Elsevier

The Lancet Oncology

Volume 9, Issue 9, September 2008, Pages 840-849
The Lancet Oncology

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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

https://doi.org/10.1016/S1470-2045(08)70204-3Get rights and content

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/cm2 [95% CI −0·146 to −0·091], p<0·0001) and trochanter (−7·3%, mean difference −0·053 g/cm2 [−0·076 to −0·030], p<0·0001). In patients who did not receive zoledronic acid, anastrozole caused greater BMD loss than tamoxifen at 36 months at the lumbar spine (−13·6%, mean difference −0·141 g/cm2 [−0·179 to −0·102] vs −9·0%, mean difference −0·095 g/cm2 [−0·134 to −0·057], p<0·0001 for both). 2 years after the completion of treatment (median follow-up 60 months [range 15·5–96·6]), patients not receiving zoledronic acid still had decreased BMD at both sites compared with baseline (lumbar spine −6·3%, mean difference −0·067 g/cm2 [−0·106 to −0·027], p=0·001; trochanter −4·1%, mean difference −0·03 g/cm2 [−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/cm2 [−0·024 to 0·032]; trochanter +0·8%, mean difference 0·006 g/cm2 [−0·018 to 0·028]) and increased BMD at 60 months at both sites (lumbar spine +4·0%, mean difference 0·039 g/cm2 [0·005–0·075], p=0·02; trochanter +3·9%, mean difference 0·028 g/cm2 [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).

Introduction

Adjuvant endocrine therapy is now used routinely in patients with hormone-responsive early breast cancer. After surgical excision of the tumour, the aim of adjuvant therapy is to prevent growth of residual tumour cells and extend patient survival. Thus, in postmenopausal patients, the introduction of selective oestrogen-receptor (ER) modulators (eg, tamoxifen) or aromatase inhibitors (eg, letrozole, anastrozole, and exemestane) has substantially improved survival.

In premenopausal women, however, ovarian ablation with surgery or radiation, or reversible ovarian suppression with gonadotropin-releasing hormone (GnRH) analogues is needed to sufficiently inhibit ovarian oestrogen production. In the adjuvant-therapy setting for premenopausal women with advanced hormone-receptor-positive breast cancer, the combination of a GnRH analogue with tamoxifen improves progression-free survival (PFS) and overall survival compared with ovarian suppression alone.1, 2 In premenopausal women with metastatic breast cancer, the combination of a GnRH analogue and tamoxifen is therefore currently the adjuvant treatment of choice. For premenopausal women with early-stage breast cancer, however, the effects of adjuvant endocrine therapy are still somewhat inconclusive.3 Additionally, combining a GnRH analogue with tamoxifen in these patients with early-stage breast cancer is at least as effective as cytotoxic chemotherapy and has a more favourable safety profile.4, 5 The 2007 St Gallen expert consensus guidelines recommend ovarian suppression with GnRH analogues in premenopausal women with hormone-responsive early breast cancer.6 Because aromatase inhibitors have proven better than tamoxifen in postmenopausal women with ER-positive breast cancer, the combination of an aromatase inhibitor with ovarian suppression is being studied in clinical trials as an alternative to tamoxifen in premenopausal patients.

The Austrian Breast and Colorectal Cancer Study Group trial-12 (ABCSG-12) was designed to assess the clinical efficacy of goserelin-induced ovarian suppression plus tamoxifen or anastrozole with or without zoledronic acid in 1803 patients. The first efficacy findings for disease-free survival (DFS), recurrence-free survival (RFS), and overall survival in patients treated with or without zoledronic acid are expected shortly and will be reported separately. A prospective bone-mineral density (BMD) substudy in 404 patients was included in the study design to quantify the long-term effects of endocrine therapy on BMD and to assess the effects of concomitant zoledronic acid on BMD. A 36-month analysis of the BMD substudy showed significant bone loss in patients who received endocrine therapy alone and maintenance of BMD in patients who received endocrine therapy plus zoledronic acid.7 However, how patients' BMD might change after cessation of adjuvant therapy is not entirely clear. A recent study in premenopausal women with breast cancer who were assigned goserelin or chemo-therapy suggests that partial BMD recovery after cessation of goserelin therapy is possible in women who regain ovarian function.8 Patients who did not recover ovarian function, however, did not have recovery of BMD. The 60-month follow-up data presented here show the BMD status of patients enrolled in the ABCSG-12 bone substudy 2 years after completion of adjuvant therapy.

Section snippets

Patients

Patients and methods have been described previously in detail.7 Briefly, premenopausal women (≥19 years of age) enrolled in the study had received surgery for stage I/II ER-positive or progesterone-receptor (PgR)-positive (or both) breast cancer, had a Karnofsky Index of 70 or greater, fewer than ten positive lymph nodes, and were scheduled to receive goserelin for 3 years. Exclusion criteria included T1a (except yT1a), T4d, or yT4 breast cancer; a history of other tumours or cytotoxic

Results

Of 1803 patients randomly assigned to the four treatment groups in the ABCSG-12 trial, 404 were prospectively included in the bone substudy (figure 1). Patient demographics and baseline disease characteristics were similar between the treatment groups, and were representative of patients enrolled in the main trial at the same trial centres (table 1). Patients in two of the treatment groups were assigned endocrine therapy (goserelin plus either tamoxifen [n=100] or anastrozole [n=105]) plus

Discussion

In the BMD substudy of the ABCSG-12, we have shown that zoledronic acid combined with ovarian suppression and with endocrine therapy for premenopausal women with early-stage breast cancer is associated with sustained BMD during 3 years of endocrine therapy and an increase in BMD 2 years after completion of therapy. We also show that much of the bone loss associated with endocrine therapy alone is still present 2 years after completion of treatment. The findings presented here offer important

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