Randomized, phase III study of adjuvant doxorubicin plus cyclophosphamide (AC), followed by docetaxel (T) with or without capecitabine (X), in high-risk early breast cancer (EBC): Efficacy results

Goals: To present efficacy data from a randomized, multicenter phase III study of adjuvant AC→T ± X in high-risk EBC. Methods: Pts aged 18-70 yrs, with histologically confirmed BC, received 4 × 3-weekly AC (A: 60 mg/m2, C: 600 mg/m2, d1) followed by 4 × 3-weekly T (100 mg/m2 d1) or XT (X: 825 mg/m2 bid, d1-14; T: 75 mg/m2 d1). Pts with HR+ disease received tamoxifen/AI for 5 yrs; after 2005, pts with HER2+ disease were offered 1-yr concurrent or post-study trastuzumab. Primary endpoint: DFS (5-yrs median follow-up); secondary endpoints: OS; safety. Results: 2611 pts were randomized to AC→T (n = 1304) or AC→XT (n = 1307); treatment arms were well balanced. After a median follow-up of 5 yrs, the primary endpoint, improvement in DFS, was not met (HR 0.84, 95% CI: 0.67-1.05; p = 0.125), with 304 events. A statistically significant improvement in OS was seen with AC→XT vs AC→T (HR 0.68, 95% CI: 0.51-0.92; p = 0.011; 183 events). Exploratory analyses demonstrated a trend towards improved distant DFS with the addition of X (HR 0.80, 95% CI: 0.63-1.02; p = 0.067), and a greater DFS and OS benefit in highly proliferative ER+ tumors (ER+/HER2-, Ki-67≥10%). No unexpected adverse events were reported. Median X dose intensity was 0.67 (range: 0.00-1.20), which is lower than reported in previous BC studies. Conclusion: The study failed to meet its primary endpoint of DFS. A statistically significant improvement in OS was seen with AC→XT vs AC→ T; given the low power of the study these results must be interpreted with caution. The potential benefit of X in highly proliferative ER+ BC must be further explored in prospective clinical trials.