Adjuvant bisphosphonate treatment in early breast cancer

Meta-analyses of individual patient data from randomised trials

J. Bergh, K. Pritchard, K. Albain, S. Anderson, R. Arriagada, W. Barlow, W. Bergsten-Nordström, J. Bliss, F. Boccardo, R. Bradley, M. Buyse, D. Cameron, M. Clarke, M. Coates, R. Coleman, C. Correa, J. Costantino, J. Cuzick, N. Davidson, C. Davies & 40 others A. Di Leo, M. Dowsett, M. Ewertz, J. Forbes, R. Gelber, R. Geyer, R. Gianni, M. Gnant, A. Goldhirsch, R. Gray, D. Hayes, C. Hill, J. Ingle, W. Janni, E. MacKinnon, M. Martín, P. McGale, L. Norton, Y. Ohashi, S. Paik, H. Pan, E. Perez, R. Peto, R. Piccart, L. Pierce, V. Raina, P. Ravdin, J. Robertson, E. Rutgers, J. Sparano, S. Swain, C. Taylor, G. Viale, G. Von Minckwitz, X. Wang, T. Whelan, N. Wilcken, E. Winer, N. Wolmark, W. Wood

Research output: Contribution to journalArticle

267 Citations (Scopus)

Abstract

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. Funding Cancer Research UK, Medical Research Council.

Original languageEnglish
Pages (from-to)1353-1361
Number of pages9
JournalLancet
Volume386
Issue number10001
DOIs
Publication statusPublished - Oct 3 2015

Fingerprint

Diphosphonates
Meta-Analysis
Breast Neoplasms
Recurrence
Bone and Bones
Therapeutics
pamidronate
zoledronic acid
Mortality
Clodronic Acid
Neoplasms
Bone Fractures
Estrogen Receptors
Biomedical Research
Appointments and Schedules
Neoplasm Metastasis

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Bergh, J., Pritchard, K., Albain, K., Anderson, S., Arriagada, R., Barlow, W., ... Wood, W. (2015). Adjuvant bisphosphonate treatment in early breast cancer: Meta-analyses of individual patient data from randomised trials. Lancet, 386(10001), 1353-1361. https://doi.org/10.1016/S0140-6736(15)60908-4

Adjuvant bisphosphonate treatment in early breast cancer : Meta-analyses of individual patient data from randomised trials. / Bergh, J.; Pritchard, K.; Albain, K.; Anderson, S.; Arriagada, R.; Barlow, W.; Bergsten-Nordström, W.; Bliss, J.; Boccardo, F.; Bradley, R.; Buyse, M.; Cameron, D.; Clarke, M.; Coates, M.; Coleman, R.; Correa, C.; Costantino, J.; Cuzick, J.; Davidson, N.; Davies, C.; Di Leo, A.; Dowsett, M.; Ewertz, M.; Forbes, J.; Gelber, R.; Geyer, R.; Gianni, R.; Gnant, M.; Goldhirsch, A.; Gray, R.; Hayes, D.; Hill, C.; Ingle, J.; Janni, W.; MacKinnon, E.; Martín, M.; McGale, P.; Norton, L.; Ohashi, Y.; Paik, S.; Pan, H.; Perez, E.; Peto, R.; Piccart, R.; Pierce, L.; Raina, V.; Ravdin, P.; Robertson, J.; Rutgers, E.; Sparano, J.; Swain, S.; Taylor, C.; Viale, G.; Von Minckwitz, G.; Wang, X.; Whelan, T.; Wilcken, N.; Winer, E.; Wolmark, N.; Wood, W.

In: Lancet, Vol. 386, No. 10001, 03.10.2015, p. 1353-1361.

