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Adju an bisphosphona e ea men in ea ly b eas cance :
me a-analyses o indi idual pa ien da a om andomised
ials
Ea ly B eas Cance T ialis s’ Collabo a i e G oup (EBCTCG)*
Summa y
Backg ound Bisphosphona es ha e p o ound eff ec s on bone physiology, and could modi y he p ocess o me as asis.
We unde ook collabo a i e me a-analyses o cla i y he isks and benefi s o adju an bisphosphona e ea men in
b eas cance .
Me hods We sough indi idual pa ien da a om all uncon ounded ials in ea ly b eas cance ha andomised
be ween bisphosphona e and con ol. P ima y ou comes we e ecu ence, dis an ecu ence, and b eas cance
mo ali y. P ima y subg oup in es iga ions we e si e o fi
s dis an ecu ence (bone o o he ), menopausal s a us
(pos menopausal [combining na u al and a ifi cial] o no ), and bisphosphona e class (aminobisphosphona e
[eg, zoled onic acid, iband ona e, pamid ona e] o o he [ie, clod ona e]). In en ion- o- ea log- ank me hods yielded
bisphosphona e e sus con ol fi s -e en a e a ios (RRs).
Findings We ecei ed da a on 18 766 women (18 206 [97%] in ials o 2–5 yea s o bisphosphona e) wi h median
ollow-up 5·6 woman-yea s, 3453 fi s ecu ences, and 2106 subsequen dea hs. O e all, he educ ions in ecu ence
(RR 0·94, 95% CI 0·87–1·01; 2p=0·08), dis an ecu ence (0·92, 0·85–0·99; 2p=0·03), and b eas cance mo ali y
(0·91, 0·83–0·99; 2p=0·04) we e o only bo de line signifi cance, bu he educ ion in bone ecu ence was mo e
defi ni e (0·83, 0·73–0·94; 2p=0·004). Among p emenopausal women, ea men had no appa en eff ec on any
ou come, bu among 11 767 pos menopausal women i p oduced highly signifi can educ ions in ecu ence (RR 0·86,
95% CI 0·78–0·94; 2p=0·002), dis an ecu ence (0·82, 0·74–0·92; 2p=0·0003), bone ecu ence (0·72, 0·60–0·86;
2p=0·0002), and b eas cance mo ali y (0·82, 0·73–0·93; 2p=0·002). E en o bone ecu ence, howe e , he
he e ogenei y o benefi was ba ely signifi can by menopausal s a us (2p=0·06 o end wi h menopausal s a us) o
age (2p=0·03), and i was non-signifi can by bisphosphona e class, ea men schedule, oes ogen ecep o s a us,
nodes, umou g ade, o concomi an chemo he apy. No diff e ences we e seen in non-b eas cance mo ali y. Bone
ac u es we e educed (RR 0·85, 95% CI 0·75–0·97; 2p=0·02).
In e p e a ion Adju an bisphosphona es educe he a e o b eas cance ecu ence in he bone and imp o e b eas
cance su i al, bu he e is defi ni e benefi only in women who we e pos menopausal when ea men began.
Funding Cance Resea ch UK, Medical Resea ch Council.
Copy igh © Ea ly B eas Cance T ialis s’ Collabo a i e G oup (EBCTCG). Open Access a icle dis ibu ed unde he
e ms o CC BY.
In oduc ion
Ci cula ing umou cells can be a ac ed o su aces wi hin
he bone whe e hey can displace haemopoie ic s em cells
and bind o he os eoblas ic niche.1 These dissemina ed
malignan cells can emain quiescen o yea s. Then, o
easons ha a e no well unde s ood, hey can exi his
do man s a e, s a o p oli e a e, and es ablish mac o-
me as ases in he bone o elsewhe e.2,3 Bisphosphona es
ha e p o ound eff ec s on os eoclas s, and aff ec T-cell
unc ion, so could also be eff ec i e as adju an ea men s,
pa icula ly in p e en ing o delaying bone ecu ence.4–6
Fo his eason, and because bisphosphona es can be added
o he a oma ase inhibi o ea men o pos menopausal
b eas cance o es ic ad e se skele al eff ec s o oes ogen
dep i a ion, eliable e idence is needed abou he eff ec s o
bisphosphona es on b eas cance ou comes.
Imp o emen s in bone-me as asis- ee su i al, disease-
ee su i al, and o e all su i al in women wi h ea ly
b eas cance ha e been epo ed in some adju an ials o
o al clod ona e7,8 o o in a enous zoled onic acid.9,10
Howe e , in o he ials o adju an bisphos phona es no
signifi can benefi s we e seen in analyses ha included all
andomised pa ien s, al hough bo h planned and
explo a o y subse analyses sugges ed benefi s ei he in
pos menopausal women11 o in olde women.12,13 This led o
he hypo hesis11–13 ha ea men is o benefi only in
pa ien s wi h low concen a ions o ep oduc i e ho mones
(ie, hose who a e pos menopausal o unde going o a ian
supp ession he apy).14–16
To help cla i y whe he adju an bisphosphona es educe
he isk o bone and o he me as ases, and whe he meno-
pausal s a us aff ec s effi cacy, we unde ook collab o a i e
Lance 2015; 386: 1353–61
This online publica ion has
been co ec ed. The co ec ed
e sion fi s appea ed a
helance .com on Dec 31, 2015
Published Online
July 24, 2015
h p://dx.doi.o g/10.1016/
S0140-6736(15)60908-4
See Commen page 1319
*Full lis o membe s a ailable a
h p://www.c su.ox.ac.uk/
esea ch/me a- ials/ebc cg/
ebc cg-page
Co espondence o:
EBCTCG Sec e a ia , Clinical T ial
Se ice Uni , Nuffi eld
Depa men o Popula ion
Heal h, Richa d Doll Building,
Ox o d OX3 7LF, UK
[email p o ec ed]
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me a-analyses o all uncon ounded andomised ials ha
compa ed b eas cance ou comes in hose alloca ed
adju an bisphosphona e e sus hose who we e no .
Me hods
Iden ifi ca ion o s udies and collec ion o da a
The me hods o iden i ying ials, seeking collabo a ion,
da a collec ion, colla ion, checking, and p es en a ion a e as
in p e ious Ea ly B eas Cance T ialis s’ Collabo a i e
G oup (EBCTCG) epo s.17–19 T ials we e eligible i hey
began be o e 2008 and andomly assigned women be-
ween a bisphosphona e o any ype, dose, and schedule
e sus a con ol g oup (open label o placebo) wi h no
bisphosphona e, all o he ea men s being simila in bo h
g oups. In o ma ion was sough du ing 2012–14 o each
indi idual pa ien on da e o andomisa ion, alloca ed ea -
men , age, menopausal s a us, umou diame e , g ade,
sp ead o loco egional lymph nodes, HER2 and oes ogen
and p oges e one ecep o (ER/PR) s a us, da es and si es
o any b eas cance ecu ence, o he second p i ma y
cance , bone ac u e, and he da e and cause o dea h.
The main defi ni ions and analysis me hods a e hose
used in p e ious EBCTCG epo s,17–19 bu wi h some
amendmen s ha efl ec he po en ial eff ec o
bisphosphona es on bone me as ases (appendix).
