Adjuvant ovarian suppression combined with tamoxifen or anastrozole, alone or in combination with zoledronic acid, in premenopausal women with hormone-responsive, stage I and II breast cancer: First efficacy results from ABCSG-12.

M. Gnant, B.
08 june 2008--Background: Zoledronic acid (ZOL) has demonstrated antitumor and antimetastatic activity in preclinical and early clinical studies. The Austrian Breast and Colorectal Cancer Study Group Trial 12 (ABCSG-12) examined the efficacy of ovarian suppression using the gonadotropin-releasing hormone analogue goserelin in combination with anastrozole (ANA) or tamoxifen (TAM) ± ZOL in premenopausal women with endocrine-responsive breast cancer (BC). Methods: 1,801 premenopausal women with endocrine-responsive BC were randomized to goserelin (3.6 mg q 28 d SC) and TAM (20 mg/d PO) ± ZOL (4 mg IV q 6 mo) or goserelin and ANA (1 mg/d PO) ± ZOL for 3 yr. Primary endpoint was disease-free survival (DFS) for both the comparison of TAM vs ANA and ZOL vs no ZOL, respectively. Relapse-free survival (RFS) and overall survival (OS) were secondary endpoints. Exploratory endpoints included bone-metastases-free survival and safety. Results: With median follow-up of 60 mo (March 31, 2008), 137 (7.6%) DFS events and 42 (2.3%) deaths have occurred. There was no significant difference in DFS between patients who received TAM alone vs ANA alone (HR = 1.10 [95% CI = 0.79, 1.54]; P = 0.59). However, endocrine therapy plus ZOL significantly reduced the risk of DFS events by 36% compared with endocrine therapy alone (HR = 0.64 [0.46, 0.91]; P = 0.01). The addition of ZOL significantly reduced the risk of RFS events by 35% (HR = 0.65 [0.46, 0.92]; P = 0.015) compared with endocrine therapy alone. For OS, there was a nonsignificant trend favoring ZOL treatment (HR = 0.60 [0.32, 1.11]; P = 0.10). Treatment was generally well tolerated among the 4 groups and consistent with known safety profiles of the drugs. Conclusions: There was no significant difference in DFS between TAM and ANA. The addition of ZOL (4 mg q 6 mo) to adjuvant endocrine therapy significantly prolonged DFS and RFS compared with adjuvant endocrine therapy alone in premenopausal women with endocrine-responsive BC. This large clinical trial demonstrates that the antitumor activity of adjuvant ZOL improves outcomes beyond the effect of endocrine therapy alone.