HER-2 and topo-isomerase IIα as predictive markers in a population of node-positive breast cancer patients randomly treated with adjuvant CMF or epirubicin plus cyclophosphamide

Background: The predictive role of HER-2 in node-positive breast cancer patients receiving CMF or an anthracycline-based adjuvant therapy remains unclear. 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 samples were collected among 777 patients entered into a multicenter phase III trial comparing classical CMF with epirubicin-cyclophosphamide (HEC) as adjuvant therapy of node-positive breast cancer. HER-2 was evaluated by immunohistochemistry (IHC) using different antibodies (Abs). Topo II alpha was evaluated 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 (EFS) 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 hazard ratios (HR) for the main study comparison HEC vs. CMF were: HER-2 positive: 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 interaction test was 0.10. When HER-2 was evaluated by TAB-250 + pAb1 Abs, the adjusted HR for the same comparison were: HER-2 positive: 1.06 (95% CI: 0.45-2.52, P = 0.90), HER-2 negative: 0.99 (95% CI: 0.58-1.68, P = 0.97); the P-value for the interaction test was 0.84. With regard to topo II alpha, the adjusted 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 patients randomly treated with CMF or an epirubicin-based regimen, the predictive value of HER-2 may vary according to the Abs used in the immunohistochemistry assay. In addition, the study supports the concept that topo II alpha might be involved in the determination of tumor responsiveness to an anthracycline-based adjuvant therapy.