Ho monal ac o s p edic i e o e ili y in pa ien s wi h b eas cance
in e up ing adju an endoc ine he apy o a emp p egnancy in
POSITIVE ial
Isabelle Demees e e
a,b,*
, Samuel M. Niman
c,d
, Ann H. Pa idge
e,
, Daniela S. Diego
g
,
Roswi ha Kammle
h
, Monica Rugge i
i
, Ma co Colleoni
j
, Chikako Shimizu
k
, C is ina Sau a
l,m
,
Ka en A. Gelmon
n
, Anna B. Sae e sdal
o
, Judi h R. K oep
p,q
, Aud ey Mailliez
,
F ede ic Aman
s, ,u
, Manuel Ruız-Bo ego
,w
, Jeong Eon Lee
x,y
, Akemi Ka aoka
z
,
Janice M. Walshe
aa,ab
, Junko Takei
ac
, Simona Bo s na
ad
, Vi ginia F. Bo ges
ae
,
Ch is obel Saunde s
a ,ag
, Snezana Susnja
ah
, Vesna Bjelic-Radisic
ai,aj
, Fa ima Ca doso
ak
,
Jane Lowe Meisel
al
, Jenni e F. Kawwass
g
, Tanja Spanic
am
, Sa a El-Abed
an
,
Ma ine Picca
an,ao
, La issa A. Ko de
ap
, A on Goldhi sch
aq,a ,1
, Richa d D. Gelbe
c,d,as,a
,
Oli ia Pagani
au,a ,aw
, Ha em A. Azim J .
ax
, Fed o A. Pecca o i
ay
, o he In e na ional B eas
Cance S udy G oup and he POSITIVE T ial Collabo a o s
a
Resea ch Labo a o y on Human Rep oduc ion, Uni e si ´
e Lib e de B uxelles (ULB), B ussels, Belgium
b
Gynecology and Obs e ics Depa men , Fe ili y Clinic, H.U.B E asme Hospi al, B ussels, Belgium
c
In e na ional B eas Cance S udy G oup S a is ical Cen e , Bos on, MA, USA
d
Depa men o Da a Science, Di ision o Bios a is ics, Dana-Fa be Cance Ins i u e, Bos on, MA, USA
e
Medical Oncology, Dana-Fa be Cance Ins i u e, Bos on, MA, USA
Ha a d Medical School, Bos on, MA, USA
g
Di ision o Rep oduc i e Endoc inology and In e ili y, Depa men o Gynecology and Obs e ics, Emo y Uni e si y School o Medicine, A lan a, GA, USA
h
T ansla ional Resea ch Coo dina ion, In e na ional B eas Cance S udy G oup, a Di ision o ETOP IBCSG Pa ne s Founda ion, Be n, Swi ze land
i
P og am o Young Pa ien s, In e na ional B eas Cance S udy G oup, a Di ision o ETOP IBCSG Pa ne s Founda ion, Be n, Swi ze land
j
Di ision o Medical Senology, IEO, Eu opean Ins i u e o Oncology, IRCCS, Milan, I aly
k
Depa men o B eas and Medical Oncology, Na ional Cen e o Global Heal h and Medicine, Tokyo, Japan
l
Vall D’Heb on Uni e si y Hospi al, Vall D’Heb on Ins i u e o Oncology, Ba celona, Spain
m
SOLTI B eas Cance Resea ch G oup, Ba celona, Spain
n
BC Cance Vancou e Cen e, Uni e si y o B i ish Columbia, Vancou e , BC, Canada
o
B eas Cance Uni , Depa men o Oncology, Di ision o Cance Medicine, Oslo Uni e si y Hospi al, Oslo, No way
p
Depa men o Medical Oncology, Leiden Uni e si y Medical Cen e , Leiden, he Ne he lands
q
Du ch B eas Cance Resea ch G oup (BOOG), he Ne he lands
Depa men o Medical Oncology, B eas Cance Uni , Cen e Osca Lamb e , Lille, F ance
s
Depa men o Oncology, KU Leu en and Leu en Cance Ins i u e, Leu en, Belgium
Depa men o Obs e ics and Gynecology, Uni e si y Hospi als Leu en, Leu en, Belgium
u
An oni an Leeuwenhoek-Ne he lands Cance Ins i u e, Ams e dam, he Ne he lands
GEICAM Spanish B eas Cance G oup, Mad id, Spain
w
Hospi al Vi gen Del Rocio Se illa, Se illa, Spain
x
B eas Di ision, Depa men o Su ge y, Samsung Medical Cen e , Sungkyunkwan Uni e si y School o Medicine, Seoul, Sou h Ko ea
y
Depa men o Clinical Resea ch and E alua ion, SAIHST, Sungkyunkwan Uni e si y, Seoul, Sou h Ko ea
z
B eas Oncology Cen e , The Cance Ins i u e Hospi al o he Japanese Founda ion o Cance Resea ch, Tokyo, Japan
aa
Cance T ials I eland, Dublin, I eland
ab
Depa men o Medical Oncology, S . Vincen ’s Uni e si y Hospi al, Dublin, I eland
ac
S Luke’s In e na ional Hospi al, B eas Cen e , Tokyo, Japan
ad
Di ision o Medical Oncology, Ins i u e o Oncology, Ljubljana, Slo enia
ae
Di ision o Medical Oncology, Depa men o Medicine, Uni e si y o Colo ado Cance Cen e , Au o a, CO, USA
a
Depa men o Su ge y, Uni e si y o Melbou ne, Melbou ne, VIC, Aus alia
ag
Royal Melbou ne Hospi al, Melbou ne, VIC, Aus alia
* Co esponding au ho . Resea ch Labo a o y on Human Rep oduc ion, Uni e si ´
e Lib e de B uxelles (ULB), B ussels, Belgium.
