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. 2018 Sep 27:13:123-135.
doi: 10.1016/j.jbo.2018.09.008. eCollection 2018 Nov.

Benefits and risks of adjuvant treatment with zoledronic acid in stage II/III breast cancer. 10 years follow-up of the AZURE randomized clinical trial (BIG 01/04)

R E Coleman  1 , M Collinson  2 , W Gregory  2 , H Marshall  2 , R Bell  3 , D Dodwell  4 , M Keane  5 , M Gil  6 , P Barrett-Lee  7 , D Ritchie  8 , A Bowman  9 , V Liversedge  2 , R H De Boer  10 , J L Passos-Coelho  11 , S O'Reilly  12 , G Bertelli  13 , J Joffe  14 , J E Brown  1 , C Wilson  1 , J C Tercero  15 , J Jean-Mairet  15 , R Gomis  16 , D Cameron  9
Affiliations

Benefits and risks of adjuvant treatment with zoledronic acid in stage II/III breast cancer. 10 years follow-up of the AZURE randomized clinical trial (BIG 01/04)

R E Coleman et al. J Bone Oncol. .

Abstract

Adjuvant bisphosphonates improve disease outcomes in postmenopausal early breast cancer (EBC) but the long-term effects are poorly described. The AZURE trial (ISRCTN79831382) was designed to determine whether adjuvant zoledronic acid (ZOL) improves disease outcomes in EBC. Previous analyses showed no effect on overall outcomes but identified benefits in postmenopausal women. Here we present the long-term risks and benefits of adjuvant ZOL with 10-years follow-up.

Patients and methods: 3360 patients with stage II/III breast cancer were included in an academic, international, phase III, randomized, open label trial. Patients were followed up on a regular schedule until 10 years. Patients were randomized on a 1:1 basis to standard adjuvant systemic therapy +/- intravenous ZOL 4 mg every 3-4 weeks x6, and then at reduced frequency to complete 5 years treatment. The primary outcome was disease free survival (DFS). Secondary outcomes included invasive DFS (IDFS), overall survival (OS), sites of recurrence, skeletal morbidity and treatment outcomes according to primary tumor amplification of the transcription factor, MAF. Pre-planned subgroup analyses focused on interactions between menopausal status and treatment effects.

Results: With a median follow up of 117 months [IQR 70.4-120.4), DFS and IDFS were similar in both arms (HRDFS = 0.94, 95%CI = 0.84-1.06, p = 0.340; HRIDFS = 0.91, 95%CI = 0.82-1.02, p = 0.116). However, outcomes remain improved with ZOL in postmenopausal women (HRDFS = 0.82, 95%CI = 0.67-1.00; HRIDFS = 0.78, 95%CI = 0.64-0.94). In the 79% of tested women with a MAF FISH negative tumor, ZOL improved IDFS (HRIDFS = 0.75, 95%CI = 0.58-0.97) and OS HROS = 0.69, 95%CI = 0.50-0.94), irrespective of menopause. ZOL did not improve disease outcomes in MAF FISH + tumors. Bone metastases as a first DFS recurrence (BDFS) were reduced with ZOL (HRB-DFS = 0.76, 95%CI = 0.63-0.92, p = 0.005). ZOL reduced skeletal morbidity with fewer fractures and skeletal events after disease recurrence. 30 cases of osteonecrosis of the jaw in the ZOL arm (1.8%) have occurred.

Conclusions: Disease benefits with adjuvant ZOL in postmenopausal early breast cancer persist at 10 years of follow-up. The biomarker MAF identified a patient subgroup that derived benefit from ZOL irrespective of menopausal status.

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Figures

Fig. 1.
Fig. 1
CONSORT diagram.
Fig. 2.
Fig. 2
Disease free (DFS) and invasive disease free survival (IDFS) by treatment allocation (Top panels - ITT analysis; Bottom panels - women who were in established menopause (> 5 years since last menses) at study entry).
Fig. 3.
Fig. 3
Cumulative incidence of bone metastases as first DFS recurrence.
Fig. 4.
Fig. 4
Overall survival in the ITT analysis (A: left) and > 5years postmenopausal subgroup (B: right).
Fig. 5.
Fig. 5
Invasive disease free (IDFS) and overall survival (OS) by treatment allocation in the 79% of patients tested who did not over-express (copy number < 2.5) the MAF gene.
Fig. 6.
Fig. 6
Exploratory analyses investigating the impact of age at randomization on disease outcomes with or without adjuvant zoledronic acid: A:top – All DFS events; B:middle – bone DFS events; C:bottom – all DFS other than bone events.
Fig. 7.
Fig. 7
Exploratory analyses investigating the impact of age at randomization on overall survival (top) and breast cancer survival (bottom) with or without adjuvant zoledronic acid.
Fig. 8.
Fig. 8
Cumulative incidence function for time to confirmed osteonecrosis of the jaw for patients receiving zoledronic acid. No cases were reported in the control population.
See this image and copyright information in PMC

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