Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 5-year follow-up of the ABCSG-12 bone-mineral density substudy

TLDR: A randomised, open-label, phase III, 4-arm trial comparing tamoxifen and goserelin versus anastrozole and zoledronic acid for preventing bone loss associated with adjuvant endocrine therapy and reports on long-term findings of bone-mineral density (BMD) during 3 years of treatment and 2 years after completing adjuant treatment with or without zoledronics acid.

Abstract: Summary Background The Austrian Breast and Colorectal Cancer Study Group trial-12 (ABCSG-12) bone substudy assesses zoledronic acid for preventing bone loss associated with adjuvant endocrine therapy and reports on long-term findings of bone-mineral density (BMD) during 3 years of treatment and 2 years after completing adjuvant treatment with or without zoledronic acid. The aim of this substudy is to gain insight into bone health in this setting. Methods ABCSG-12 is a randomised, open-label, phase III, 4-arm trial comparing tamoxifen (20 mg/day orally) and goserelin (3·6 mg subcutaneously every 28 days) versus anastrozole (1 mg/day orally) and goserelin (3·6 mg subcutaneously every 28 days), both with or without zoledronic acid (4 mg intravenously every 6 months) for 3 years in premenopausal women with endocrine-responsive breast cancer. This prospective bone subprotocol measured BMD at 0, 6, 12, 36, and 60 months. The primary endpoint of the bone substudy (secondary endpoint in the main trial) was change in BMD at 12 months, assessed by dual-energy X-ray absorptiometry in assessable patients. Analyses were intention to treat. Statistical significance was assessed by t tests. The ABCSG-12 trial is registered on the ClinicalTrials.gov website, number NCT00295646. Findings 404 patients were prospectively included in the bone substudy and randomly assigned to endocrine therapy alone (goserelin and anastrozole or goserelin and tamoxifen; n=199) or endocrine therapy concurrent with zoledronic acid (goserelin, anastrozole, and zoledronic acid or goserelin, tamoxifen, and zoledronic acid; n=205). After 3 years of treatment, endocrine therapy alone caused significant loss of BMD at the lumbar spine (−11·3%, mean difference −0·119 g/cm 2 [95% CI −0·146 to −0·091], p 2 [−0·076 to −0·030], p 2 [−0·179 to −0·102] vs −9·0%, mean difference −0·095 g/cm 2 [−0·134 to −0·057], p 2 [−0·106 to −0·027], p=0·001; trochanter −4·1%, mean difference −0·03 g/cm 2 [−0·062 to 0·001], p=0·058). Patients who received zoledronic acid had stable BMD at 36 months (lumbar spine +0·4%, mean difference 0·004 g/cm 2 [−0·024 to 0·032]; trochanter +0·8%, mean difference 0·006 g/cm 2 [−0·018 to 0·028]) and increased BMD at 60 months at both sites (lumbar spine +4·0%, mean difference 0·039 g/cm 2 [0·005–0·075], p=0·02; trochanter +3·9%, mean difference 0·028 g/cm 2 [0·003–0·058], p=0·07) compared with baseline. Interpretation Goserelin plus tamoxifen or anastrozole for 3 years without concomitant zoledronic acid caused significant bone loss. Although there was partial recovery 2 years after completing treatment, patients receiving endocrine therapy alone did not recover their baseline BMD levels. Concomitant zoledronic acid prevented bone loss during therapy and improved BMD at 5 years. Funding AstraZeneca (London, UK) and Novartis (Basel, Switzerland).