Ou comes
The p e-defi ned cop ima y endpoin s we e any ecu ence
o b eas cance (dis an , loco egional, o new p ima y in
he con ala e al b eas ); dis an ecu ence, igno ing any
p e ious loco egional o con ala e al ecu ence; and
b eas cance mo ali y (es ima ed by log- ank sub ac ion,
as in p e ious EBCTCG epo s18,19).
Seconda y ou comes we e all-cause mo ali y; dea h
wi hou ecu ence; bone ecu ence as he fi s dis an
ecu ence (wi h o wi hou concu en o he ecu ence);
o he fi s (ex askele al) dis an ecu ence (wi h all
analyses o dis an ecu ence igno ing any p e ious
loco egional o con ala e al ecu ence); loco egional
ecu ence as fi s e en (ipsila e al b eas , ches wall, o
loco egional lymph nodes); con ala e al new p ima y
b eas cance as fi s e en ; and any bone ac u es.
S a is ical analyses
Time- o-e en analyses we e s a ifi ed by age, ER s a us,
nodal s a us, and ial. Wi hin each s a um, hey
compa ed all hose alloca ed bisphosphona e e sus
all hose alloca ed con ol, ega dless o ea men
compliance (yielding in en ion- o- ea analyses).
Log- ank s a is ics we e used o assess he eff ec s
(bisphosphona e s con ol) on a ious ou comes, and,
o each, o es ima e fi s -e en a e a ios (RRs) and hei
CIs. We did s a is ical analyses using EBCTCG in-house
Fo an p og ams.
P e-specifi ed p ima y subg oup in es iga ions we e o
si e o fi s dis an ecu ence (bone, o he ), menopausal
s a us (p emenopausal, pe imenopausal, pos menopausal
[na u al o induced, ei he po en ially e e sibly, using
lu einising ho mone- eleasing ho mone analogues, o
pe manen ly by oopho ec omy] o , i menopausal s a us
was una ailable, yea s o age, g ouped as <45, 45–54,
≥55 yea s), and class o bisphosphona e (amino bisphos-
phona e [zoled onic acid, iband ona e, pamid ona e,
ised ona e, alend ona e], o he [clod ona e]). Explo a o y
in es iga ions we e unde aken o po en ial in e ac ions
be ween ea men effi cacy and ER s a us, nodal s a us,
his ological g ade, use o no o adju an chemo he apy,
and ollow-up pe iod. I app op ia e, es s compa ing
eff ec s in diff e en subg oups we e o end a he han
he e ogenei y.
We p e-specifi ed ha compa isons o ea men effi cacy
wi hin subg oups would exclude local and con ala e al
ecu ence i he p io hypo hesis ha bisphosphona es
would educe dis an bu no local o con ala e al
ecu ence was es ablished om analyses o he o e all
esul s in all andomised pa ien s. As bone ecu ence
was he only ype o ecu ence signifi can ly educed by
bisphosphona es we used his ins ead as he p ima y
endpoin o subg oup compa isons, bu he appendix
includes subg oup analyses o any dis an ecu ence.
Because he ABCSG-129 and AZURE11,14 ials had helped
gene a e he hypo hesis o he ele ance o menopausal
s a us o he eff ec s o ea men , we p o ide sensi i i y
analyses o his hypo hesis ha ea ed hese ials as
hypo hesis-gene a ing, wi h he emaining ials
hypo hesis- es ing. The policy on da a sha ing om his
s udy is a ailable online.
See Online o appendix
S udies iden ifi ed S udies wi h da a ecei ed
T ials (n) Pa ien s (n) T ials (n) Pa ien s (n) %* Yea s†
Up o 1 yea o ea men
<1 yea clod ona e 2 120 1 72 60% 0·5
<1 yea aminobisphosphona e 2 208 1 40 19% 0·1
1 yea aminobisphosphona e 7 1088 3 448 41% 1·0
To al o ≤1 yea o ea men 11 1416 5 560 40% 0·9
2–5 yea s o ea men
2 yea s clod ona e 4 3978 3 3912 98% 2·0
3–5 yea s clod ona e 1 1069 1 1069 100% 3·0
2 yea s aminobisphosphona e 10 3654 8 3514 96% 2·0
3–5 yea s aminobisphosphona e 12 11 910‡ 9 9711 82%‡ 4·5
To al o 2–5 yea s o ea men 27 20 611‡ 21 18 206 88%‡ 3·5
Any clod ona e egimen 7 5167 5 5053 98% 2·6
Any aminobisphosphona e§ 31 16 860‡ 21 13 713 81%‡ 3·8
To al, all egimens 38 22 027‡ 26 18 766 85%‡ 3·4
*Numbe o pa ien s wi h da a ecei ed as a pe cen age o all andomised pa ien s in iden ifi ed s udies. †Mean
scheduled ea men du a ion (weigh ed in p opo ion o numbe s o pa ien s wi h da a ecei ed). ‡Includes wo ials
(2116 pa ien s) s ill in p og ess; excluding hese, he o al wi h da a ecei ed is 94%. §The aminobisphosphona es in
hese ials we e zoled onic acid (9290 pa ien s wi h da a ecei ed, 1582 ecu ences [46% o all ecu ences]),
iband ona e (3072 pa ien s, 380 ecu ences [11%]), pamid ona e (953 pa ien s, 473 ecu ences [14%]),
ised ona e (398 pa ien s, 13 ecu ences [0·4%]), and alend ona e (no ials wi h da a ecei ed); he only
non-aminobisphosphona e in hese ials was clod ona e (5053 pa ien s, 1005 [29%] ecu ences).
Table: Numbe s o uncon ounded andomised ials o an adju an bisphosphona e iden ifi ed, and
numbe s wi h da a ecei ed, by du a ion and ype o bisphosphona e ea men
Fo he CTSU policy on da a
sha ing see h p://www.c su.ox.
ac.uk/ esea ch/da a-access-
policies/da a-access-and-
sha ing-policy/ iew
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Role o he unding sou ce
The unde s o he s udy had no ole in s udy design,
da a collec ion, da a analysis, da a in e p e a ion, o
w i ing o he epo . The w i ing commi ee had ull
access o all he da a in he s udy and had fi nal
esponsibili y o he decision o submi o publica ion.
Resul s
Indi idual pa ien da ase s we e p o ided o 26 ials
wi h 18 766 pa icipan s, 97% o all 19 291 women in he
32 comple ed ials ha eco ded ecu ence da a ( able,
appendix). In ou o he ials (620 women) ecu ence was
no eco ded, and om he wo ongoing ials (2116 women)
ou come da a canno ye be p o ided. Mean scheduled
ea men du a ion was 3·4 yea s; 18 206 (97%) o
18 766 pa icipan s we e in ials o 2–5 yea s o ea men .
Median ollow-up was 5·6 woman-yea s (IQR 3·7–8·0).
3453 women had a ecu ence, a e which 2106 died.
Recu ence a es we e sligh ly lowe wi h han wi hou
bisphosphona es, bu his was no signifi can in analyses
ha included all 18 766 women (RR 0·94, 95% CI
0·87–1·01; 2p=0·08; fi gu e 1). Howe e , he e was a
bo de line signifi can educ ion in he isk o dis an
ecu ence, igno ing any p e ious local o con ala e al
Figu e 1: Recu ence by si e and b eas cance mo ali y in 24 ials o bisphosphona e e sus no bisphosphona e (con ol)
Kaplan-Meie g aphs showing eff ec s o ea men alloca ion on 10-yea ou comes in all 18 766 pa ien s. (A) Any ecu ence. (B) Dis an ecu ence. (C) Bone ecu ence.
