Evaluation of the prognostic/predictive value of HER2/TOP2A gene amplification and protein overexpression in patients with high-risk breast cancer treated with dose-dense sequential adjuvant chemotherapy.

Abstract

e21059 Background: The prognostic/predictive value of HER2 and topoisomerase II alpha (TOP2A) gene status in patients with breast cancer treated with adjuvant dose-dense sequential chemotherapy is not well defined. Anthracyclines and taxanes are considered to be important drugs in this setting. Methods: Formalin-fixed tumor tissue samples were obtained from 354 patients participating in a phase III trial, in which 595 high-risk breast cancer patients were randomized to receive postoperative dose-dense sequential chemotherapy with epirubicin and CMF, with or without paclitaxel. HER2 and TOP2A gene amplification was evaluated by chromogen in situ hybridization (CISH) using ZYMED (InVitrogen) technology in 285 and 266 patients, respectively and protein expression was assessed by immunohistochemistry (IHC) in 297 and 248 patients, respectively. Results: Among the 52 tumors classified HER2-positive by IHC (3+, strong membranous staining in ≥30% of the tumor cells), 50 tumors (96%) were amplified by CISH. As for TOP2A, among the 153 tumors classified positive by IHC (2+ and 3+, moderate and strong nuclear staining in ≥5% of the tumor cells), only 13 (9%) of the tumors were amplified by CISH. 64% of the HER2-positive tumors were also TOP2A-positive when assessed by IHC, while only 21% of the HER2-amplified tumors were also TOP2A-amplified by CISH. Univariate Cox regression analysis did not show any association of HER2 and TOP2A gene amplification or IHC-positivity with OS or DFS, except for an increased risk for progression (HR=1.71, 95% CI: 1.07-2.73, Wald p=0.024) in HER2-positive patients by IHC. No benefit from paclitaxel treatment was detected for HER2 or TOP2A gene amplified or protein overexpressing tumors. Conclusions: HER2 and TOP2A gene amplification or protein overexpression do not appear to be predictive for response to paclitaxel in high-risk breast cancer patients treated with dose-dense sequential adjuvant chemotherapy. Evaluation of mRNA expression and gene amplification of HER2 and TOP2A by RT-PCR and FISH is in progress and the data will be presented at the meeting.