E-mail add ess: [email p o ec ed] (I. Demees e e).
Con en s lis s a ailable a ScienceDi ec
The B eas
jou nal homepage: www.jou nals.else ie .com/ he-b eas
h ps://doi.o g/10.1016/j.b eas .2025.104547
Recei ed 18 May 2025; Recei ed in e ised o m 11 July 2025; Accep ed 23 July 2025
The B eas 83 (2025) 104547
A ailable online 26 July 2025
0960-9776/© 2025 The Au ho s. Published by Else ie L d. This is an open access a icle unde he CC BY-NC-ND license ( h p://c ea i ecommons.o g/licenses/by-
nc-nd/4.0/ ).
i An upda e o his a icle is included a he end
ah
Depa men o Medical Oncology, Ins i u e o Oncology and Radiology o Se bia, Belg ade, Se bia
ai
B eas Uni , Helios Uni e si y Hospi al Wuppe al, Uni e si y Wi en/He decke, Wuppe al, Ge many
aj
Aus ian B eas and Colo ec al S udy G oup (ABCSG), Aus ia
ak
B eas Uni , Champalimaud Founda ion and Ad anced B eas Cance (ABC) Global Alliance, Lisbon, Po ugal
al
Depa men o Hema ology and Medical Oncology, Winship Cance Ins i u e, Emo y Uni e si y, A lan a, GA, USA
am
Eu opa Donna, Ljubljana, Slo enia and Eu opa Donna – The Eu opean B eas Cance Coali ion, Milan, I aly
an
B eas In e na ional G oup, B ussels, Belgium
ao
Ins i u Jules Bo de and Uni e si ´
e Lib e de B uxelles, B ussels, Belgium
ap
B eas and Melanoma The apeu ics, Cance The apy E alua ion P og am, Na ional Cance Ins i u e, Be hesda, MD, USA
aq
In e na ional B eas Cance S udy G oup, Di ision o ETOP IBCSG Pa ne s Founda ion, Be n, Swi ze land
a
IEO, Eu opean Ins i u e o Oncology, IRCCS, Milan, I aly
as
F on ie Science Founda ion, Bos on, MA, USA
a
Ha a d TH Chan School o Public Heal h, Bos on, MA, USA
au
Gene a Uni e si y Hospi als, Gene a, Swi ze land
a
Lugano Uni e si y, Lugano, Swi ze land
aw
Swiss G oup o Clinical Cance Resea ch (SAKK), Be n, Swi ze land
ax
Cai o Cu e Oncology Cen e , Cai o, Egyp
ay
Fe ili y and P oc ea ion Uni , Gynecologic Oncology P og am, Eu opean Ins i u e o Oncology IRCCS, Milan, I aly
ARTICLE INFO
Keywo ds:
B eas cance
P egnancy
Assis ed ep oduc i e echnology
O a ian ese e
P ema u e o a ian insu iciency
ABSTRACT
Pu pose: The POSITIVE ial showed ha p emenopausal women wi h b eas cance (BC) can sa ely pause
adju an endoc ine ea men (ET) o a emp concep ion. 74 % o pa ien s concei ed spon aneously o h ough
assis ed ep oduc i e echnology (ART); In es iga ing ho monal ac o s ha p edic e ili y was a key seconda y
endpoin .
Me hods: Ho monal ac o s we e assessed in non-p egnan women a mon hs 3, 6, and 12 a e ET in e up ion.
