PD05-02: Effect of HER2/Topoisomerase II alpha (TOP2A) Gene Status or Protein Expression and Chromosome 17 (CEP17) Polysomy on the Outcome of Breast Cancer Patients Treated with Anthracycline-Containing Dose-Dense Sequential Adjuvant Chemotherapy with or without Paclitaxel – A Pooled Analysis of Two Hellenic Cooperative Oncology Group (HeCOG) Phase III Trials.

Abstract

Abstract Background: The HER2 gene has been established as a valid biomarker in the treatment of breast cancer patients with trastuzumab and probably with other agents, such as paclitaxel or anthracyclines. The TOP2A gene has been associated with response to anthracyclines. The relationship of HER2/TOP2A gene status in the presence of CEP17 polysomy with patients’ outcome following adjuvant treatment with anthracyclines with or without paclitaxel is not established. Patients and methods: Formalin-fixed paraffin-embedded (FFPE) tumor tissue blocks from 1,033 patients (61.5% of 1,681 randomized patients) with high-risk operable breast cancer enrolled in two sequential phase III trials1,2 were assessed in a central laboratory for HER2/TOP2A gene amplification and CEP17 polysomy by fluorescence in situ hybridization (FISH) and tumors were categorized according to the 2007 American Society of Clinical Oncology/College of American Pathologists guidelines. HER2 and TOP2A amplification was defined as a gene/CEP17 ratio of >=2.2 and >=2.0, respectively or a gene copy number of >6. Additionally HER2, TOP2A, ER/PgR, Ki67, CK5 and EGFR protein expression were assessed by immunohistochemistry (IHC) and all patients were classified according to their IHC phenotype. Treatment consisted of epirubicin-based dose-dense sequential adjuvant chemotherapy followed by hormonal therapy and radiation, as indicated. Results: Disease-free survival (DFS) and overall survival (OS) did not differ significantly between treatment groups. Median follow-up was 92 months, while 5-year DFS (OS) rates were 74% (88%), 69% (81%) and 75% (86%) for the E-T-CMF, E-CMF and ET-CMF groups, respectively. HER2 amplification was found in 24.1% of the patients and TOP2A amplification in 10.3%. In total, 46.7% of HER2 amplified tumors demonstrated TOP2A co-amplification. The median (range) of HER2, TOP2A and CEP17 copy numbers was 2.55 (0.70−45.15), 2.2 (0.50−26.15) and 2.05 (0.45−26.55), respectively. 21% of the tumors were considered to be polysomic (32.5% of those with HER2 amplification). Adjusting for treatment groups in the Cox model, TOP2A amplification, CEP17 polysomy and HER2/TOP2A co-amplification were not associated with either relapse or death. Treatment with paclitaxel was associated with improved survival in the HER2−amplified subgroup (HR=0.493, interaction p=0.036; adjusting for clinicopathological prognostic factors: HR=0.553, interaction p=0.054), an association that was not apparent for DFS. Conclusions: HER2 amplification was predictive for OS benefit from adjuvant treatment with paclitaxel in patients treated with epirubicin-based dose-dense sequential adjuvant chemotherapy, but not for DFS. TOP2A amplification, CEP17 polysomy and HER2/TOP2A co-amplification were not associated with outcome. 1. Ann Oncol 16:1762–71, 2005; 2. Ann Oncol 19:853–60, 2008. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD05-02.