(D) B eas cance mo ali y. O–E=obse ed minus expec ed. V= a iance o O–E. RR= a e a io (exp[{O–E}/V]). E o ba s a e SE.
Recu ence a e/yea (%), e en s/woman-yea s and log- ank s a is ics
Alloca ion
Bisphosphona e
Con ol
Ra e a io (95% CI)
om (O–E)/V
18
766 women
RR 0·94 (95% CI 0·87–1·01)
Log- ank 2p=0·08
10-yea gain 1·1% (95% CI –0·7 o 2·9)
Con ol 25·9%
Bisphosphona e 24·9%
Yea s 0–4
3·63 (1415/38
979)
3·85 (1384/35
984)
0·93 (0·85–1·01)
–41·9/593·7
Yea s 5–9
2·34 (308/13 171)
2·36 (314/13 322)
0·98 (0·81–1·14)
–3·1/139·4
Yea s ≥10
0·87 (15/1724)
0·95 (17/1790)
0·72 (CI 0·01–1·43)
–1·8/5·5
17·4%
16·3%
0
10
20
30
40
50
Recu ence (%)
A
Dis an ecu ence a e/yea (%), e en s/woman-yea s and log- ank s a is ics
Alloca ion
Bisphosphona e
Con ol
Ra e a io (95% CI)
om (O–E)/V
18
766 women
RR 0·92 (95% CI 0·85–0·99)
Log- ank 2p=0·03
10-yea gain 1·4% (95% CI –0·3 o 3·1)
Con ol 21·8%
Bisphosphona e 20·4%
Yea s 0–4
2·97 (1173/39 559)
3·20 (1170/36 571)
0·91 (0·83–0·99)
–47·5/499·9
Yea s 5–9
1·84 (253/13 746)
1·82 (253/13 931)
0·99 (0·81–1·18)
–0·7/114·3
Yea s ≥10
0·67 (13/1932)
1·08 (21/1941)
0·47 (0·21–1·03)
–4·5/5·9
14·8%
13·5%
0
10
20
30
40
50
Dis an ecu ence (%)
B
Bone ecu ence a e/yea (%), e en s/woman-yea s and log- ank s a is ics
Alloca ion
Bisphosphona e
Con ol
Ra e a io (95% CI)
om (O–E)/V
18
766 women
RR 0·83 (95% CI 0·73–0·94)
Log- ank 2p=0·004
10-yea gain 1·1% (95% CI –0·1 o 2·3)
Con ol 9·0%
Bisphosphona e 7·8%
0 5 10
Yea s 0–4
0·99 (391/39 559)
1·21 (441/36 571)
0·79 (0·66–0·92)
–45·0/189·5
Yea s 5–9
0·76 (104/13 746)
0·71 (99/13 031)
1·02 (0·73–1·31)
0·8/46·8
Yea s ≥10
0·10 (2/1932)
0·10 (2/1941)
0·61 (0·08–2·25)
–0·4/0·9
Yea s
5·9%
4·7%
0
10
20
30
40
50
Bone ecu ence (%)
C
Dea h a es (%/yea : o al a e minus a e in women wi hou ecu ences) and log- ank s a is i
Alloca ion
Bisphosphona e
Con ol
Ra e a io (95% CI)
om (O–E)/V
18
766 women
RR 0·91 (95% CI 0·83–0·99)
Log- ank 2p=0·04
10-yea gain 1·7% (95% CI 0·0 o 3·5)
Con ol 18·4%
Bisphosphona e 16·6%
0 5 10
Yea s 0–4
1·83 (1·70–1·97)
1·98 (1·84–2·12)
0·91 (0·81–1·01)
–30·5/321·7
Yea s 5–9
1·81 (1·59–2·03)
1·97 (1·75–2·20)
0·92 (0·75–1·10)
–9·5/121·0
Yea s ≥10
1·21 (0·72–1·69)
1·69 (1·12–2·25)
0·66 (0·18–1·15)
–4·5/10·9
Yea s
9·7%
8·9%
0
10
20
30
40
50
B eas cance mo ali y (%)
D
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Figu e 2: Mul iple subg oup analyses o eff ec s on bone ecu ence in ials o bisphosphona e e sus no bisphosphona e (con ol)
Resul s a e plo ed as black squa es wi h ho izon al lines ha deno e 99% a he han 95% CIs o allow o mul iple hypo hesis es ing. To al is plo ed as a whi e
diamond ha deno es 95% CI. ER=oes ogen ecep o . O–E=obse ed minus expec ed.
Ca ego y Ra e a io (CI)E en s/women
Alloca ed
bisphosphona e
Alloca ed
con ol
(a) Age, yea s ( end χ2
1=4·9; 2p=0·03)
<45
45–54
55–69
≥70
Age unknown
(b) Menopausal s a us ( end χ2
1=3·5; 2p=0·06)
P emenopausal
Pe imenopausal
Pos menopausal
(c) ER s a us (χ2
1=0·6; 2p=0·4)
ER nega i e
ER unknown
ER posi i e
(d) Nodal s a us ( end χ2
1=0·5; 2p=0·5)
N0/N–
N1–3
N4+
N o he /unknown
(e) Tumou g ade ( end χ2
1=0·4; 2p=0·5)
Well diffe en ia ed
Mode a ely diffe en ia ed
Poo ly diffe en ia ed
G ade unknown
( ) Bisphosphona e ype (χ2
4=0·3; 2p=0·6)
Clod ona e
Aminobisphosphona e
(g) Bisphosphona e (χ2
4=5·9; 2p=0·21)
Clod ona e
Zoled onic acid
Pamid ona e
Iband ona e
Rised ona e
Alend ona e
(h) Bisphosphona e dose (χ2
1=0·4; 2p=0·5)
Mo e in ensi e
Low in ensi y
(i) Bisphosphona e du a ion ( end χ2
1=0·2; 2p=0·7)
<1 yea
2 yea s
>2 yea s
(j) Chemo he apy (χ2
1=0·3; 2p=0·6)
Absence
P esence
(k) Follow-up pe iod, yea s ( end χ2
1=2·5; 2p=0·11)
0–1
2–4
5–9
≥10
To al
164/2475 (6·6%)
152/3532 (4·3%)
168/3314 (5·1%)
13/531 (2·4%)
0/4 (0·0%)
151/2141 (7·1%)
173/3224 (5·4%)
196/3022 (6·5%)
22/521 (4·2%)
0/2 (0·0%)
–0·3
–14·2
–25·1
–5·1
71·3
74·3
84·4
7·1
217/3296 (6·6%)
28/461 (6·1%)
252/6099 (4·1%)
212/2875 (7·4%)
19/367 (5·2%)
311/5668 (5·5%)
–7·9
2·0
–42·1
96·4
8·8
128·0
107/1964 (5·4%)
42/637 (6·6%)
348/7255 (4·8%)
135/1684 (8·0%)
47/690 (6·8%)
360/6536 (5·5%)
–15·7
1·2
–26·9
56·4
20·9
169·1
1·00 (0·79–1·26)
0·83 (0·61–1·11)
0·74 (0·56–0·98)
0·49 (0·19–1·29)
0·92 (0·71–1·20)
0·72 (0·57–0·90)
0·76 (0·54–1·07)
1·06 (0·60–1·86)
0·85 (0·70–1·04)
4/277 (1·4%)
169/3081 (5·5%)
324/6498 (5·0%)
4/283 (1·4%)
154/2091 (1·4%)
384/6536 (5·9%)
0·8
–18·5
–26·9
1·7
68·6
166·9
0·76 (0·56–1·04)
0·85 (0·70–1·04)
39/1616 (2·4%)
458/8240 (5·6%)
53/1616 (3·3%)
489/7294 (6·7%)
–6·3
–38·3
21·0
216·2
0·74 (0·48–1·14)
0·84 (0·70–1·00)
0·829 (0·730–0·941)
2p=0·004
70/2638 (2·7%)
225/4323 (5·2%)
160/1205 (13·3%)
42/1690 (2·5%)
68/2631 (2·6%)
231/3352 (6·9%)
