Introduction: Recent clinical trials suggest potential anticancer activity for bisphosphonates combined with adjuvant endocrine therapy in patients with hormone receptor-positive (HR+) early breast cancer (EBC). Data from the interim analysis of AZURE suggest that the benefits of adding zoledronic acid (ZOL) may be greatest in patients with low estrogen levels (Coleman RE, et al. SABCS 2010). In ZO-FAST, we have previously demonstrated that adding ZOL to adjuvant therapy significantly improved bone mineral density (BMD) and prolonged disease-free survival (DFS) vs delayed ZOL (de Boer R, et al. SABCS 2010). We report here the effect of time since menopause at breast cancer diagnosis (ie, baseline menopausal status) on DFS benefits with ZOL. Methods: Postmenopausal women with HR+ EBC receiving letrozole (LET; 2.5 mg qd x 5 yr) with a BMD T-score ≥-2 (N=1065) were randomized to ZOL (4 mg q6mo): immediate (IMZOL) or delayed (DZOL; initiated for postbaseline T-score Results: At 60 months’ follow-up in the overall population (N=1065), IMZOL significantly reduced the risk of a DFS event by 34% vs DZOL (hazard ratio [HR]=0.66; 95% confidence interval [CI], 0.44−0.97; P=.034). In exploratory analyses of women who were postmenopausal for >5 years or >60 years old at study entry (n=670), IMZOL improved DFS (HR=0.63; 95% CI, 0.39−1.01; P=.052) and significantly prolonged OS (HR=0.50; 95% CI, 0.27−0.92; P=.022) vs DZOL. Additional subgroup analyses including patterns of breast cancer recurrence will be presented. During 5 years of treatment, osteonecrosis of the jaw (ONJ) was reported in 4/669 patients (0.6%) who received ZOL, and there was no increase in renal adverse events (AEs) in the ZOL-treated patients. Overall, AEs were consistent with the known safety profiles of both study drugs. Conclusions: Long-term follow-up in ZO-FAST confirms the overall survival benefits of adding ZOL (4 mg q6mo) to adjuvant LET therapy for EBC. However, subset analyses suggest that women with established postmenopausal status may benefit from ZOL therapy more than others. These results are consistent with observations in the AZURE trial, and support potentially greater ZOL benefits in a low-estrogen environment. Additional studies are needed to fully define the patient populations most likely to benefit from adjuvant ZOL in this setting. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S1-3.