HER-2 and topo-isomerase II alpha as predictive markers in a population ofnode-positive breast cancer patients randomly treated with adjuvant CMF orepirubicin plus cyclophosphamide

Background: The predictive role of HER-2 in node-positive breast cancer pat ients receiving CMF or an anthracycline-based adjuvant therapy remains uncl ear. In addition, topo-isomerase II alpha (topo II alpha), as the cellular target of anthracyclines, might have value as a predictive marker. Patients and methods: Four hundred eighty-one archival primary tumor sample s were collected among 777 patients entered into a multicenter phase III tr ial comparing classical CMF with epirubicin-cyclophosphamide (HEC) as adjuv ant therapy of node-positive breast cancer. HER-2 was evaluated by immunohi stochemistry (IHC) using different antibodies (Abs). Topo II alpha was eval uated by IHC using the Ab KiS 1. In each subgroup of patients identified by HER-2 and topo II alpha, adjusted hazard ratios for event-free survival (E FS) and the corresponding 95% confidence intervals have been calculated for the different study comparisons. An interaction test has been performed to investigate the role of HER-2 and topo II alpha as predictive markers. Results: When HER-2 was evaluated by CB-11 and 4D5 mAbs, the EFS adjusted h azard ratios (HR) for the main study comparison HEC vs. CMF were: HER-2 pos itive: 0.33 (95% confidence interval (95% CI): 0.09-1.27, P = 0.08), HER-2 negative: 1.16 (95% CI: 0.71-1.90, P = 0.56); the P-value for the interacti on test was 0.10. When HER-2 was evaluated by TAB-250 + pAb1 Abs, the adjus ted HR for the same comparison were: HER-2 positive: 1.06 (95% CI: 0.45-2.5 2, P = 0.90), HER-2 negative: 0.99 (95% CI: 0.58-1.68, P = 0.97); the P-val ue for the interaction test was 0.84. With regard to topo II alpha, the adj usted HR for the EFS comparison HEC vs. CMF were: topo II alpha positive: 0 .66 (95% CI: 0.32-1.36, P = 0.25), topo II alpha negative: 1.26 (95% CI: 0. 63-2.50, P = 0.51); the P-value for the interaction test was 0.13. Conclusions: This study suggests that in node-positive breast cancer patien ts randomly treated with CMF or an epirubicin-based regimen, the predictive value of HER-2 may vary according to the Abs used in the immunohistochemis try assay. In addition, the study supports the concept that topo II alpha m ight be involved in the determination of tumor responsiveness to an anthrac ycline-based adjuvant therapy.