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

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 II alpha (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. Oncogene (2010) 29, 5231-5240; doi:10.1038/onc.2010.286; published online 2 August 2010