New Understanding of the Role of Anthracyclines in Early-Stage Breast Cancer: Patient Selection Considerations

In the past decade, a considerable effort has been made to Identify molecular markers that predict anthracycline activity. A number of retrospective studies that evaluated the clinical activity of anthracyclines according to HER2 status suggested that the additional benefit of these agents, as compared with non-anthracycline-based chemotherapy, is confined to HER2-positive tumors. More recently, 2 meta-analyses, based on abstracted data, have reinforced this concept, challenging the use of adjuvant anthracyclines in patients with HER2-negative tumors. Additional data suggested that patients who derive the largest clinical benefit from anthracycline-based chemotherapy have TOP2A gene-amplified tumors. The last hypothesis is based on the fact that topoisomerase Il alpha protein is the molecular target of Topo II inhibitors such as anthracyclines. The TOP2A gene is located on chromosome 17q12-17q21, next to the HER2/neu gene. TOP2A gene aberrations (amplifications or deletions) are more frequent in HER2/neu-amplified than in HER2/neu-nonamplified tumors. Approximately 35% and 25% of HER2/neu-amplified tumors carry TOP2A gene amplifications and deletions, respectively; however, although TOP2A gene aberrations are detected most frequently in HER2-amplified tumors, topoisomerase Il alpha protein overexpression (largely regulated by proliferation signals) and DNA repair dysfunctions are observed in different breast cancer subtypes, independent of HER2 status. This finding suggests that hypersensitivity to anthracyclines might not be confined to HER2-positive tumors, and as a consequence, some patients with HER2-negative disease also could derive clinically relevant benefit from these compounds.