Targeting anthracyclines in early breast cancer: new candidate predictive biomarkers emerge

Abstract

The search for a predictive marker of sensitivity to anthracycline-based chemotherapy has proven challenging. Despite human epidermal growth factor receptor 2 (HER2) being a strong prognostic marker in breast cancer, the only therapies with which there is a recognized functional link to the HER2 oncogene are those directly targeting the molecule itself. Despite this, HER2 has been extensively assessed as a predictive marker in a variety of chemotherapy regimens including anthracyclines. Analysis of anthracycline response in patients with HER2 amplification has given conflicting results. This led to the suggestion that HER2 amplification was acting as a surrogate for the gene encoding topoisomerase IIa (TOP2A), a direct cellular target of anthracyclines. Despite an attractive functional link between TOP2A and anthracyclines, published studies have failed to show strong evidence of an interaction between TOP2A genetic aberrations and anthracycline response. A number of other biomarkers have also been assessed for their role in predicting anthracycline response, including TP53 (tumour protein 53) and BRCA1 (breast cancer 1, early onset), together with an increasing emergence of gene expression profiling to produce predictive signatures of response. Moreover, recent evidence has emerged from presentations suggesting new candidate markers of response that warrant further investigation: Chr17CEP duplication and tissue inhibitor of metalloproteases 1. This review will discuss research into HER2 and TOP2A as predictive markers of anthracycline response and will focus on current research into other possible candidate predictive markers.

Phosphorylation and Stabilization of Topoisomerase IIα Protein by p38γ Mitogen-activated Protein Kinase Sensitize Breast Cancer Cells to Its Poisons

“…Therefore, the regulation and stabilization of Topo II␣ by p38␥ have important clinical implications. Although it has long been recognized that Topo II-targeting drugs are more effective in ER-negative breast cancer patients, the mechanisms have been mostly unknown (41,42). While the cytotoxicity of Topo II drugs is directly correlated with Topo II␣ levels (40), clinical studies have failed to show any connection between Topo II␣ and ER protein expression in primary breast cancer (43), indicating that other factor(s) must regulate Topo II␣ levels and the activity of Topo II drugs.…”

Assessment of HER2 status in patients with gastroesophageal adenocarcinoma treated with epirubicin-based chemotherapy: heterogeneity-related issues and prognostic implications

“…In breast cancer, the predictive role of HER2 status and TOP2A abnormalities has been challenged by controversial findings across different series [10] and by the results of a meta-analysis [29]. However, a pooled analysis of adjuvant trials indicates that both TOP2A abnormalities and/or duplication of CEP17 independently predict for anthracycline responsiveness [30], and recent attention has turned again on reappraising the role of TOP2A.…”

“…In breast cancer, despite conflicting results, observational studies indicated that HER2 amplification or HER2 overexpression, along with topoisomerase 2 alpha (TOP2A) genomic abnormalities, is a potential predictive biomarker of benefit from adjuvant epirubicin-based chemotherapy [10]. The topoisomerase 2 alpha protein is the gene product of TOP2A, and it is a key molecular target of anthracyclines.…”

Predictive Factors Determining Neoadjuvant Chemotherapy Outcomes in Breast Cancer - a Single Center Experience

“…In spite of the tremendous amount of evidence, the impact of ER, PR, HER2, and Topo IIα expression on the efficacy of neoadjuvant chemotherapy remains controversial (Järvinen et al, 1998;Di Leo et al, 2001;Harris et al, 2001;Coon et al, 2002;Lips et al, 2012). For example, some findings suggest that HER2 overexpression or gene amplification together with Topo IIα positive or negative status could collectively predict the response to anthracycline-based chemotherapy; however, this finding has been questioned by other studies (Di Leo et al, 2002;Järvinen et al, 2003;Arpino et al, 2005;Fritz et al, 2005;Harris et al, 2009;Munro et al, 2010). Moreover, an increasing number of factors, such as Ki67, oncoprotein K-RAS, and tumor suppressor p53, have been proposed to affect neoadjuvant chemotherapy in breast cancer, but the overall consensus remains inconclusive (Bonnefoi et al, 2011;Dowsett et al, 2011;Generali et al, 2011;Oshima et al, 2011;Petrarca et al, 2011).…”