Fast track — ArticlesAdjuvant 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
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.
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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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