The equency o low o a ian ese e, de ined as an i-Mulle ian ho mone (AMH) <0.5 ng/mL a mon h 3, and o
p ema u e o a ian insu iciency (POI), de ined as ollicle s imula ing ho mone (FSH) >25 IU/L a mon h 12,
we e p ima y measu es. Seconda y analyses o p edic p egnancy included AMH, FSH, hy oid s imula ing
ho mone (TSH), p olac in and o ula o y s a us (de ined as p oges e one >3 ng/mL a mon h 6), conside ing
co a ia es such as age, ea men , and ART use.
Resul s: O 518 women en olled in POSITIVE, 438 we e eligible o low o a ian ese e analysis. Low o a ian
ese e was obse ed in 209 women (47.7 %), mo e equen ly among olde women and hose wi h p io
chemo he apy, bu no in ela ion o ET ype o du a ion. O e all, low o a ian ese e was associa ed wi h
educed odds o p egnancy (OR:0.52; 95 % CI:0.31–0.87). O 142 pa ien s e alua ed o POI, 16.7 % o hose who
ecei ed p io chemo he apy expe ienced POI. FSH a mon h 3 was associa ed wi h POI, bu only modes ly wi h
spon aneous p egnancy (OR:0.96; 95 %CI: 0.93–1.00); o he ac o s we e no p edic i e o p egnancy.
Conclusion: Ho monal ac o s a e associa ed wi h p egnancy in BC pa ien s pausing adju an ET o concei e, and
hei assessmen may help o op imize e ili y counseling.
T ial egis a ion: ClinicalT ials.go numbe NCT02308085.
1. In oduc ion
B eas cance (BC) is he mos equen cance diagnosed in women
o ep oduc i e age [1,2]. While p ognosis con inues o imp o e, he
po en ial de imen al e ec s o (neo)adju an sys emic he apy on
e ili y may signi ican ly impac ea men decisions, adhe ence, and
u u e quali y o li e [3]. Pa ien s wi h ho mone ecep o -posi i e (HR+)
BC ha e adi ionally been ad ised o delay childbea ing un il
comple ing 5–10 yea s o adju an endoc ine he apy (ET), which con-
ibu es o educed e ili y due o ad ancing age [4,5]. Recen indings
om he POSITIVE ial, demons a ing no inc ease in sho - e m isk o
BC ecu ence in pa ien s who in e up ed ET o p egnancy, will likely
lead o an inc easing numbe o pa ien s choosing o empo a ily pause
ea men o concei e [6]. While mos pa ien s became p egnan on
POSITIVE, ques ions emain ega ding p edic i e ac o s o p egnancy
in his popula ion, gi en he s udy allowed o na u al p egnancy o he
use o Assis ed Rep oduc i e Technology (ART) [7].
His o ically mens ua ion has se ed as a su oga e indica o o
o a ian unc ion eco e y in young BC su i o s ollowing ea men
[8]. Howe e , e en in he p esence o con inued mens ual cycles,
gonado oxic cance ea men can lead o a p ema u e deple ion o
p imo dial ollicles, esul ing in a educed o a ian ese e and, ul i-
ma ely, p ema u e o a ian insu iciency (POI) - de ined as he loss o
o a ian unc ion and abili y o concei e be o e he age o 40 [9,10]. The
isk o POI makes e ili y p ese a ion p io o cance ea men c i i-
cally impo an [10].
The an i-Mulle ian Ho mone (AMH) le el has been ecognized as he
mos accu a e ma ke o o a ian ese e [11]. AMH le els a e s ong
p edic o s o he numbe o ma u e oocy es e ie ed du ing o a ian
s imula ion cycles [12], howe e , hey do no p edic he likelihood o
achie ing spon aneous p egnancy [13,14]. I has been shown o signi -
ican ly dec ease in BC pa ien s du ing chemo he apy, wi h a po en ial
o pa ial eco e y wi hin he i s yea o ollow-up [15–17]. The
impac o pos - ea men o a ian ese e deple ion on he abili y o
concei e and he isk o POI emain inadequa ely explo ed in his pop-
ula ion [14]. Fu he esea ch is needed o e alua e he eliabili y o
pos - ea men ho mone p o ile and o he po en ial p edic i e ac o s o
p egnancy o imp o ing e ili y counseling.
He e, we e alua ed he ho mone p o ile o he POSITIVE ial coho
o iden i y ho monal ac o s a e ET in e up ion p edic i e o subse-
quen p egnancy.
2. Pa ien s and me hods
2.1. Popula ion
Ho mone assessmen was a p ede ined seconda y endpoin o he
POSITIVE ial, a p ospec i e, in e na ional, mul icen e , single-a m
ial conduc ed ac oss 20 coun ies. The s udy design, pa ien
1
Deceased.
