ORIGINAL ARTICLE – BREAST ONCOLOGY Topoisomerase 2 Alpha and the Case for Individualized Breast Cancer Therapy Ronan W. Glynn, MBCHB, Nicola Miller, PhD, Maria C. Whelan, MD, and Michael J. Kerin, MD Department of Surgery, National University of Ireland, Galway, Clinical Science Institute, Galway, Ireland ABSTRACT Background. Many patients with breast cancer receive no benefit from their treatment. This has led to a search for novel therapeutic targets whose identification may facilitate a more tailored approach, thereby avoiding unnecessary toxicity. Of these, topoisomerase 2 alpha (TOP2A), located at the HER2/ neu amplicon on chromosome 17, has generated particular interest because its expression has been shown to correlate with response to anthracycline-based therapies. Methods. We evaluated the relationship between TOP2A and its collocated gene, HER2/neu, and summarized the evidence for and against confining anthracycline-based therapies to those patients who demonstrate increased expression or amplification of these targets. Results. The emerging consensus supports the restriction of anthracyclines to those patients who are HER2/neu positive, with the evidence suggesting that alterations in the status of TOP2A are almost completely restricted to this group of patients. Conclusions. It seems increasingly likely that response to anthracyclines is predicated on these alterations. Breast cancer is a clinically heterogenous disease that may be categorized into four distinct subtypes: luminal A, luminal B, HER2/neu overexpressing, and basal. The semi- nal work by Sorlie and Perou that identified these subtypes, 1 together with the identification of HER2/neu and develop- ment of the targeted therapy trastuzumab for those who overexpress it, have been the most important milestones in the search for individualized therapy. Recognition of the biological heterogeneity inherent in breast cancer means that clinicians are increasingly focusing on the estrogen receptor (ER), progesterone receptor (PR), and HER2/neu status of patients, with pharmacological treatment options centered around these parameters. Many questions remain, however, and it is clear that many patients will receive no benefit from their treatment, as exemplified by the 40% of ER-positive patients with disease that is resistant to tamoxifen and the 75% of HER2/ neu-positive patients with disease that will not respond to monotherapy with trastuzumab. 2,3 Unfortunately, recogni- tion of the limitations inherent in individual therapies has not resulted in the streamlining of treatment regimens, with many patients still placed at unnecessary risk in terms of both short- and long-term toxicity. This is particularly the case for anthracycline-based chemotherapies and their attendant risks of cardiotoxicity and myelodysplasia. To address this situation, the molecular classification of breast cancer will need to be further refined such that subtypes within subtypes are elucidated, thereby allowing more judicious use of the therapeutic options currently available such that therapy, and its associated risk of toxicity, may be confined to those who have a high chance of benefit. ASSOCIATION BETWEEN HER2/NEU AND RESPONSE TO ANTHRACYCLINES In addition to predicting benefit from Herceptin, HER2/ neu has also been shown to be predictive of response to anthracycline-based regimens. 4–7 This is particularly rele- vant because, although anthracycline-based regimens have been shown to have a statistically significant benefit over other forms of chemotherapy in the adjuvant setting, this benefit is restricted to a small proportion of patients. 8,9 Furthermore, an increasing body of evidence suggests that the premise on which clinical trials have been based for the past 30 years—that anthracycline-based regimens are superior to nonanthracycline regimens for all patients—is erroneous and that, in fact, this superiority is confined to a Ó Society of Surgical Oncology 2010 First Received: 6 October 2009; Published Online: 9 March 2010 N. Miller, PhD e-mail: nicola.miller@nuigalway.ie Ann Surg Oncol (2010) 17:1392–1397 DOI 10.1245/s10434-009-0855-0