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)

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dc.contributor.author Coleman, R. E.
dc.contributor.author Collinson, M.
dc.contributor.author Gregory, W.
dc.contributor.author Marshall, H.
dc.contributor.author Bell, R.
dc.contributor.author Dodwell, D.
dc.contributor.author Keane, M.
dc.contributor.author Gil, M.
dc.contributor.author Barrett-Lee, P.
dc.contributor.author Ritchie, D.
dc.contributor.author Bowman, A.
dc.contributor.author Liversedge, V.
dc.contributor.author De Boer, R. H.
dc.contributor.author Passos-Coelho, J. L.
dc.contributor.author O'Reilly, S.
dc.contributor.author Bertelli, G.
dc.contributor.author Joffe, J.
dc.contributor.author Brown, J. E.
dc.contributor.author Wilson, C.
dc.contributor.author Tercero, J. C.
dc.contributor.author Jean-Mairet, J.
dc.contributor.author Gomis, R.
dc.contributor.author Cameron, D.
dc.date.accessioned 2019-09-09T16:11:49Z
dc.date.available 2019-09-09T16:11:49Z
dc.date.issued 2018-09-27
dc.identifier.citation Coleman, R.E., Collinson, M., Gregory, W., Marshall, H., Bell, R., Dodwell, D., Keane, M., Gil, M., Barrett-Lee, P., Ritchie, D. and Bowman, A., 2018. 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). Journal of bone oncology, 13,(12pp). DOI:10.1016/j.jbo.2018.09.008 en
dc.identifier.volume 13 en
dc.identifier.startpage 123 en
dc.identifier.endpage 135 en
dc.identifier.issn 2212-1374
dc.identifier.uri http://hdl.handle.net/10468/8491
dc.identifier.doi 10.1016/j.jbo.2018.09.008 en
dc.description.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. en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher Elsevier GmbH en
dc.relation.uri http://www.sciencedirect.com/science/article/pii/S2212137418302628
dc.rights © 2018 The Authors. Published by Elsevier GmbH en
dc.rights.uri https://creativecommons.org/licenses/by-nc-nd/4.0/ en
dc.subject Zoledronic acid en
dc.subject Breast cancer en
dc.subject AZURE en
dc.subject Adjuvant treatment en
dc.title 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) en
dc.type Article (peer-reviewed) en
dc.internal.authorcontactother Seamus O'Reilly, Department of Medicine, University College Cork, Cork, Ireland. +353-21-490-3000 Email: seamus.oreilly@ucc.ie en
dc.internal.availability Full text available en
dc.description.version Published Version en
dc.contributor.funder University of Sheffield en
dc.contributor.funder Novartis en
dc.contributor.funder Bayer en
dc.contributor.funder Amgen en
dc.contributor.funder Janssen Biotech en
dc.contributor.funder Cologne en
dc.contributor.funder Inbiomotion en
dc.description.status Peer reviewed en
dc.identifier.journaltitle Journal of Bone Oncology en
dc.internal.IRISemailaddress seamus.oreilly@ucc.ie en


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© 2018 The Authors. Published by Elsevier GmbH Except where otherwise noted, this item's license is described as © 2018 The Authors. Published by Elsevier GmbH
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