183/1190 (15·4%)
60/1737 (3·5%)
0·6
–24·0
–14·3
–6·9
32·3
104·1
76·1
24·6
1·02 (0·72–1·44)
0·79 (0·62–1·02)
0·83 (0·62–1·11)
0·76 (0·45–1·27)
24/877 (2·7%)
196/3667 (5·3%)
156/2801 (5·6%)
121/2511 (4·8%)
26/793 (3·3%)
203/3249 (6·2%)
174/2326 (7·5%)
139/2542 (5·5%)
–1·6
–11·7
–17·6
–4·4
10·9
94·4
76·8
61·4
0·88 (0·68–1·15)
0·80 (0·59–1·07)
0·93 (0·67–1·29)
173/9856 (1·8%)
218/8445 (2·6%)
104/5711 (1·8%)
2/706 (0·3%)
497/9856 (5·0%)
204/8910 (2·3%)
237/7609 (3·1%)
99/5614 (1·8%)
2/758 (0·3%)
542/8910 (6·1%)
–25·0
–20·0
0·8
–0·4
–44·6
85·0
104·6
46·8
0·9
237·1
0·75 (0·56–0·99)
0·83 (0·64–1·06)
1·02 (0·73–1·31)
139/2514 (5·5%)
200/4642 (4·3%)
80/460 (17·4%)
78/2040 (3·8%)
0/200 (0·0%)
(no da a)
165/2539 (6·5%)
250/4648 (5·4%)
76/493 (15·4%)
49/1032 (4·7%)
2/198 (1·0%)
–16·7
–24·1
5·1
–8·0
–0·9
67·5
108·7
33·1
27·3
0·5
0·78 (0·57–1·07)
0·80 (0·63–1·03)
1·17 (0·83–1·64)
0·75 (0·46–1·22)
434/7040 (6·2%)
63/2816 (2·2%)
457/6089 (7·5%)
85/2821 (3·0%)
–34·5
–10·1
201·7
35·5
0·84 (0·70–1·01)
0·75 (0·49–1·16)
139/2514 (5·5%)
358/7342 (4·9%)
165/2539 (6·5%)
377/6371 (5·9%)
–16·7
–27·9
67·5
169·7
0·78 (0·57–1·07)
0·85 (0·70–1·03)
Bisphosphona e e en s
Log- ank
O–E
Va iance
o O–E
1·00·50 1·5 2·0
Con ol be e Bisphosphona e be e
Ra io o annual e en a es
bisphosphona e : con ol
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1357
b eas ecu ence (10-yea isk 20·4% bisphosphona e s
21·8% con ol; RR 0·92, 95% CI 0·85–0·99; 2p=0·03;
fi gu e 1), whe eas he e was no signifi can eff ec on he
incidence o local ecu ence as fi s e en (RR 1·10,
0·94–1·28; 2p=0·25; appendix) o o con ala e al b eas
cance as fi s e en (RR 0·96, 0·74–1·25; 2p=0·79). The
g ea e effi cacy o bis phosphona es in p e en ing dis an
ecu ence han in p e en ing o he (local o con ala e al)
b eas cance ecu ence was signifi can ( es o
in e ac ion 2p=0·01).
The eff ec on dis an ecu ence was mainly because o a
educ ion in bone ecu ence (10-yea isk 7·8% s 9·0%;
RR 0·83, 95% CI 0·73–0·94; 2p=0·004; fi gu e 1). The e
was signifi can ly (p=0·04) g ea e eff ec on bone ecu ence
han on o he fi s dis an ecu ence (RR 0·98, 95% CI
0·89–1·08; 2p=0·69; appendix), al hough his appa en
lack o effi cacy could be pa ly because delay o bone
ecu ence wi h bisphosphona e in a woman who would
o he wise ha e had bo h bone and o he dis an ecu ence
allowed he o he ecu ence o be he fi s e en .
B eas cance mo ali y was bo de line signifi can ly
lowe in pa ien s alloca ed bisphosphona e han con ol
(10-yea isk 16·6% s 18·4%; RR 0·91, 95% CI 0·83–0·99;
2p=0·04; fi gu e 1), and all-cause mo ali y was simila ly
educed (10-yea isk 20·8% s 22·3%; RR 0·92,
0·85–1·00; 2p=0·06; appendix). O 2607 dea hs om any
cause, 501 (19%) we e in ecu ence- ee women; his
non-b eas cance mo ali y appea ed o be unaff ec ed by
he ea men alloca ion (RR 0·99, 95% CI 0·82–1·19;
2p=0·91).
We did many subg oup analyses o in es iga e he eff ec s
o bisphosphona es on any ecu ence, dis an ecu ence,
bone ecu ence, and b eas cance mo ali y (appendix).
In he o e all analyses, among all 18 766 women, he
clea es e idence o eff ec o bis phosphona es was, as
an icipa ed, on bone ecu ence, so he mos in o ma i e
subg oup analyses should ela e o his endpoin (fi gu e 2).
The effi cacy o bisphosphona es in educing bone
ecu ence appea ed o be g ea e in olde women
(2p=0·03 o end wi h age in ea men eff ec ) o ,
simila ly, in pos menopausal women (2p=0·06 o end
wi h menopausal s a us). As menopausal s a us and age
a e closely co ela ed, we canno de e mine eliably which
is mo e ele an (appendix). Among he 4616 women
younge han 45 yea s, bone ecu ence appea ed o be
unaff ec ed by he ea men alloca ion (RR 1·00, 95% CI
0·79–1·26; 2p=0·97), bu among he 7388 women 55 yea s
o olde he e was a highly signifi can ea men eff ec (RR
0·72, 0·59–0·88; 2p=0·002). Sensi i i y analyses o he
possible ele ance o age and menopausal s a us ha
omi ed he hypo hesis-gene a ing ABCSG-129 and
AZURE11,14 s udies s ill showed signifi can (2p=0·004)
benefi only in pos menopausal women (appendix). As
was he case o bone ecu ence, he educ ions in any
dis an ecu ence wi h bisphosphona e we e also
signifi can ly g ea e in olde women (2p=0·003 o end
wi h age) and pos menopausal women (2p=0·01).
None o he o he subg oup analyses o bone ecu ence
in fi gu e 2 e ealed any signifi can e idence o
he e ogenei y o benefi by umou ype (o o o he
b eas cance ou comes; appendix). Al hough he benefi
appea ed somewha la ge in ER-nega i e han ER-posi i e
disease and in node-posi i e han node-nega i e umou s,
his appa en he e ogenei y o ea men eff ec did no
app oach signifi cance and could be a chance fi nding.
