Association of topoisomerase II-alpha (TOP2A) gene amplification with responsiveness to anthracycline-containing chemotherapy among women with metastatic breast cancer entered in the Herceptin H0648g pivotal clinical trial

Abstract

9543 Background: Because approximately 40% of breast cancers with HER2 gene amplification also have amplification of the TOP2A gene and because TOP2A is the known target for anthracyclines, it has been suggested, but not established, that TOP2A gene amplification, not HER2 amplification, may be the predictive marker for responsiveness to anthracycline chemotherapy. Methods: We retrospectively evaluated both HER2 and TOP2A gene amplification in breast cancer tissue from women who were entered in a randomized clinical trial (H0648g) of anthracycline-containing chemotherapy (AC) with or without addition of trastuzumab (Herceptin) immunotherapy. Results: Tissue sections were successfully analyzed for both HER2 and TOP2A gene status for 339 of the 469 (72%) cases originally randomized in the H0648g clinical trial. HER2 was amplified in 279 of 339 (82%) while TOP2A was amplified in 99 of 339 (29%). All cases with TOP2A gene amplification had co-amplification of HER2. Among those women entered to an AC treatment arm, either with or without addition of Herceptin, there was a survival advantage associated with TOP2A gene amplification that did not achieve statistical significance (p = 0.0841). However, analysis of clinical outcome by individual treatment arm demonstrated that for AC patients treated with Herceptin, TOP2A gene amplification did not correlate with outcome; however, in the absence of Herceptin, TOP2A gene amplification was associated with a statistically significant overall survival advantage for those women who were treated with AC alone (p = 0.0147). Conclusions: TOP2A gene amplification in breast cancer tissue is associated with responsiveness to AC chemotherapy in this retrospective analysis of a randomized clinical trial. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech