Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials

Jonas Bergh ,Emiel J Rutgers ,Timothy J Whelan ,Lori J Pierce ,Giuseppe Viale ,Rosie Bradley ,James N Ingle ,Jf Forbes ,N Davidson ,Luca Gianni ,Nicholas Wilcken ,Marc Buyse ,Mitch Dowsett ,W Bergsten-Nordström ,Aron Goldhirsch ,Gϋnter Von Minckwitz ,Joseph P Costantino ,Angelo Di Leo ,Stewart J Anderson ,Robert E Coleman ,R.d Gelber ,E González Pérez ,William E Barlow ,R Arriagada ,Richárd Pető ,Michael Clarke ,J F R Robertson ,Marianne Ewertz ,Judith Bliss ,Larry Norton ,Paul Mcgale ,Catherine Hill ,Peter M Ravdin ,Claire Davies ,Carolyn Taylor ,R Piccart ,Yasuo Ohashi ,Jack Cuzick ,Kathy S Albain ,Eric P Winer ,Joseph A Sparano ,Francesco Boccardo ,Richard Gray ,Vinod Raina ,Daniel Hayes ,Elizabeth Mackinnon ,Michael R Coates ,Miguel Martín ,Sandra M Swain ,Russell Geyer ,X Wang ,Soon Young Paik ,Michael Gnant ,Candace R Correa ,Kathleen I Pritchard ,W Janni ,Norman Wolmark ,H Pan ,David Cameron ,William C Wood

doi:10.1016/s0140-6736(15)60908-4

Jonas Bergh , Emiel J Rutgers + Show 58 more

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https://doi.org/10.1016/s0140-6736(15)60908-4

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Journal: The Lancet	Publication Date: Jul 23, 2015
Citations: 592	License type: cc-by

Affiliation: Cancer Research UK Edinburgh Centre

Abstract

Bisphosphonates have profound effects on bone physiology, and could modify the process of metastasis. We undertook collaborative meta-analyses to clarify the risks and benefits of adjuvant bisphosphonate treatment in breast cancer. We sought individual patient data from all unconfounded trials in early breast cancer that randomised between bisphosphonate and control. Primary outcomes were recurrence, distant recurrence, and breast cancer mortality. Primary subgroup investigations were site of first distant recurrence (bone or other), menopausal status (postmenopausal [combining natural and artificial] or not), and bisphosphonate class (aminobisphosphonate [eg, zoledronic acid, ibandronate, pamidronate] or other [ie, clodronate]). Intention-to-treat log-rank methods yielded bisphosphonate versus control first-event rate ratios (RRs). We received data on 18,766 women (18,206 [97%] in trials of 2-5 years of bisphosphonate) with median follow-up 5·6 woman-years, 3453 first recurrences, and 2106 subsequent deaths. Overall, the reductions in recurrence (RR 0·94, 95% CI 0·87-1·01; 2p=0·08), distant recurrence (0·92, 0·85-0·99; 2p=0·03), and breast cancer mortality (0·91, 0·83-0·99; 2p=0·04) were of only borderline significance, but the reduction in bone recurrence was more definite (0·83, 0·73-0·94; 2p=0·004). Among premenopausal women, treatment had no apparent effect on any outcome, but among 11 767 postmenopausal women it produced highly significant reductions in recurrence (RR 0·86, 95% CI 0·78-0·94; 2p=0·002), distant recurrence (0·82, 0·74-0·92; 2p=0·0003), bone recurrence (0·72, 0·60-0·86; 2p=0·0002), and breast cancer mortality (0·82, 0·73-0·93; 2p=0·002). Even for bone recurrence, however, the heterogeneity of benefit was barely significant by menopausal status (2p=0·06 for trend with menopausal status) or age (2p=0·03), and it was non-significant by bisphosphonate class, treatment schedule, oestrogen receptor status, nodes, tumour grade, or concomitant chemotherapy. No differences were seen in non-breast cancer mortality. Bone fractures were reduced (RR 0·85, 95% CI 0·75-0·97; 2p=0·02). Adjuvant bisphosphonates reduce the rate of breast cancer recurrence in the bone and improve breast cancer survival, but there is definite benefit only in women who were postmenopausal when treatment began. Cancer Research UK, Medical Research Council.

Highlights

Circulating tumour cells can be attracted to surfaces within the bone where they can displace haemopoietic stem cells and bind to the osteoblastic niche.[1]
The reductions in recurrence (RR 0·94, 95% CI 0·87–1·01; 2p=0·08), distant recurrence (0·92, 0·85–0·99; 2p=0·03), and breast cancer mortality (0·91, 0·83–0·99; 2p=0·04) were of only borderline significance, but the reduction in bone recurrence was more definite (0·83, 0·73–0·94; 2p=0·004)
Improvements in bone-metastasis-free survival, diseasefree survival, and overall survival in women with early breast cancer have been reported in some adjuvant trials of oral clodronate[7,8] or of intravenous zoledronic acid.[9,10]

Summary

Introduction

Circulating tumour cells can be attracted to surfaces within the bone where they can displace haemopoietic stem cells and bind to the osteoblastic niche.[1]. Improvements in bone-metastasis-free survival, diseasefree survival, and overall survival in women with early breast cancer have been reported in some adjuvant trials of oral clodronate[7,8] or of intravenous zoledronic acid.[9,10] in other trials of adjuvant bisphosphonates no significant benefits were seen in analyses that included all randomised patients, both planned and exploratory subset analyses suggested benefits either in postmenopausal women[11] or in older women.[12,13] This led to the hypothesis[11,12,13] that treatment is of benefit only in patients with low concentrations of reproductive hormones (ie, those who are postmenopausal or undergoing ovarian suppression therapy).[14,15,16]

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