Elsevier

The Lancet Oncology

Volume 12, Issue 7, July 2011, Pages 631-641
The Lancet Oncology

Articles
Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial

https://doi.org/10.1016/S1470-2045(11)70122-XGet rights and content

Summary

Background

Analysis of the Austrian Breast and Colorectal Cancer Study Group trial-12 (ABCSG-12) at 48 months' follow-up showed that addition of zoledronic acid to adjuvant endocrine therapy significantly improved disease-free survival. We have now assessed long-term clinical efficacy including disease-free survival and disease outcomes in patients receiving anastrozole or tamoxifen with or without zoledronic acid.

Methods

ABSCG-12 is a randomised, controlled, open-label, two-by-two factorial, multicentre trial in 1803 premenopausal women with endocrine-receptor-positive early-stage (stage I–II) breast cancer receiving goserelin (3·6 mg every 28 days), comparing the efficacy and safety of anastrozole (1 mg per day) or tamoxifen (20 mg per day) with or without zoledronic acid (4 mg every 6 months) for 3 years. Randomisation (1:1:1:1 ratio) was computerised and based on the Pocock and Simon minimisation method to balance the four treatment arms across eight prognostic variables (age, neoadjuvant chemotherapy, pathological tumour stage; lymph-node involvement, type of surgery or locoregional therapy, complete axillary dissection, intraoperative radiation therapy, and geographical region). Treatment allocation was not masked. The primary endpoint was disease-free survival (defined as disease recurrence or death) and analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00295646; follow-up is ongoing.

Findings

At a median follow-up of 62 months (range 0–114·4 months), more than 2 years after treatment completion, 186 disease-free survival events had been reported (53 events in 450 patients on tamoxifen alone, 57 in 453 patients on anastrozole alone, 36 in 450 patients on tamoxifen plus zoledronic acid, and 40 in 450 patients on anastrozole plus zoledronic acid). Zoledronic acid reduced risk of disease-free survival events overall (HR 0·68, 95% CI 0·51–0·91; p=0·009), although the difference was not significant in the tamoxifen (HR 0·67, 95% CI 0·44–1·03; p=0·067) and anastrozole arms (HR 0·68, 95% CI 0·45–1·02; p=0·061) assessed separately. Zoledronic acid did not significantly affect risk of death (30 deaths with zoledronic acid vs 43 deaths without; HR 0·67, 95% CI 0·41–1·07; p=0·09). There was no difference in disease-free survival between patients on tamoxifen alone versus anastrozole alone (HR 1·08, 95% CI 0·81–1·44; p=0·591), but overall survival was worse with anastrozole than with tamoxifen (46 vs 27 deaths; HR 1·75, 95% CI 1·08–2·83; p=0·02). Treatments were generally well tolerated, with no reports of renal failure or osteonecrosis of the jaw. Bone pain was reported in 601 patients (33%; 349 patients on zoledronic acid vs 252 not on the drug), fatigue in 361 (20%; 192 vs 169), headache in 280 (16%; 147 vs 133), and arthralgia in 266 (15%; 145 vs 121).

Interpretation

Addition of zoledronic acid improved disease-free survival in the patients taking anastrozole or tamoxifen. There was no difference in disease-free survival between patients receiving anastrozole and tamoxifen overall, but those on anastrozole alone had inferior overall survival. These data show persistent benefits with zoledronic acid and support its addition to adjuvant endocrine therapy in premenopausal patients with early-stage breast cancer.

Funding

AstraZeneca; Novartis.

Introduction

Historically, treatment for early-stage breast cancer has focused on direct targeting of cancer cells. However, increasing evidence suggests that modification of the microenvironment surrounding cancer cells can have potent anticancer effects.1 Bisphosphonates have shown anticancer potential in various cancer types in preclinical and clinical studies,2 and there is growing awareness that combination of tumour-targeted therapy with treatments that affect the cancer-cell environment, such as bisphosphonates, can improve anticancer response and long-term outcomes.