Research output: Contribution to journalArticle

Bergh, J, Pritchard, K, Albain, K, Anderson, S, Arriagada, R, Barlow, W, Bergsten-Nordström, W, Bliss, J, Boccardo, F, Bradley, R, Buyse, M, Cameron, D, Clarke, M, Coates, M, Coleman, R, Correa, C, Costantino, J, Cuzick, J, Davidson, N, Davies, C, Di Leo, A, Dowsett, M, Ewertz, M, Forbes, J, Gelber, R, Geyer, R, Gianni, R, Gnant, M, Goldhirsch, A, Gray, R, Hayes, D, Hill, C, Ingle, J, Janni, W, MacKinnon, E, Martín, M, McGale, P, Norton, L, Ohashi, Y, Paik, S, Pan, H, Perez, E, Peto, R, Piccart, R, Pierce, L, Raina, V, Ravdin, P, Robertson, J, Rutgers, E, Sparano, J, Swain, S, Taylor, C, Viale, G, Von Minckwitz, G, Wang, X, Whelan, T, Wilcken, N, Winer, E, Wolmark, N & Wood, W 2015, 'Adjuvant bisphosphonate treatment in early breast cancer: Meta-analyses of individual patient data from randomised trials', Lancet, vol. 386, no. 10001, pp. 1353-1361. https://doi.org/10.1016/S0140-6736(15)60908-4
Bergh, J. ; Pritchard, K. ; Albain, K. ; Anderson, S. ; Arriagada, R. ; Barlow, W. ; Bergsten-Nordström, W. ; Bliss, J. ; Boccardo, F. ; Bradley, R. ; Buyse, M. ; Cameron, D. ; Clarke, M. ; Coates, M. ; Coleman, R. ; Correa, C. ; Costantino, J. ; Cuzick, J. ; Davidson, N. ; Davies, C. ; Di Leo, A. ; Dowsett, M. ; Ewertz, M. ; Forbes, J. ; Gelber, R. ; Geyer, R. ; Gianni, R. ; Gnant, M. ; Goldhirsch, A. ; Gray, R. ; Hayes, D. ; Hill, C. ; Ingle, J. ; Janni, W. ; MacKinnon, E. ; Martín, M. ; McGale, P. ; Norton, L. ; Ohashi, Y. ; Paik, S. ; Pan, H. ; Perez, E. ; Peto, R. ; Piccart, R. ; Pierce, L. ; Raina, V. ; Ravdin, P. ; Robertson, J. ; Rutgers, E. ; Sparano, J. ; Swain, S. ; Taylor, C. ; Viale, G. ; Von Minckwitz, G. ; Wang, X. ; Whelan, T. ; Wilcken, N. ; Winer, E. ; Wolmark, N. ; Wood, W. / Adjuvant bisphosphonate treatment in early breast cancer : Meta-analyses of individual patient data from randomised trials. In: Lancet. 2015 ; Vol. 386, No. 10001. pp. 1353-1361.
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title = "Adjuvant bisphosphonate treatment in early breast cancer: Meta-analyses of individual patient data from randomised trials",
abstract = "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. Funding Cancer Research UK, Medical Research Council.",
author = "J. Bergh and K. Pritchard and K. Albain and S. Anderson and R. Arriagada and W. Barlow and W. Bergsten-Nordstr{\"o}m and J. Bliss and F. Boccardo and R. Bradley and M. Buyse and D. Cameron and M. Clarke and M. Coates and R. Coleman and C. Correa and J. Costantino and J. Cuzick and N. Davidson and C. Davies and {Di Leo}, A. and M. Dowsett and M. Ewertz and J. Forbes and R. Gelber and R. Geyer and R. Gianni and M. Gnant and A. Goldhirsch and R. Gray and D. Hayes and C. Hill and J. Ingle and W. Janni and E. MacKinnon and M. Mart{\'i}n and P. McGale and L. Norton and Y. Ohashi and S. Paik and H. Pan and E. Perez and R. Peto and R. Piccart and L. Pierce and V. Raina and P. Ravdin and J. Robertson and E. Rutgers and J. Sparano and S. Swain and C. Taylor and G. Viale and {Von Minckwitz}, G. and X. Wang and T. Whelan and N. Wilcken and E. Winer and N. Wolmark and W. Wood",
year = "2015",
month = "10",
day = "3",
doi = "10.1016/S0140-6736(15)60908-4",
language = "English",
volume = "386",
pages = "1353--1361",
journal = "The Lancet",
issn = "0140-6736",
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TY - JOUR

T1 - Adjuvant bisphosphonate treatment in early breast cancer

T2 - Meta-analyses of individual patient data from randomised trials

AU - Bergh, J.

AU - Pritchard, K.

AU - Albain, K.

AU - Anderson, S.

AU - Arriagada, R.

AU - Barlow, W.

AU - Bergsten-Nordström, W.

AU - Bliss, J.

AU - Boccardo, F.

AU - Bradley, R.

AU - Buyse, M.

AU - Cameron, D.

AU - Clarke, M.

AU - Coates, M.

AU - Coleman, R.

AU - Correa, C.

AU - Costantino, J.

AU - Cuzick, J.

AU - Davidson, N.

AU - Davies, C.

AU - Di Leo, A.

AU - Dowsett, M.

AU - Ewertz, M.

AU - Forbes, J.

AU - Gelber, R.

AU - Geyer, R.

AU - Gianni, R.

AU - Gnant, M.

AU - Goldhirsch, A.

AU - Gray, R.

AU - Hayes, D.

AU - Hill, C.

AU - Ingle, J.

AU - Janni, W.

AU - MacKinnon, E.

AU - Martín, M.

AU - McGale, P.

AU - Norton, L.

AU - Ohashi, Y.

AU - Paik, S.

AU - Pan, H.

AU - Perez, E.

AU - Peto, R.

AU - Piccart, R.

AU - Pierce, L.

AU - Raina, V.

AU - Ravdin, P.

AU - Robertson, J.

AU - Rutgers, E.

AU - Sparano, J.

AU - Swain, S.

AU - Taylor, C.

AU - Viale, G.

AU - Von Minckwitz, G.

AU - Wang, X.

AU - Whelan, T.

AU - Wilcken, N.

AU - Winer, E.

AU - Wolmark, N.

AU - Wood, W.

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. Funding Cancer Research UK, Medical Research Council.

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. Funding Cancer Research UK, Medical Research Council.

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JO - The Lancet

JF - The Lancet

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