High TOP2A mRNA expression occurs in the absence of TOP2A or ERBB2 gene amplification

Abstract

22057 Background: Topoisomerase II alpha, encoded by TOP2A, is the putative molecular target of anthracycline drug action. Recently, it has been shown that TOP2A gene amplification occurs almost exclusively in conjunction with ERBB2 amplification. Since no benefit of anthracylines was observed in ERRB2 negative patients it was hypothesized that any anthracycline benefit might be restricted to those patients with TOP2A and ERBB2 co-amplification. Since alternative treatment options exist for ERBB2 positive breast cancer, the role of anthracycline-based therapy in the adjuvant treatment of breast cancer has been questioned Methods: In a series of 53 formalin-fixed paraffin-embedded (FFPE) tissue samples from patients with invasive breast carcinomas we analysed TOP2A and ERBB2 gene amplification as well as RNA expression. Amplifications were determined using the HER2 FISH pharmDx™ kit and the TOP2A FISH pharmDxTM kit (both from DakoCytomation, Denmark A/S, Glostrup). In addition, RNA was isolated from corresponding formalin fixed tumors and TOP2A and ERBB2 expression was determined by real time RT-PCR. Results: Neither ERBB2 nor TOP2A amplifications were detected in 40 samples (75.5%). ERBB2 and TOP2A co-amplification was observed in six samples (11.3%). Additional six samples showed ERBB2 but no TOP2A amplification (11.3%). Only one sample (1.9%) exhibited TOP2A amplification without concomitant ERBB2 amplification. ERBB2 m-RNA expression was distinctly higher in ERBB2 amplified compared to non-amplified tumors. In contrast, a considerable fraction of TOP2A non-amplified tumors showed a similar high TOP2A mRNA expression as TOP2A amplified or TOP2A/ERBB2 co-amplified tumors. Conclusions: Our data confirm that TOP2A amplification predominantly occurs as co-amplification with ERBB2. However, TOP2A gene amplification is not a prerequisite for high TOP2A RNA expression. Therefore, it should be considered that anthracylines might still be a valuable treatment option in ERBB2 negative tumors with high TOP2A mRNA expression. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Siemens Medical Solutions Diagnostics