Likewise, he e was no signifi can he e ogenei y
be ween he appa en eff ec s on bone ecu ence o
he diff e en bisphosphona e egimens es ed in hese
ials. Fo his ou come, he benefi s o he non-
amino bisphosphona e (clod ona e, n=5053) and o he
wo mos widely es ed aminobisphosphona es (zoled onic
acid, n=9290, and iband ona e, n=3072) appea ed simila ,
bu he e was no appa en benefi in he smalle o al
pamid ona e g oup (n=953).
Fo bone ecu ence, he benefi s appea ed o be simila
in ials o low-in ensi y an i-os eopo osis schedules (eg,
6-mon hly in a enous zoled onic acid) and in ials o
mo e in ensi e schedules such as hose app o ed o use
in me as a ic bone disease (eg, mon hly zoled onic acid,
daily o al iband ona e, o daily o al clod ona e). Likewise,
he a e age eff ec appea ed simila in ials ha es ed
diff e en du a ions o ea men ( ials o 2 yea s
bisphosphona e s none: RR 0·76, 95% CI 0·60–0·97;
2p=0·026; ials o 3–5 yea s bisphosphona e s none:
RR 0·85, 0·73–0·99; 2p=0·037; fi gu e 2), and in he
p esence o absence o chemo he apy. The e we e
signifi can educ ions in bone ecu ence du ing yea s
0–1 and yea s 2–4 a e andomisa ion bu he e appea ed
o be no u he educ ion he ea e . Again, hough, his
dec ease in ea men eff ec o e ime was no signifi can
( end 2p=0·11), pe haps because he e is hus a only
limi ed ollow-up a e he fi s 5 yea s.
The 10-yea disease ou comes o p emenopausal and
pos menopausal women sepa a ely a e summa ised in
fi gu e 3 and he appendix. In p emenopausal women,
ea men appea ed o ha e li le eff ec on bone me as ases
o b eas cance mo ali y, whe eas in pos menopausal
women i p oduced highly signifi can educ ions in
ecu ence (RR 0·86, 95% CI 0·78–0·94; 2p=0·002;
appendix), dis an ecu ence (RR 0·82, 0·74–0·92;
2p=0·0003; appendix), bone ecu ence (RR 0·72,
0·60–0·86; 2p=0·0002), and b eas cance mo ali y
(RR 0·82, 0·73–0·93; 2p=0·002). In bo h menopausal
subg oups, a es o fi s dis an ecu ence a si es o he
han bone appea ed o be unaff ec ed by ea men . In he
pos menopausal subg oup, o bone ecu ence he
absolu e gain om ea men was 2·2% (95% CI 0·6–3·8)
(10-yea isks 6·6% s 8·8%; RR 0·72, 95% CI 0·60–0·86;
2p=0·0002), whe eas o b eas cance mo ali y he
absolu e gain was 3·3% (95% CI 0·8–5·7) (10-yea isks
14·7% s 18·0%; RR 0·82, 0·73–0·93; 2p=0·002).
To enhance s a is ical powe , he mul iple subg oup
analyses o bone ecu ence (fi gu e 2) and he
co esponding analyses o o he ou comes (appendix) can

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Figu e 3: Main ou comes in
p emenopausal (excluding
pe imenopausal) and in
pos menopausal women in
ials o bisphosphona e
e sus no bisphosphona e
(con ol)
Kaplan-Meie g aphs showing
he eff ec s o ea men
alloca ion on 10-yea b eas
cance ou comes.
(A) P emenopausal and
(B) pos menopausal bone
ecu ence. (C) P emenopausal
and (D) pos menopausal
dis an ecu ence ou side he
bone. (E) P emenopausal and
(F) pos menopausal b eas
cance mo ali y.
O-E=obse ed minus
expec ed. V= a iance o O–E.
RR= a e a io (exp[{O–E}/V]).
E o ba s a e SE .
Bone ecu ence a e/yea (%), e en s/woman-yea s and log- ank s a is ics
Alloca ion
Bisphosphona e
Con ol
Ra e a io (95% CI)
om (O–E)/V
6171 women RR 0·92 (95% CI 0·75–1·12)
Log- ank 2p=0·42
10-yea gain 0·0% (95% CI –2·1 o 2·2)
Con ol 10·3%
Bisphosphona e 10·3%
Yea s 0–4
1·35 (169/12
510)
1·54 (175/11
390)
0·86 (0·66–1·07)
–11·4/77·4
Yea s 5–9
1·00 (47/4710)
0·69 (36/5196)
1·24 (0·73–1·74)
3·9/18·5
Yea s ≥10
0·07 (1/1390)
0·07 (1/1424)
0·37 (0·02–2·33)
–0·4/0·4
7·4%
6·5%
0
10
20
30
40
50
Bone ecu ence (%)
A
Bone ecu ence a e/yea (%), e en s/woman-yea s and log- ank s a is ics
Alloca ion
Bisphosphona e
Con ol
Ra e a io (95% CI)
om (O–E)/V
11
767 women RR 0·72 (95% CI 0·60–0·86)
Log- ank 2p=0·0002
10-yea gain 2·2% (95% CI 0·6 o 3·8)
Con ol 8·8%
Bisphosphona e 6·6%
Yea s 0–4
0·78 (197/25 220)
1·06 (251/23 642)
0·68 (0·52–0·84)
–39·3/101·2
Yea s 5–9
0·67 (55/8157)
0·76 (60/7870)
0·90 (0·54–1·26)
–2·8/26·8
Yea s ≥10
0·0 (0/513)
0·0 (0/484)
5·4%
3·6%
0
10
20
30
40
50
Bone ecu ence (%)
B
Recu ence ou side bone a e/yea (%), e en s/woman-yea s and log- ank s a is ics
Alloca ion
Bisphosphona e
Con ol
Ra e a io (95% CI)
om (O–E)/V
6171 women RR 1·08 (95% CI 0·92–1·26)
Log- ank 2p=0·35
10-yea loss 1·1% (95% CI 1·4 o 3·6)
Bisphosphona e 17·0%
Con ol 15·9%
Yea s 0–4
2·64 (330/12 510)
2·41 (275/11 390)
1·12 (0·93–1·30)
14·2/128·4
Yea s 5–9
1·25 (59/4710)
1·14 (59/5196)
1·03 (0·64–1·42)
0·7/26·1
Yea s ≥10
0·43 (6/1390)
0·77 (11/1424)
0·37 (0·13–1·08)
–3·0/3·1
12·2%
11·1%
0
10
20
30
40
50
Dis an ecu ence ou side bone (%)
C
Recu ence ou side bone a e/yea (%), e en s/woman-yea s and log- ank s a is ics
Alloca ion
Bisphosphona e
Con ol
Ra e a io (95% CI)
om (O–E)/V
11
767 women RR 0·90 (95% CI 0·79–1·02)
Log- ank 2p=0·10
10-yea gain 1·6% (95% CI –0·4 o 3·5)
Con ol 13·6%
Bisphosphona e 12·1%
Yea s 0–4
1·67 (420/25 220)
1·98 (427/23 642)
0·90 (0·77–1·04)
–18·4/182·4
Yea s 5–9
1·04 (85/8157)
1·17 (92/7870)
0·89 (0·60–1·19)
–4·5/39·7
Yea s ≥10
0·78 (4/513)
1·65 (8/484)
0·38 (0·09–1·34)
–1·7/1·8
8·7%
7·8%
0
10
20
30
40
50
Dis an ecu ence ou side bone (%)
D
Dea h a es (%/yea : o al a e minus a e in women wi hou ecu ence) and log- ank s a is ics
Alloca ion
Bisphosphona e
Con ol
Ra e a io (95% CI)
om (O–E)/V
6171 women RR 1·00 (95% CI 0·86–1·15)
Log- ank 2p=0·96
10-yea gain 0·1% (95% CI –2·9 o 3·0)
Con ol 20·7%
Bisphosphona e 20·6%
0 5 10
Yea s 0–4
2·43 (2·16–2·69)
2·50 (2·22–2·79)
0·97 (0·81–1·14)
–3·3/130·6
Yea s 5–9
2·26 (1·84–2·67)
2·03 (1·65–2·40)
1·10 (0·81–1·40)
