Randomized, phase III study of adjuvant doxorubicin plus cyclophosphamide (AC) → docetaxel (T) with or without capecitabine (X) in high-risk early breast cancer: Exploratory Ki-67 analyses.

Abstract

500 Background: First results of study USON 01062 comparing adjuvant AC→T vs AC→XT in high-risk EBC [O’Shaughnessy, SABCS 2010] showed the primary endpoint, improvement in DFS, was not met (median FU 5 yrs: HR 0.84, 95% CI: 0.67–1.05; p%0.125; 304 events), but a statistically significant improvement in OS was seen with AC→XT (HR 0.68, 95% CI: 0.51–0.92; p%0.011; 183 events). Given the current understanding of a lesser benefit of adjuvant chemotherapy in indolent BC, we performed unplanned exploratory subset analyses of Ki-67 expression, distant DFS and benefit from XT. Methods: Pts aged 18–70 yrs with surgically resectable EBC received 4 x 3-weekly AC (A: 60mg/m2, C: 600mg/m2, d1) → 4 x 3-weekly T (100mg/m2 d1) or XT (X: 825mg/m2 bid, d1–14; T: 75mg/m2 d1). ER+ pts received endocrine therapy, and, after 2005, HER2+ pts were offered 1-yr of trastuzumab. Primary endpoint: DFS; secondary endpoints: OS; safety. Ki-67 staining was done locally. Results: 2,611 pts were randomized: AC→T (n%1304); AC→XT (n%1307). Treatment arms were balanced. Exploratory distant DFS analysis favored the XT group (HR 0.80, 95% CI: 0.63–1.02; p%0.067). Analyses by Ki-67 expression showed a treatment effect with XT vs T in pts with Ki-67 ≥10% (HR for DFS: 0.70; OS: 0.52) (table). Very few events (DFS/OS) were seen in pts with Ki-67 <10%, with no difference in DFS with XT vs T. In pts with ER+/HER2- tumors and Ki-67 ≥10%, a trend towards DFS (HR 0.66) and OS (0.30) benefit with XT was also seen. Conclusions: Exploratory Ki-67 analyses suggested benefit of X in more highly proliferative tumors, reflecting the importance of pt selection in adjuvant trials. Pt group Pts, n AC→T events AC→XT events HR (95% CI) DFS All 2,611 164 140 0.84 (0.67–1.05) Ki-67 (All pts) <10% 326 9 12 1.34 (0.57–3.19) ≥10% 1,194 84 57 0.70 (0.50–0.98) Unknown 1,076 71 71 0.91 (0.65–1.26) Ki-67 (ER+/HER2-) <10% 273 6 9 1.47 (0.52–4.15) ≥10% 570 34 21 0.66 (0.38–1.13) Unknown 600 32 33 0.95 (0.58–1.54) OS All 2,611 108 75 0.68 (0.51–0.92) Ki-67 (All pts) <10% 326 7 5 0.72 (0.23–2.27) ≥10% 1,194 56 28 0.52 (0.33–0.82) Unknown 1,076 45 42 0.85 (0.56–1.30) Ki-67 (ER+/HER2-) <10% 273 5 4 0.79 (0.21–2.94) ≥10% 570 18 5 0.30 (0.11–0.81) Unknown 600 17 17 0.92 (0.47–1.81)