CMF (cyclophosphamide/methotrexate/5-fluorouracil) with weekly epirubicin in stage I/II breast cancer. HER2 expression was determined by immunohistochemistry (IHC) using the monoclonal antibody CB11. Initially, any cell showing definite membrane staining was counted, and HER2 overexpression was analyzed as a continuous variable and as a dichotomous variable, with a cutoff of > 50% of positively stained cells. Subsequently, the same slides were reanalyzed with the HercepTest®. Of the 266 tumors immunostained for HER2, 34% exhibited nearly homogeneous staining with > 50% positive cells. When the HercepTest® was applied, 8% of tumors were IHC 3+ and 8% were IHC 2+. At 8 years, no statistically significant difference in relapse-free survival (RFS) and overall survival (OS) was observed between the treatment arms in patients with low versus high HER2 overexpression, although the number of events is low. The OS was statistically shorter in patients with high HER2 overexpression in the CMF arm, whereas no difference was observed in the epirubicin arm, suggesting that patients whose cancer overexpresses HER2 could benefit more from anthracycline-based therapy. HER2 overexpression was associated with a poorer OS but not a poorer RFS. However, a Cox regression model did not confirm the prognostic role of HER2 for OS.