5·0/50·0
Yea s ≥10
1·13 (0·58–1·68)
1·29 (0·71–1·88)
0·71 (0·34–1·50)
–2·3/6·9
Yea s
12·1%
11·8%
0
10
20
30
40
50
B eas cance mo ali y (%)
E
Dea h a es (%/yea : o al a e minus a e in women wi hou ecu ence) and log- ank s a is ics
Alloca ion
Bisphosphona e
Con ol
Ra e a io (95% CI)
om (O–E)/V
11
767 women RR 0·82 (95% CI 0·73–0·93)
Log ank 2p=0·002
10-yea gain 3·3% (95% CI 0·8 o 5·7)
Con ol 18·0%
Bisphosphona e 14·7%
0 5 10
Yea s 0–4
1·56 (1·41–1·72)
1·74 (1·58–1·91)
0·86 (0·72–0·99)
–27·1/174·9
Yea s 5–9
1·57 (1·30–1·84)
2·04 (1·74–2·35)
0·76 (0·55–0·97)
–18·0/65·0
Yea s ≥10
1·30 (0·34–2·26)
2·73 (1·30–4·16)
0·52 (0·18–1·44)
–2·4/3·6
Yea s
8·7%
7·5%
0
10
20
30
40
50
B eas cance mo ali y (%)
F
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1359
all be es ic ed o pos menopausal women (appendix). In
pos menopausal women, he e was signifi can (p=0·01)
he e ogenei y be ween agen s in he educ ions in bone
ecu ence, explained by he appa en lack o benefi om
pamid ona e. The clod ona e esul s did appea somewha
mo e p omising han he aminobisphosphona e esul s
bu his diff e ence was no signifi can o dis an
ecu ence o o bone ecu ence, and was o only
bo de line signifi cance o b eas cance mo ali y, e en
hough he educ ion in pos menopausal b eas cance
mo ali y was signifi can wi h clod ona e bu no wi h he
agg ega e o all aminobisphosphona e egimens.
In o ma ion on ac u es was a ailable om only
13 341 (71%) o 18 766 women. Among hem, 422 (6·3%) o
6649 bisphosphona e-alloca ed pa ien s had a ac u e
epo ed, as agains 487 (7·3%) o 6692 con ol pa ien s
(RR 0·85, 95% CI 0·75–0·97; 2p=0·02; appendix), and he
5-yea ac u e isk was educed om 6·3% o 5·1%, wi h
li le eff ec in yea s 0–1 and mos o he gain in yea s 2–4.
A e yea 5 he e appea ed o be li le u he gain, bu in
bo h g oups he absolu e a es a e yea 5 we e lowe han
in yea s 0–4, pe haps efl ec ing incomple e asce ainmen .
Discussion
Taking all women oge he , ega dless o menopausal
s a us, his collabo a i e me a-analysis o indi idual
pa ien da a om 18 766 women andomised in ials o
adju an bisphosphona es ound a highly signifi can
educ ion only in bone ecu ence, and no in o he
b eas cance ou comes. Subg oup analyses sugges ed
benefi jus in pos menopausal women, among whom
he e we e highly signifi can educ ions no only in bone
ecu ence bu also in any dis an ecu ence (bone o
o he ), b eas cance mo ali y, and o e all mo ali y.
Nei he in he o e all esul s no in he esul s jus
among pos menopausal women, howe e , was he e any
signifi can eff ec on dis an ecu ence a ex a-osseous
si es, on loco egional ecu ence, o on he incidence o
con ala e al b eas cance . The lack o eff ec on new
con ala e al b eas cance s is consis en wi h fi ndings
o he la ge FIT and HORIZON-PFT ac u e p e en ion
ials,20 bu con as s wi h epo s om epidemiological
s udies ha b eas cance incidence is educed in
pos menopausal women aking bisphosphona es o
os eopo osis.21,22 Thus, he andomised e idence p o ides
no suppo o he use o bisphosphona es as a b eas
cance chemop e en ion s a egy.
Though he s a is ical signifi cance o he appa en
in e ac ion be ween menopausal s a us and ea men
effi cacy is no ex eme, g ea e benefi o pos menopausal
women had been hypo hesised o explain he appa en
disco dance be ween he ABCSG-129 and AZURE11,14 ial
esul s. Sensi i i y analyses ha excluded hese wo
hypo hesis-gene a ing da ase s only ma ginally weakened
he e idence o an in e ac ion wi h menopausal s a us,
and he benefi was s ill signifi can in he emaining
pos menopausal women.
Mo eo e , he e is some p eclinical e idence ha
ep oduc i e ho mones can inhibi bisphosphona e
effi cacy agains cance cells in he bone. The eff ec s o
zoled onic acid (100 μg/kg weekly) on he g ow h o
dissemina ed MDA-231 b eas cance cells in bone we e
compa ed in o a iec omised mice (modelling he
pos menopausal se ing) and in sham-ope a ed mice
(modelling he p emenopausal se ing). Zoled onic acid
dec eased he numbe o de ec able umou s in bone only
in he o a iec omised animals.23 Likewise, in a p os a e
cance mouse model he abili y o dissemina ed umou
cells in he bone o o m de ec able umou s was inhibi ed
by zoled onic acid only in cas a ed mice, no in sham-
ope a ed mice.24
The eff ec s on bone ecu ence emphasise he po en ial
impo ance o hos mic oen i onmen ac o s o
me as asis. Fu he s udies a e needed o cla i y why
menopausal s a us should impo an ly aff ec he esponse
o bisphosphona es. The complex in e ac ions be ween
ep oduc i e ho mones, umou biology, bone cell
unc ion, and bone ma ow s em cells could well change
as pa ien s p og ess om he p emenopausal se ing,
whe e oes adiol and inhibin a e o majo impo ance in
bones, o he pos menopausal se ing, whe e ac i in and
o he membe s o he TGF-β supe amily become he
main egula o s o bone cell me abolism.25 A clea e
unde s anding o some o he o he mechanisms in ol ed
in he de elopmen o bone me as asis is now eme ging,
al hough how hese ela e o menopausal s a us and
ep oduc i e ho mones emains unknown.26
O he han he appa en eff ec o menopausal s a us o ,
simila ly, age on ea men effi cacy, he p opo ional
educ ions in bone ecu ence and b eas cance mo ali y
wi h ea men did no depend signifi can ly on o he
pa ien o clinico pa hological p ima y umou cha ac e -
is ics, including ER s a us, axilla y lymph node in ol e-
men , and umou g ade. Simila educ ions we e seen in
he p esence and absence o chemo he apy, sugges ing
ha he benefi s o bisphosphona es a e app oxima ely
addi i e o hose o chemo he apy, and ice e sa.
