Alteration of topoisomerase II-alpha gene in human breast cancer: Association with responsiveness to anthracycline-based chemotherapy.

Abstract

518 Background: Approximately 35% of HER2-amplified breast cancers have coamplification of the topoisomerase II-alpha (TOP2A) gene which encodes an enzyme that is a major target of anthracyclines. This study determines whether TOP2A rather than HER2 gene alterations may be predictive for unique responsiveness to anthracyclines in some breast cancers. Methods: Approximately 5,000 breast cancers were analyzed for alterations in TOP2A and HER2. Using fluorescence in situ hybridization, a test set of tumor tissues from metastatic breast cancer patients treated in a study of chemotherapy with or without trastuzumab and subsequent, large validation set trials were evaluated for amplification or deletion of these genes. Association between these alterations and clinical outcomes was determined. Results: The test set demonstrated that cases containing HER2 amplification treated with doxorubicin, cyclophosphamide (AC) plus trastuzumab had a longer progression-free survival compared to those treated with AC alone (p = 0.03). However, patients treated with AC alone whose tumors contain HER2/TOP2A coamplification experienced a similar significant increase in survival compared to those with only HER2 amplification (p = 0.004). Conversely, in patients treated with paclitaxel, HER2/TOP2A coamplification was not associated with improved outcomes. These observations were confirmed in validation set cases, where HER2/TOP2A coamplification was again associated with longer survival when anthracycline-containing chemotherapy was used compared to cancers lacking TOP2A coamplification. Conclusions: Both the test set and validation set demonstrate that TOP2A coamplification, not HER2 amplification, is the clinically useful predictive marker of a large increment in response to anthracycline-based chemotherapy in a small number of breast cancer patients. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration IDDI AstraZeneca, Genentech, GlaxoSmithKline, Merck, Novartis, Roche, sanofi-aventis, Ventana Medical Sysems IDDI AstraZeneca, Genentech, Merck, Novartis, Roche, sanofi-aventis Genentech, GlaxoSmithKline, Roche, sanofi-aventis, Ventana Medical Systems