TY - JOUR
T1 - Adjuvant bisphosphonate treatment in early breast cancer
T2 - Meta-analyses of individual patient data from randomised trials
AU - Coleman, R.
AU - Gray, R.
AU - Powles, T.
AU - Paterson, A.
AU - Gnant, M.
AU - Bergh, J.
AU - Pritchard, K. I.
AU - Bliss, J.
AU - Cameron, D.
AU - Bradley, R.
AU - Gray, R.
AU - Pan, H.
AU - Peto, R.
AU - Coleman, R.
AU - Gray, R.
AU - Powles, T.
AU - Bradley, R.
AU - Burrett, J.
AU - Clarke, M.
AU - Davies, C.
AU - Duane, F.
AU - Evans, V.
AU - Gettins, L.
AU - Godwin, J.
AU - Gray, R.
AU - Liu, H.
AU - McGale, P.
AU - Mackinnon, E.
AU - McHugh, T.
AU - James, S.
AU - Morris, P.
AU - Pan, H.
AU - Peto, R.
AU - Read, S.
AU - Taylor, C.
AU - Wang, Y.
AU - Wang, Z.
AU - Coleman, R.
AU - Powles, T.
AU - Paterson, A.
AU - Gnant, M.
AU - Anderson, S.
AU - Diel, I.
AU - Gralow, J.
AU - von Minckwitz, G.
AU - Moebus, V.
AU - Bergh, J.
AU - Pritchard, K. I.
AU - Bliss, J.
AU - Geyer, C.
AU - Early Breast Cancer Trialists’ Collaborative Group (EBCTCG)
N1 - Funding Information:
We thank the tens of thousands of women who took part in the trials, the many staff in trial centres and participating clinics who helped conduct the trials, and the trialists who shared their data. Funding for individual trials was chiefly from manufacturers (see trial publications) but no commercial funding was sought or used by the secretariat. Funding for the EBCTCG secretariat is through the direct support from Cancer Research UK and the UK Medical Research Council, to the Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, UK.
Funding Information:
Clinical Trial Service Unit (CTSU) staff policy excludes honoraria or consultancy fees for any member of the Early Breast Cancer Trialists' Collaborative Group Secretariat. EBCTCG is funded by Cancer Research UK and UK Medical Research Council grants to the CTSU. SA reports grants from National Institutes of Health (U10 CA069974 and U10 CA69651), during the conduct of the study. JBe reports that Karolinska University Hospital and Karolinska Institutet have received payments for academic clinical studies and research grants for molecular biological studies and PET studies from Amgen, AstraZeneca, Bayer, Merck, Pfizer, Roche, and Sanofi-Aventis; he was Swedish principal investigator (PI) for an adjuvant bisphosphonate study for which oral pamidronate was provided free-of-charge (this formulation is not licensed); he is also Swedish PI for the ongoing ABCSG-18 adjuvant denosumab study (the drug was provided free-of-charge); he reports no personal payments in the past 3 years. DC reports support from Novartis to attend the American Society of Clinical Oncology and San Antonio Breast Cancer Symposium conferences, outside the submitted work. RC reports personal fees from Novartis (for expert testimony), outside the submitted work. MG reports grants and personal fees from Novartis and personal fees from Amgen, during the conduct of the study; outside the submitted work he has received grants and personal fees from Novartis, Roche, and GlaxoSmithKline, grants from Sanofi-Aventis, Pfizer, and Smith Medical, and personal fees from AstraZeneca, Nanostring Technologies, and Accelsiors. JG reports grants from Novartis, Amgen, and Roche, outside the submitted work. VM reports grants and personal fees from Amgen and Roche, grants from Novartis, and personal fees from Celgene, outside the submitted work. KIP reports grants and personal fees from AstraZeneca, Pfizer, Roche, Novartis, and Eisai, and personal fees from Amgen and GlaxoSmithKline, outside the submitted work. JBl, RB, ID, VE, RG, HP, AP, RP, TP, and GvM declare no competing interests.
PY - 2015/10/3
Y1 - 2015/10/3
N2 - Background 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. Methods 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). Findings 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). Interpretation 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.
AB - Background 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. Methods 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). Findings 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). Interpretation 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.
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U2 - 10.1016/S0140-6736(15)60908-4
DO - 10.1016/S0140-6736(15)60908-4
M3 - Article
C2 - 26211824
AN - SCOPUS:84944177030
VL - 386
SP - 1353
EP - 1361
JO - The Lancet
JF - The Lancet
SN - 0140-6736
IS - 10001
ER -