As subg oup analyses can yield e a ic esul s, i is
diffi cul o de e mine om hem whe he diff e en
bisphosphona e egimens ha e diff e en eff ec s. The
endpoin ha should yield he mos eliable subg oup
analyses is bone ecu ence. Bo h o all women and o
pos menopausal women, subg oup analyses o bone
ecu ence sugges ed simila eff ec s o o al clod ona e
and o he agg ega e o all aminobisphosphona e
egimens (mainly in a enous zoled onic acid). Likewise,
hey sugges ed no signifi can he e ogenei y in effi cacy
be ween he diff e en aminobisphosphona es, hough no
benefi was seen wi h o al pamid ona e (which could be
eal, as o al pamid ona e is poo ly abso bed, has li le
eff ec on bone eso p ion bioma ke s o he unde lying
me as a ic bone disease, and ailed o show effi cacy in
myeloma27,28). Numbe s we e insuffi cien o assess he
effi cacy o he s anda d ea men s o os eopo osis, o al
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ised ona e o alend ona e, as he apy o ea ly b eas
cance . Subg oup analyses based ins ead on b eas cance
mo ali y sugges ed a g ea e eff ec wi h clod ona e han
wi h aminobisphosphona es. Howe e , as he wo d ugs
appea ed o ha e simila eff ec s on bone ecu ence, hei
appa en ly diff e en eff ec s on b eas cance mo ali y
could be a chance fi nding.
Much mo e eliable compa isons o diff e en bis-
phosphona e egimens will eme ge om ongoing ials
ha compa e hem di ec ly. The SWOG0307 ial
(NCT00127205) compa ing clod ona e e sus zoled onic
acid e sus iband ona e in 5400 pa ien s has comple ed
ec ui men and add esses he choice o agen ; he
SUCCESS ial (NCT02181101) compa ing 5 yea s e sus
2 yea s o zoled onic acid in 3800 pa ien s has also
comple ed ec ui men and add esses du a ion. Simila ly,
esul s om wo ongoing ials (HOBOE-p emenopausal
[NCT00412022] and TEAM-IIb [ISRCTN17633610]), plus
longe ollow-up o he ials included in his me a-
analysis, will e en ually p o ide be e e idence on any
eff ec o bisphosphona es in p emenopausal women, and
will p o ide mo e s able es ima es o he 10-yea ou comes
in pos menopausal women.
Consis en wi h he known eff ec s on bone mine al
densi y and quali y, he use o adju an bisphosphona es
was associa ed wi h a small educ ion in ac u e incidence.
Al hough no highly signifi can , i can be accep ed as eal
because o e idence o ac u e educ ion in o he ypes
o pa ien . The e was no appa en eff ec o adju an
bisphosphona es on non-b eas cance mo ali y. Majo
ad e se e en s wi h bisphosphona es a e uncommon, bu
can include impai ed enal unc ion and os eonec osis o
he jaw. F om he da a p o ided, we we e unable o assess
he incidence o os eonec osis o he jaw, bu p e ious
epo s sugges i anges om unde 1% wi h clod ona e,
iband ona e, o 6-mon hly zoled onic acid12,13,29 o abou 2%
wi h mo e in ensi e zoled onic acid schedules.30
These ials ha e shown ha some yea s o adju an
bisphosphona e ea men can educe b eas cance
ecu ence a es in bone and imp o e b eas cance
su i al, bu ha e p o ided clea e idence o benefi only
in women who a e pos menopausal (na u al o induced)
a he ime bisphosphona es a e s a ed. The use o
bisphosphona es in b eas cance is mainly o educe
bone loss and isk o ac u e in pos menopausal
women wi h ER-posi i e disease ea ed wi h a oma ase
inhibi o s. Ou esul s show ha such bisphosphona e
ea men can, in addi ion, p o ide oncological benefi ,
and sugges ha adju an bis phosphona es should be
conside ed in a b oade ange o pos menopausal women.
Con ibu o s
Analyses we e planned by R Coleman, R G ay, T Powles, A Pa e son,
M Gnan , J Be gh, K I P i cha d, J Bliss, and D Came on, and
unde aken by R B adley, R G ay, H Pan, and R Pe o in Ox o d.
R Coleman, R G ay, T Powles, and A Pa e son d a ed he epo and
e ised i wi h ad ice om all w i ing commi ee membe s. The
EBCTCG sec e a ia (R B adley, J Bu e , M Cla ke, C Da ies, F Duane,
V E ans, L Ge ins, J Godwin, R G ay, H Liu, P McGale, E MacKinnon,
T McHugh, S James, P Mo is, H Pan, R Pe o, S Read, C Taylo , Y Wang,
Z Wang) iden ifi ed ials, ob ained da ase s, and had ull access o hem.
W i ing commi ee
R Coleman (Sheffi eld Cance Resea ch Cen e, Wes on Pa k Hospi al,
Uni e si y o Sheffi eld, UK); T Powles (Royal Ma sden Hospi al, Su on,
Su ey, UK); A Pa e son (Tom Bake Cance Cen e and Uni e si y o
Calga y, Calga y, Albe a, Canada); M Gnan (Depa men o Su ge y and
Comp ehensi e Cance Cen e , Medical Uni e si y o Vienna, Aus ian
B eas & Colo ec al Cance S udy G oup, Vienna, Aus ia); S Ande son
(Depa men o Bios a is ics, Uni e si y o Pi sbu gh G adua e School o
Public Heal h, Pi sbu gh, PA, USA); I Diel (Cen e o Gynecological
Oncology, Mannheim, Ge many); J G alow (Uni e si y o Washing on
School o Medicine, Sea le, WA, USA); G on Minckwi z (Ge man B eas
G oup, Neu-Isenbu g, Ge many); V Moebus (Klinikum F ank u Höchs ,
F ank u , Ge many); J Be gh (Ka olinska Ins i u e and Uni e si y
Hospi al, S ockholm, Sweden); K I P i cha d (Sunnyb ook Ode e Cance
Cen e and Uni e si y o To on o, To on o, Canada); J Bliss (ICR-CTSU,
Di ision o Clinical S udies, The Ins i u e o Cance Resea ch, London,
UK); D Came on (Edinbu gh Cance Resea ch Cen e, Uni e si y o
Edinbu gh, Edinbu gh, UK); V E ans (Clinical T ial Se ice Uni , Nuffi eld
Depa men o Popula ion Heal h, Uni e si y o Ox o d, Ox o d, UK);
H Pan (Clinical T ial Se ice Uni , Nuffi eld Depa men o Popula ion
Heal h, Uni e si y o Ox o d, Ox o d, UK); R Pe o (Clinical T ial Se ice
Uni , Nuffi eld Depa men o Popula ion Heal h, Uni e si y o Ox o d,
Ox o d, UK); R B adley (Clinical T ial Se ice Uni , Nuffi eld Depa men
o Popula ion Heal h, Uni e si y o Ox o d, Ox o d, UK); R G ay (Clinical
T ial Se ice Uni , Nuffi eld Depa men o Popula ion Heal h, Uni e si y
o Ox o d, Ox o d, UK).