Although bisphosphonates are a bone-targeted treatment, their anticancer activity might not be limited to bone. For example, at 36 months' follow-up in the Zometa-Femara Adjuvant Synergy Trial (ZO-FAST) study in postmenopausal women with early breast cancer (N=1065), addition of zoledronic acid to adjuvant endocrine therapy reduced the relative risk of disease-free survival events (hazard ratio [HR] 0·59, 95% CI 0·36–0·96; p=0·0314),3 and continued to reduce the risk at 48 months' follow-up (HR 0·59, 0·38–0·92; p=0·0175).4 In this trial, adjuvant zoledronic acid reduced disease recurrence in bone and non-bone sites. In the Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE) trial (N=3360) in women with early (stage II or III) breast cancer,5 although there were no statistically significant improvements in disease-free survival (HR 0·98, 95% CI 0·85–1·13; p=0·79) or survival (HR 0·85, 0·72–1·01; p=0·07) in the overall population, a tapered dosing regimen of zoledronic acid significantly reduced the risk of disease-free survival events (HR 0·76, 0·60–0·98; p<0·05) and the risk of death (HR 0·71, 0·54–0·94; p=0·017) in patients who were postmenopausal for longer than 5 years before study entry (n=1041; n=1101 when patients older than 60 years were included). Moreover, other subset analyses from the AZURE trial6 showed that addition of monthly zoledronic acid to neoadjuvant chemotherapy significantly reduced residual invasive tumour size by 44% (15·5 vs 27·4 mm, respectively; p=0·006), improved the rate of pathological complete response, and reduced the need for mastectomy (n=205 for neoadjuvant subset). Further evidence from three recent retrospective database analyses (total N=164 718)7, 8, 9 suggests that oral bisphosphonates might prevent breast cancer in healthy postmenopausal women receiving treatment for osteoporosis. Taken together, these data suggest that bisphosphonate anticancer effects might be beneficial early in the disease course.

In the Austrian Breast and Colorectal Cancer Study Group trial-12 (ABCSG-12), the event-driven primary endpoint for comparisons of zoledronic acid versus no zoledronic acid and tamoxifen versus anastrozole was first reported after a median follow-up of 48 months (range 0–101·8).10 However, because patients in this trial have a good prognosis, there was an insufficient number of events to assess definitively the effects of individual treatments on overall survival or to examine benefits in informative patient subgroups. For example, there was a non-significant difference in overall survival favouring patients receiving tamoxifen versus patients receiving anastrozole,10 which is counter to previous reports of superior oestrogen depletion in premenopausal women11 and a significant increase in disease-free survival in postmenopausal patients with breast cancer treated with aromatase inhibitors versus tamoxifen.12, 13, 14

Now, after a median follow-up of 62 months (range 0–114·4; longer than 2 years after completion of therapy based on a median treatment duration of 35·9 months in this study) in ABCSG-12, 49 (186 vs 137; 36%) more patients have had disease-free survival events and there have been 31 (73 vs 42; 74%) more deaths on study than were reported at 48 months' follow-up.10 We undertook an analysis at 62 months' follow-up to clarify previously unanswered questions about disease-free and overall survival outcomes in ABCSG-12 and to provide additional information about tolerability and persistent benefits of zoledronic acid combined with endocrine therapy in these patients.

Section snippets

Trial design and patients

The trial design was described previously.10 Briefly, ABCSG-12 is a randomised, phase 3 trial in premenopausal women with stage I or II oestrogen-receptor-positive and/or progesterone-receptor-positive breast cancer. Patients' premenopausal status was defined by a clinically estimated regular menstrual cycle or a last menstrual cycle occurring not more than 1 year before study entry. In women with indeterminate menstrual status (eg, posthysterectomy), serum concentrations of

Results

1803 patients were randomly assigned to treatment groups in the ABCSG-12 trial (figure 1), including 1375 (76%) with T1-stage cancer, and 550 (31%) with node-positive cancer. Median age at randomisation was 45 years (range 25–58 years), and all tumours were endocrine-responsive (oestrogen-receptor-positive, progesterone-receptor-positive, or both). Disease and demographic characteristics were well balanced between groups (table 1). The first patient was enrolled on June 17, 1999, and the last

Discussion

The primary endpoint of the ABCSG-12 trial, using a two-by-two factorial design, was to compare disease-free survival for zoledronic acid versus no zoledronic acid and tamoxifen versus anastrozole in premenopausal women receiving adjuvant ovarian suppression for early breast cancer. With longer follow-up and substantially more events than in our earlier report, our new analyses confirmed previous findings and showed that the the benefits of zoledronic acid extend for 2 years after treatment

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