Alteration of topoisomerase II-alpha gene in human breast cancer and its association with responsiveness to anthracycline- based chemotherapy

Abstract

524 Background: Topoisomerase II-alpha (TOP2A) gene amplification, and not HER2 amplification, may be the predictive marker for responsiveness to anthracycline chemotherapy. Methods: To address this issue we performed a test set-validation set series of analyses. Amplification of TOP2A and HER2 was evaluated by fluorescence in situ hybridization (FISH) in patients with metastatic breast cancer who participated in a randomized trial (H0648g, n = 469) of anthracycline-based chemotherapy with or without trastuzumab. This group represented the test set. To validate our observations in the H0648g test set we analyzed breast cancers from two other, large, randomized clinical studies of anthracycline-based chemotherapy; one with HER-2 amplification and trastuzumab-based therapy (BCIRG006, n = 3,222) and one without HER-2 amplification and combination-based chemotherapy (BCIRG005, n = 3,298), comparing TOP2A status with clinical outcome. Both of the latter trials were adjuvant trials. Results: In the H0648g test set patients whose breast cancers had TOP2A gene co- amplification and who were treated with doxorubicin, cyclophosphamide (AC) and trastuzumab had a longer progression-free survival compared to those who were treated with AC alone (p = 0.03). Patients treated solely with AC, whose breast cancers had TOP2A gene co-amplification had a statistically significant improvement in duration of survival compared to those without TOP2A gene amplification (p = 0.004). Among all women entered in the HER2-positive BCIRG 006 clinical trial, as well as among women who were treated with anthracycline-containing chemotherapy alone, women whose breast cancers showed TOP2A gene co-amplification had a significantly longer disease-free (p <0.001), recurrence-free (p <0.001) and overall survival (p = 0.01) compared to women whose breast cancers lacked TOP2A amplification. Unexpectedly, the added beneficial effect of trastuzumab was not seen among TOP2A co-amplified breast cancer patients in the larger BCIRG006 trial. Conclusions: In patients treated with chemotherapy alone the findings demonstrate that TOP2A gene co-amplification is a useful predictive marker of responsiveness to anthracycline-containing chemotherapy. No significant financial relationships to disclose.