Gene expression of topoisomerase II alpha (TOP2A) by microarray analysis is highly prognostic in estrogen receptor (ER) positive breast cancer

Abstract

Introduction Overexpression of Topoisomerase II alpha (TOP2A) has been implicated with gene amplification of the 17q21 amplicon and consecutively with ErbB2 overexpression and amplification. However, gene amplification does not necessarily correlate with RNA and protein expression. There is growing evidence that TOP2A protein expression is a strong prognostic and TOP2A gene amplification might be a predictive marker (particularly for the use of anthracyclines). Methods Large scale analysis was performed using Affymetrix microarray data from n = 1,681 breast cancer patients to evaluate TOP2A expression. Results TOP2A expression showed a strong correlation with tumor size (v 2 -test, P \ 0.001), grading (P \ 0.001), ErbB2 (P \ 0.001) and Ki67 expression (P \ 0.001) as well as nodal status (P = 0.042). Survival analysis revealed a significant prognostic value in ER positive (n = 994; log rank P \ 0.001), but not in ER negative breast cancer patients (n = 369, P = 0.35). The prognostic impact of TOP2A expression was independent of Ki67 expression in ER positive tumors (P = 0.002 and P = 0.007 for high and low Ki67, respectively). Moreover a worse prognosis of high TOP2A expressing tumors was found in the subgroup of ErbB2 negative tumors (P \ 0.001) and a trend among ErbB2 positive tumors (P = 0.11). The prognostic value of TOP2A was independent of whether the patients were untreated or had received adjuvant therapy. In multivariate Cox regression analysis including standard parameters TOP2A emerged to be the top prognostic marker (HR 2.40, 95% CI 1.68-3.43, P \ 0.001). Conclusion TOP2A expression is an independent prognostic factor in ER positive breast cancer and could be helpful for risk assessment in ER positive breast cancer patients.

Changes in Expression of Genes Representing Key Biologic Processes after Neoadjuvant Chemotherapy in Breast Cancer, and Prognostic Implications in Residual Disease

“…The genes were chosen from literature review on the basis of their being identified as (i) possible prognostic factors in residual disease at protein (4,(6)(7)(8)(9)(10) or mRNA level (11), (ii) as significantly up-or downregulated, but of unknown prognostic value in residual disease (12)(13)(14)(15)(16)(17)(18)(19)(20), (iii) as predictive of chemotherapy resistance (6,11,16,19,(21)(22)(23)(24)(25)(26)(27)(28)(29), and/or (iv) identified as possible prognostic factors over several previous datasets (26,(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41). In addition to the previously established prognostic factors ESR1 and ERBB2, the genes were also chosen to represent different pathways and biological processes of known implication in tumor progression or response to therapy, such as stemcellness (ALDH1A1, CD44, and STAT3), proliferation (TOP2A, MKI67, and AURKA), apoptosis (BCL2, BCL2L1, and PAWR), immunologic response (CD3D, CXCL13, and STAT1), epithelial-to-mesenchymal transition (EMT; SNAI1, SNAI2, SOX9, and TWIST), stromal activation (DECORIN, ...…”

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.…”

“…As such it has been widely investigated for potential applications in breast cancer detection and management. 7,8 Anthracyclines are one of the most effective cytotoxic agents used in the treatment of breast cancer patients and inhibit TOP2A by trapping the DNA strand intermediates, leading to persistent DNA cleavage. 8 However, data supporting a potential predictive role for TOP2A status and its sensitivity are mixed.…”

“…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. Rody et al 7 found that a worse prognosis of high TOP2A expressing tumors was observed in the subgroup of HER2-negative breast tumors. In our study, based on the principle of optimizing observed sensitivity and specificity, 45.0 and 0.45 were identified as cutoffs for TOP2A-QD and TOP2A-IHC, respectively; patients with higher TOP2A expression had worse DFS, vice versa.…”

“…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. Interestingly, we found that the study concentrated mainly on T1 (67.6%) and grade 2 (80%) subgroups, which suggested that most early-stage TNBC patients were included in this study.…”