From the "Sandro Pitigliani" Medical Oncology Unit, Hospital of Prato, Istituto Toscano Tumori, Prato, Italy
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Angelo Di Leo, MD, PhD, "Sandro Pitigliani" Medical Oncology Unit, Hospital of Prato, Istituto Toscano Tumori, Piazza Ospedale 2, 59100, Prato, Italy; e-mail: adileo{at}usl4.toscana.it
Overview: Preclinical and clinical data on the correlation between anthracycline activity and topoisomerase II alpha gene aberrations, protein overexpression, or DNA repair dysfunction are now available. These data suggest that sensitivity to anthracyclines seems to be regulated by topoisomerase II alpha gene aberrations, but the protein expression can be up or downregulated independently of gene status. In particular, proliferation signals play a relevant role in regulating protein levels. Retrospective clinical studies suggest that protein levels can be important predictors of response to anthracyclines independent of gene status. Additionally, the DNA-damaging effect induced by anthracyclines, independent of topoisomerase II alpha inhibition, would render some breast cancer subtypes, such as basal-like, particularly sensitive to this class of cytotoxic agents. These data suggest that regulation of sensitivity to anthracyclines is likely multifactorial and that the cohort of patients who derive the largest benefit from these compounds is not necessarily confined to the human epidermal growth factor receptor 2 (HER2)-positive subgroup, as previously shown in some retrospective studies. Although available data on topoisomerase II alpha as a predictive marker are consistent, topoisomerase II alpha use cannot be recommended in the clinical setting for the selection of the most suitable patients for anthracycline-based therapy.
