P2-17-01: Influence of Delayed Zoledronic Acid Initiation on Disease-Free Survival in Postmenopausal Women with Endocrine Receptor-Positive Early Breast Cancer Receiving Adjuvant Letrozole: Exploratory Analyses from the ZO-FAST Trial.
Authors: Coleman R , De Boer R , Eidtmann H , Neven P , von Minckwitz G , Martin N , Modi A , Bundred N 
Published: June 2012

Introduction: Bisphosphonates (BPs) combined with adjuvant endocrine therapy have been shown to prevent aromatase inhibitor-associated bone loss (AIBL) and improve outcomes in recent clinical trials in patients with hormone receptor-positive (HR+) early breast cancer (EBC). Accelerated bone turnover (a common phenomenon during AIBL) has been associated with increased risk of bone metastasis in EBC (Lipton A, et al. St. Gallen 2009. abs #244), but little is known about the effect of BPs on the disease course in women with EBC and progressing AIBL. 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. P5-11-01). We report here the prognostic factors for DFS and the effect of ZOL initiation in the delayed ZOL (DZOL) arm of the ZO-FAST trial at 5 years’ median follow-up.

Methods: The ZO-FAST trial randomized postmenopausal women with HR+ EBC initiating letrozole (LET; 2.5 mg qd x 5 years) with a BMD T-score ≥ −2 (N=1,065) to immediate (IMZOL; 4 mg q 6 months) or DZOL (initiated for post-baseline T-score &lt; −2, or nontraumatic/asymptomatic fractures). The primary endpoint was change in BMD at 12 months; patients were followed for disease recurrence and overall survival for 5 years (secondary endpoints). Exploratory Cox regression analyses were performed to identify prognostic factors for DFS in the DZOL arm.

Results: At 60-months follow-up, IMZOL significantly reduced the risk of a DFS event by 34% vs DZOL (42 vs 62 events; ∼80% distant recurrences and 20% local; hazard ratio [HR]=0.66; 95% confidence interval [CI], 0.44−0.97; P=.034) in the intent-to-treat population (N=1,065; n=532 IMZOL; n=533 DZOL). In exploratory analyses of the DZOL arm (n=535; safety population), patients who initiated DZOL treatment (n=144) had significantly improved DFS (10 events; HR=0.462; 95% CI, 0.23−0.94; P=.033) compared with DZOL arm patients who never initiated ZOL (53 events; n=391). Other significant prognostic factors for DFS events in the DZOL arm were age ≥65 years at study entry (HR=1.949; 95% CI, 1.09−3.47; P=.024 vs age &lt;65 years) and cancer T-stage ≥2 (HR=2.155; 95% CI, 1.03−4.51; P=.042 vs T-stage &lt;2).

Conclusions: Exploratory analyses of the ZO-FAST database revealed significant DFS benefits from initiation of ZOL treatment for postbaseline fractures or T-scores &lt; −2, suggesting that ZOL (even if initiated late) can positively influence the disease course in patients with AIBL. Together with other studies showing DFS benefits from ZOL in patients with complete ovarian suppression/postmenopausal status (Coleman RE, et al. SABCS 2010. abs #S4-5; Gnant M, et al. NEJM 2009;360:679–691), these data suggest that treating (and ideally, preventing) AIBL may also improve DFS in patients with HR+ EBC.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-17-01.