G oups con ibu ing da a o he adju an bisphosphona es me a-analyses
Aus ian B eas Cance S udy G oup, Vienna, Aus ia (R Ba sch,
P Dubsky, C Fesl, H Fohle , M Gnan , R G eil, R Jakesz, A Lang,
G Luschin-Ebeng eu h, C Ma h, B Mline i sch, H Samonigg, C F Singe ,
G G S ege , H S öge ); B i ish Columbia Cance Agency, Vancou e ,
Canada (I Oli o o, J Ragaz); Danish B eas Cance Coope a i e G oup,
Copenhagen, Denma k (P Ch is iansen, B Ejle sen, M Ewe z,
M-B Jensen, S Mølle , H T Mou idsen); Ge man Adju an B eas G oup,
F ank u , Ge many (W Eie mann, J Hil ich, W Jona , M Kau mann,
R K eienbe g, M Schumache ); Ge man B eas G oup, Neu-Isenbu g,
Ge many (J U Blohme , S D Cos a, H Eid mann, B Ge be , C Jackisch,
S Loibl, G on Minckwi z); Hellenic B eas Su geons Socie y, G eece
(U Da ni, C Ma kopoulos); Helsinki Uni e si y, Finland (C Blomq is ,
T Saa o); Ko ean Cance S udy G oup, Seoul, Sou h Ko ea (J-H Ahn,
K H Jung); Is i u o Nazionale Tumo i IRCCS Fondazione Pascale, Naples,
I aly (F Pe one); Na ional Su gical Adju an B eas and Bowel P ojec ,
Pi sbu gh, PA, USA (S Ande son, G Bass, A B own [deceased],
J B yan [deceased], J Cos an ino, J Dignam, B Fishe , C Geye ,
E P Mamounas, S Paik, C Redmond, S Swain, L Wicke ham, N Wolma k);
No h Cen al Cance T ea men G oup, Mayo Clinic, Roches e , MN, USA
(E Pe ez, JN Ingle, V J Suman); P oBONE s udy g oup, Ma bu g, Ge many
(P Hadji); Royal Ma sden Hospi al, London and Su on, UK (R A’He n,
M Dowse , A Mak is, M Pa on, K Penne , T J Powles, I E Smi h,
J R Ya nold); SABRE ial g oup (in e na ional) (G Clack, C Van Poznak);
Tel A i Sou asky Medical Cen e , Is ael (T Sa a); Uni e si y o Leeds, UK
(R Bell, D Came on, RE Coleman, D Dodwell, S Hinsley, H C Ma shall);
Uni e si y o Saa land, Ge many (E Solomaye , T Fehm); Uni e si y o
Sheffi eld, UK (R E Coleman, J Les e , M C Win e , J M Ho sman);
Washing on Uni e si y, S Louis, Missou i, USA (R A ); Z-FAST,
ZO-FAST & E-ZO-FAST s udy g oups (in e na ional) (A M B u sky,
R Coleman, H A Llomba on behal o No a is Pha maceu icals).
EBCTCG s ee ing commi ee
J Be gh (co-chai ), K P i cha d (co-chai ), K Albain, S Ande son,
R A iagada, W Ba low, E Be gs en-No ds öm, J Bliss, F Bocca do,
R B adley*, M Buyse, D Came on, M Cla ke*, A Coa es, R Coleman,
C Co ea, J Cos an ino, J Cuzick, N Da idson, C Da ies*, A Di Leo,
M Dowse , M Ewe z, J Fo bes, R Gelbe , C Geye , L Gianni, M Gnan ,
A Goldhi sch, R G ay*, D Hayes, C Hill, J Ingle, W Janni, E MacKinnon*,
M Ma ín, P McGale*, L No on, Y Ohashi, S Paik, H Pan*, E Pe ez,
R Pe o*, M Picca , L Pie ce, V Raina, P Ra din, J Robe son, E Ru ge s,
J Spa ano, S Swain, C Taylo *, G Viale, G on Minckwi z, X Wang,
T Whelan, N Wilcken, E Wine , N Wolma k, W Wood. *Sec e a ia .
A icles
www. helance .com Vol 386 Oc obe 3, 2015
1361
Decla a ion o in e es s
Clinical T ial Se ice Uni (CTSU) s aff policy excludes hono a ia o
consul ancy ees o any membe o he Ea ly B eas Cance T ialis s’
Collabo a i e G oup Sec e a ia . EBCTCG is unded by Cance Resea ch
UK and UK Medical Resea ch Council g an s o he CTSU. SA epo s
g an s om Na ional Ins i u es o Heal h (U10 CA069974 and U10
CA69651), du ing he conduc o he s udy. JBe epo s ha Ka olinska
Uni e si y Hospi al and Ka olinska Ins i u e ha e ecei ed paymen s o
academic clinical s udies and esea ch g an s o molecula biological
s udies and PET s udies om Amgen, As aZeneca, Baye , Me ck, Pfi ze ,
Roche, and Sanofi -A en is; he was Swedish p incipal in es iga o (PI) o
an adju an bisphosphona e s udy o which o al pamid ona e was
p o ided ee-o -cha ge ( his o mula ion is no licensed); he is also
Swedish PI o he ongoing ABCSG-18 adju an denosumab s udy ( he
d ug was p o ided ee-o -cha ge); he epo s no pe sonal paymen s in he
pas 3 yea s. DC epo s suppo om No a is o a end he Ame ican
Socie y o Clinical Oncology and San An onio B eas Cance Symposium
con e ences, ou side he submi ed wo k. RC epo s pe sonal ees om
No a is ( o expe es imony), ou side he submi ed wo k. MG epo s
g an s and pe sonal ees om No a is and pe sonal ees om Amgen,
du ing he conduc o he s udy; ou side he submi ed wo k he has
ecei ed g an s and pe sonal ees om No a is, Roche, and
GlaxoSmi hKline, g an s om Sanofi -A en is, Pfi ze , and Smi h Medical,
and pe sonal ees om As aZeneca, Nanos ing Technologies, and
Accelsio s. JG epo s g an s om No a is, Amgen, and Roche, ou side
he submi ed wo k. VM epo s g an s and pe sonal ees om Amgen
and Roche, g an s om No a is, and pe sonal ees om Celgene, ou side
he submi ed wo k. KIP epo s g an s and pe sonal ees om
As aZeneca, Pfi ze , Roche, No a is, and Eisai, and pe sonal ees om
Amgen and GlaxoSmi hKline, ou side he submi ed wo k. JBl, RB, ID,
VE, RG, HP, AP, RP, TP, and G M decla e no compe ing in e es s.
Acknowledgmen s
We hank he ens o housands o women who ook pa in he ials, he
many s aff in ial cen es and pa icipa ing clinics who helped conduc
he ials, and he ialis s who sha ed hei da a. Funding o indi idual
ials was chiefl y om manu ac u e s (see ial publica ions) bu no
comme cial unding was sough o used by he sec e a ia . Funding o
he EBCTCG sec e a ia is h ough he di ec suppo om Cance
Resea ch UK and he UK Medical Resea ch Council, o he Clinical T ial
Se ice Uni and Epidemiological S udies Uni , Nuffi eld Depa men o
Popula ion Heal h, Uni e si y o Ox o d, UK.
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