Topoisomerase IIa gene amplification predicts favorable outcome of tailored and dose-escalated anthracycline-based adjuvant chemotherapy in HER-2 positive breast cancer. Results from the randomized trial SBG 9401

Abstract

9518 Background: Amplification of the HER-2/neu and topoisomerase IIα (TOP2A) genes has been linked to the effects of anthracyclines. Their role in predicting outcome of anthracycline-based adjuvant chemotherapy for breast cancer patients has remained controversial. Methods: High-risk breast cancer patients (with 5 or more positive axillary lymph nodes) were included in the present substudy of the SBG 9401 study, comparing an epirubicin-based regimen (9 courses of tailored and dose-escalated 5-fluorouracil, epirubicin and cyclophosphamide; FEC) with 3–4 courses of standard FEC followed by marrow-supported high-dose chemotherapy with cyclophosphamide, thiotepa and carboplatin (CTCb). Amplification of HER-2/neu and TOP2A were determined retrospectively on paraffin-embedded tumor tissue sections by chromogenic in situ hybridization (CISH), tissue samples were available from 396/525 (75%) patients. The primary end-point was time to recurrence of breast cancer. Results: HER-2/neu amplification, present in 32.7% of the tumors, was a strong prognostic factor for short relapse-free survival (p=0.0034), but did not predict treatment outcome in either treatment group separately. TOP2A gene amplification, present in 37% of HER-2/neu positive tumors, was associated with a statistically significantly better relapse-free survival than TOP2A non-amplified tumors in patients treated with tailored and dose-escalated FEC (HR=0.44, p=0.049). There was no such correlation seen in patients treated with standard FEC followed by the marrow-supported CTCb regimen (HR=0.95; p=0.87). TOP2A amplification was not associated with tumor size, lymph node status or hormone receptor status. Conclusions: Topoisomerase IIa gene amplification defines a subgroup of HER-2 amplified tumors patients who benefit from the tailored and dose-escalated FEC regimen, indicating that epirubicin should be given with sufficient dose intensity and total dose for a better outcome for this small subgroup. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb, Roche Finland Aventis, Bristol-Myers Squibb Hoffmann-La Roche Aventis, Lilly Oncology, Pierre Fabre, Roche