Final 5‐year results of Z‐FAST trial

Abstract

BACKGROUND: Postmenopausal breast cancer (BC) patients receiving adjuvant aromatase inhibitor therapy are at risk of progressive bone loss and fractures. Zoledronic acid inhibits osteoclastic bone resorption, is effective in maintaining bone health, and may therefore be beneficial in this setting. METHODS: Overall, 602 postmenopausal women with early, hormone receptor-positive BC receiving adjuvant letrozole were randomized (301 each group) to receive upfront or delayed-start zoledronic acid (4 mg intravenously every 6 months) for 5 years. The primary endpoint was the change in lumbar spine (LS) bone mineral density (BMD) at month 12. Secondary endpoints included changes in LS BMD, total hip BMD, and bone turnover markers at 2, 3, and 5 years; fracture incidence at 3 years; and time to disease recurrence. RESULTS: At month 61, the adjusted mean difference in LS and total hip BMDs between the upfront and delayed groups was 8.9% and 6.7%, respectively (P < .0001, for both). Approximately 25% of delayed patients received zoledronic acid by month 61. Only 1 patient experienced grade 4 renal dysfunction; no confirmed cases of osteonecrosis of the jaw were reported. Fracture rates (upfront, 28 [9.3%]; delayed, 33 [11%]; P ¼ .3803) and KaplanMeier disease recurrence rates (upfront, 9.8 [95% confidence interval (CI), 6.0-10.3]; delayed, 10.5 [95% CI, 6.6-14.4]; P ¼ .6283) were similar at month 61. CONCLUSIONS: Upfront zoledronic acid seems to be the preferred treatment strategy versus delayed administration, as it significantly and progressively increases BMD in postmenopausal women with early BC receiving letrozole for 5 years, and long-term coadministration of letrozole and zoledronic acid is well tolerated.

Mechanisms of action of bisphosphonates in oncology: a scientific concept evolving from antiresorptive to anticancer activities

“…19 In the companion North American trial to ZO-FAST (the ZometaFemara Adjuvant Synergy Z-FAST study; n ¼ 602), immediate zoledronate also reduced disease recurrence, but did not result in a statistically significant difference in disease-free survival compared with the delayed-zoledronate group (16 vs 21 at 61 months' follow-up) ( Table 1). 20 However, taken together these findings [17][18][19][20] suggested that zoledronate may improve diseasefree survival in breast cancer patients.…”

“…19 Although not statistically significant, locoregional recurrences in the Z-FAST trial also occurred in slightly more patients in the delayed-zoledronate group compared with the immediatezoledronate group (4 vs 2 at 61 months' follow-up). 20 Thus, zoledronate released from bone might therefore block tumor self-seeding. Additionally, zoledronate could block mechanisms of secondary spread from bone by inhibiting the recruitment of bone marrow-derived cells to sites of premetastatic niches.…”

Breast Cancer and Osteoporosis - Management of Cancer Treatment-Induced Bone Loss in Postmenopausal Women with Breast Cancer

“…4 mg zoledronic acid twice a year) to prevent AIBL in women with a high fracture risk [33]. These results were confirmed by 4 randomized controlled studies with more than 4,000 women with BC, who were treated with an AI [48,49,50,51]. …”

Bone Homeostasis and Breast Cancer: Implications for Complex Therapy and the Maintenance of Bone Integrity

“…The oral bisphosphonate risedronate has been found to be effective in preventing chemotherapyinduced bone loss in premenopausal women [33]. In the Z-FAST study, 602 postmenopausal patients receiving adjuvant letrozole therapy were randomized to upfront vs. delayed zoledronate therapy (in the delayed group therapy was started if the BMD decreased to −2.0) [36]. In the companion studies ZO-FAST and E-ZO-FAST, similar results were found, despite the fact that the 3 studies included patients from different geographical areas [37,38].…”