Abstract
The purpose of this study is to evaluate the relationship between TOP2A RNA expression and recurrence in patients with operable estrogen receptor (ER)-positive breast cancer. We evaluated TOP2A expression in a pooled analysis of four independent datasets with gene expression data including 752 patients with early stage, ER-positive, HER2-negative breast cancer, most of whom received either no adjuvant therapy or only endocrine therapy without chemotherapy. We also used an algorithm to simulate the Oncotype DX Recurrence Score (simRS) and the proliferation component of the Recurrence Score (simPS). Results are expressed as the hazard ratio (HR) for estimates of the effect of a 1SD increase in the value of the log gene expression (x + 1SD vs. x) as a continuous function. TOP2A expression was significantly associated with recurrence (HR 1.56, p < 0.0001), and after adjustment for simRS (HR 1.26, p = 0.003). TOP2A correlated somewhat with simRS (0.45), but more strongly with simPS (0.69). For those with an intermediate simRS, high TOP2A expression (above the median) was associated with significantly higher relapse rates at 5 years (HR 1.82, p = 0.007). TOP2A expression provides prognostic information in patients with ER-positive, HER2-negative breast cancer, a population known to have low incidence of TOP2A gene alterations. These findings confirm prior reports indicating that TOP2A expression provides prognostic information in ER-positive breast cancer. TOP2A expression may also be useful for identifying those with an intermediate RS who are more likely to relapse, although additional validation in datasets including measured rather than simulated RS will be required.
Similar content being viewed by others
References
Paik S, Shak S, Tang G et al (2004) A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351:2817–2826
Paik S, Tang G, Shak S, et al (2006) Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol 24:3726–3734
Sparano JA, Paik S (2008) Development of the 21-gene assay and its application in clinical practice and clinical trials. J Clin Oncol 26:721–728
Oratz R, Kim B, Chao C et al (2011) Physician survey of the effect of the 21-gene recurrence score assay results on treatment recommendations for patients with lymph node-positive, estrogen receptor-positive breast cancer. J Oncol Pract 7:94–99
Lo SS, Mumby PB, Norton J et al (2010) Prospective multicenter study of the impact of the 21-gene recurrence score assay on medical oncologist and patient adjuvant breast cancer treatment selection. J Clin Oncol 28:1671–1676
Rody A, Karn T, Ruckhaberle E et al (2009) Gene expression of topoisomerase II alpha (TOP2A) by microarray analysis is highly prognostic in estrogen receptor (ER) positive breast cancer. Breast Cancer Res Treat 113:457–466
Brase JC, Schmidt M, Fischbach T et al (2010) ERBB2 and TOP2A in breast cancer: a comprehensive analysis of gene amplification, RNA levels, and protein expression and their influence on prognosis and prediction. Clin Cancer Res 16:2391–2401
Liu LF (1989) DNA topoisomerase poisons as antitumor drugs. Annu Rev Biochem 58:351–375
Oakman C, Moretti E, Sotiriou C et al (2009) Re: Topoisomerase II alpha and responsiveness of breast cancer to adjuvant chemotherapy. J Natl Cancer Inst 101:1735–1936 author reply 1736–1737
Sparano JA, Goldstein LJ, Childs BH et al (2009) Relationship between topoisomerase 2A RNA expression and recurrence after adjuvant chemotherapy for breast cancer. Clin Cancer Res 15:7693–7700
Villman K, Stahl E, Liljegren G et al (2002) Topoisomerase II-alpha expression in different cell cycle phases in fresh human breast carcinomas. Modern Pathol 15:486–491
Wang Y, Klijn JG, Zhang Y et al (2005) Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer. Lancet 365:671–679
van de Vijver MJ, He YD, van’t Veer LJ (2002) A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 347:1999–2009
Desmedt C, Piette F, Loi S et al (2007) Strong time dependence of the 76-gene prognostic signature for node-negative breast cancer patients in the TRANSBIG multicenter independent validation series. Clin Cancer Res 13:3207–3214
Loi S, Haibe-Kains B, Desmedt C et al (2007) Definition of clinically distinct molecular subtypes in estrogen receptor-positive breast carcinomas through genomic grade. J Clin Oncol 25:1239–1246
Loi S, Haibe-Kains B, Desmedt C et al (2008) Predicting prognosis using molecular profiling in estrogen receptor-positive breast cancer treated with tamoxifen. BMC Genomics 9:239
McShane LM, Altman DG, Sauerbrei W et al (2005) Reporting recommendations for tumor marker prognostic studies (REMARK). J Natl Cancer Inst 97:1180–1184
Sparano JA (2006) TAILORx: trial assigning individualized options for treatment (Rx). Clin Breast Cancer 7:347–350
Acknowledgments
This study was supported in part by Grants from the Department of Health and Human Services and the National Institutes of Health (CA23318 to the ECOG statistical center).
Conflict of interest
The authors report on conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Sparano, J.A., Goldstein, L.J., Davidson, N.E. et al. TOP2A RNA expression and recurrence in estrogen receptor-positive breast cancer. Breast Cancer Res Treat 134, 751–757 (2012). https://doi.org/10.1007/s10549-012-2112-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-012-2112-7