ERBB2 and TOP2A in Breast Cancer: A Comprehensive Analysis of Gene Amplification, RNA Levels, and Protein Expression and Their Influence on Prognosis and Prediction

Abstract

Purpose: The prognostic and predictive relevance of epidermal growth factor receptor 2 (ERBB2) and topoisomerase II α (TOP2A) have long been a matter of debate. However, the correlation of DNA amplification, RNA levels, and protein expression and their prognostic role and association with anthracycline responses in node-negative breast cancer have not yet been evaluated.Experimental Design: We first analyzed TOP2A and ERBB2 at the levels of gene amplification, and RNA and protein expression, and studied their correlations. Additionally, TOP2A and ERBB2 were analyzed in 782 node-negative breast carcinomas in patients who did not receive systemic therapy and in 80 patients treated with epirubicin and cyclophosphamide (EC) prior to surgery.Results: TOP2A gene amplification did not correlate with protein expression (P = 0.283) and showed an association with gene expression with only borderline significance (P = 0.047). By contrast, TOP2A RNA levels correlated with protein expression (P < 0.001). TOP2A gene expression was significantly associated with the metastasis-free interval (MFI; P < 0.001) and was associated with complete remission in patients treated with EC (P = 0.002). In contrast to TOP2A, ERBB2 gene amplification correlated with RNA level (P < 0.001) and protein expression (P < 0.001). ERBB2 gene expression was associated with the MFI only in estrogen receptor-positive carcinomas, whereas ERBB2 protein expression (P = 0.032) was associated with MFI in the entire cohort.Conclusions: Overall, our study indicates that the TOP2A RNA level is a good prognostic marker and is also associated with a favorable response to anthracyclin-based therapy. By contrast, ESR1 was associated with poorer responses to anthracyclin-based therapy, whereas the association with ERBB2 RNA was not significant. Clin Cancer Res; 16(8); 2391-401. ©2010 AACR.

Quantum dot-based immunofluorescent imaging and quantitative detection of TOP2A and prognostic value in triple-negative breast cancer

“…29 Furthermore, with regard to the precise prognostic value of TOP2A expression, the existing evidence base is mixed with numerous conflicting results. 7,25,29,34,37,38 Qiao et al 25 reported a subgroup analysis, which demonstrated no significant differences in overall survival or DFS between TOP2A-positive and TOP2A-negative groups in patients with breast cancer. However, Brase et al 34 reported that TOP2A expression was significantly associated with the metastasis-free interval and complete remission in patients with breast cancer.…”

“…This is consistent with other studies. 7,12,34 Romero et al 12 reported that TOP2A expression in breast cancer was associated with high proliferation and aggressive tumor subtypes. Rody et al 7 found that TOP2A expression showed a strong correlation with tumor size, grading, HER2, and Ki67 expression as well as nodal status.…”

TOP2A Amplification in Breast Cancer in the Absence of That of HER-2: Myth or Reality?

“…For instance, in the case of HER-2, we and other authors have previously shown that HER-2 amplification is well correlated with HER-2 mRNA expression. However, gene amplification and expression are not always correlated [10], as already reported for TOP2A [11,12], and a statement that high mRNA expression is equivalent to gene amplification cannot be considered scientifically valid.…”

Pegylated liposomal doxorubicin as first-line monotherapy in elderly women with locally advanced or metastatic breast cancer: Novel treatment predictive factors identified

“…However, sensitivity to anthracycline-based therapy has also been related to high TOP2A expression levels and we hypothesized that high TOPOIIα levels, also in the absence of gene amplification, might be predictive [26].…”