Abstract P5-11-01: The Effect of Zoledronic Acid on Aromatase Inhibitor Associated Bone Loss in Postmenopausal Women with Early Breast Cancer Receiving Adjuvant Letrozole: The ZO-FAST Study 5-Year Final Follow-Up

Abstract

Abstract Background: Letrozole (LET) is an accepted adjuvant endocrine therapy for hormone receptor-positive (HR+) postmenopausal early breast cancer (EBC) with superior efficacy to tamoxifen. Long term aromatase inhibitors (AI) treatment reduces estrogen levels well below postmenopausal levels leading to acceleration of bone loss. Zoledronic acid (ZOL), effectively inhibits osteoclastic bone resorption in both benign and malignant bone disorders. The primary analysis at 12 months of the Z-FAST, ZO-FAST and E-ZO-FAST studies demonstrated that lumbar spine (LS) bone mineral density (BMD) loss secondary to LET can effectively be prevented by ZOL. In addition, the 36 month (mo) follow-up for ZO-FAST demonstrated ZOL improved disease free survival (DFS). This 5 yr analysis of ZO-FAST reports the final BMD results, long term safety and DFS. Additionally, we examine the characteristics of patients in the delayed arm who required ZOL to maintain BMD. Materials and Methods: 1065 postmenopausal women (PMW) hormone receptor positive (HR+) EBC receiving LET (2.5 mg qd x 5 yrs) with a BMD T-score ≥-2 were randomized to immediate ZOL arm (IMZOL, n=532) vs delayed ZOL arm (DZOL, n=533). ZOL was initiated in DZOL when postbaseline T-score decreased to <-2 SD, a non-traumatic or asymptomatic fracture occurred. Patients were followed for disease recurrence (DR) and survival until 5 years after the closure of enrollment. Results: At 60 mo, LS BMD is maintained with IMZOL with a mean percent change from baseline of 4.3 vs -5.4 in DZOL (least square difference of 10%, P<0.0001). 144 pts (26.9%) in the DZOL started ZOL at a median of 12.8 mo (range 0.9-62.1 mo). Patients on the DZOL who started ZOL were 81/165 (49%) initially osteopenic (-2≤ Tscore <-1.0) and 63/370 (17%) had a normal BMD (Tscore >-1.0). Additional risk factors regarding bone health were evaluated in a subset of patients. The fracture rate for the two arms is 39 (7.4%) in IMZOL and 38 (7.1%) DZOL. A total of 104 patients (31 DR and 11 deaths in the IMZOL vs. 48 DR and 14 deaths in the DZOL) experienced a DFS event. The hazard ratio for the comparison is 0.66 with a 95% confidence interval (0.44, 0.97), (p = 0.034). In the IMZOL, there were 29 patients (5.5%) with a distant recurrence vs 41 (7.7%) in the DZOL. Patients with local recurrences were 5 (0.9%) vs 12 (2.3%) in the respective arms. Over the 5 year study duration, osteonecrosis of the jaw (ONJ) was found in 4/669 patients who received ZOL (0.6%). Adverse events remain as previously reported and are consistent with the known safety profile of both study drugs. Conclusion: The 5 yr final analysis confirms the primary endpoint that ZOL 4mg IV q 6 mos is effective in preventing bone loss associated with adjuvant AI therapy in HR+ PMW with EBC. With longer follow up, the data continues to demonstrate a significant DFS benefit in the upfront ZOL arm supporting the antitumor efficacy of ZOL seen in several tumor types. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-11-01.