I. Demees e e e al.
The B eas 83 (2025) 104547
2
cha ac e is ics, and p ima y esul s we e p e iously desc ibed [6,18]. In
b ie , a o al o 518 p emenopausal pa ien s aged ≤42 yea s wi h s age I
o III HR +BC who ecei ed adju an ET o ≥18 bu ≤30 mon hs we e
en olled in he ial om Decembe 2014 o Decembe 2019. Pa ien s
we e ecommended o in e up ET o a maximum o 2 yea s o a emp
p egnancy a e a 3-mon h ET washou pe iod.
The chemo he apy egimens we e p e iously desc ibed in he coho
o pa ien s included in he POSITIVE ial. The majo i y o pa ien s (67.2
%) who ecei ed chemo he apy we e ea ed wi h a combina ion o
an h acycline and axane he apy. Addi ionally, 20.6 % ecei ed axane-
based he apy while he emaining pa ien s ecei ed ei he an h acy-
cline alone o o he chemo he apy egimens [6].
In o ma ion on esump ion o mens ual cycles and me hod o
concep ion as well as p egnancy and disease ou comes we e p e iously
epo ed [6,7].
The s udy was sponso ed by he IBCSG in acco dance wi h he In-
e na ional Council o Ha moniza ion Good Clinical P ac ice guide-
lines, he Decla a ion o Helsinki, and local clinical esea ch egula ions.
All pa ien s ga e w i en in o med consen . The IBCSG was esponsible
o ial design, da a collec ion and managemen , blood sample
cen aliza ion, and s a is ical analysis. Pa icipa ing cen e s we e a ili-
a ed wi h coope a i e g oups o he B eas In e na ional G oup and he
Uni ed S a es Na ional Clinical T ials Ne wo k.
2.2. S udy objec i es
This analysis aims o e alua e he isk o low o a ian ese e and POI
in POSITIVE ial pa icipan s a e ET in e up ion, and o cha ac e ize
he associa ion o AMH and FSH le els wi h he likelihood o p egnancy,
also conside ing co a ia es such as age, adju an he apy (ET ±
chemo he apy), and use o ART which we p e iously in es iga ed [7].
O he ac o s e alua ed include hy oid unc ion, p olac in (PRL) and
o ula o y s a us.
2.3. Ho monal assays and de ini ions
Ho mone assessmen o pa ien s who we e no p egnan included, 3-
mon h pos -ET in e up ion, o a ian ese e (AMH), o a ian unc ion
( ollicle s imula ing ho mone -FSH and es adiol -E2), and o ula o y
s a us (p oges e one) (Fig. 1). Low o a ian ese e was de ined as AMH
alues <0.5 ng/ml a mon h 3 (o a mon h 12 i AMH a mon h 3 was
no a ailable) [8,15,16]. O a ian unc ion was e alua ed using FSH
du ing he ea ly ollicula phase (day 2–5 o he mens ual cycle) a
mon h 3 and a mon h12 in non-p egnan women. POI was de ined as
FSH >25IU/L a mon h 12 du ing ea ly ollicula phase in non-p egnan
women [19].I ameno hea, samples we e collec ed a any ime.
O ula o y s a us was de ined as p oges e one le els >3 ng/ml in he
lu eal phase (days 21–25 o he mens ual cycle) a mon h 6 [20].
FSH, E2, p oges e one and AMH we e cen ally measu ed as
desc ibed in he Supplemen a y Ma e ial – Popula ions and Me hods.
Thy oid s imula ing ho mone (TSH) and PRL le els we e assessed
locally a mon h 3 and eco ded as ‘No mal’ o ‘High’ o PRL, and
‘No mal’, Low’, o ‘High’ o TSH. I abno mal, PRL and TSH measu e-
men s we e epea ed a mon h 12.
2.4. T ans aginal Ul asound
T ans aginal Ul asound was pe o med a mon h 3 o assess,
op ionally, an al ollicula coun (AFC).
2.5. S a is ical me hods
The seconda y endpoin popula ion consis ed o 497 ou o he 518
pa ien s en olled in he POSITIVE ial [6]. Fig. 2 shows he low dia-
g am o pa ien s in he di e en analysis popula ions, u he de ined in
he Supplemen a y Ma e ial – Popula ions and Me hods and Supple-
men a y Table 1.
All AMH samples in non-p egnan women we e conside ed o
analysis i espec i e o he days o he cycle conside ing ha AMH is
s able du ing he mens ual cycle [21]. Classi ica ion o low o a ian
ese e (Yes/No) was based on se um AMH samples aken a mon h 3, o
i una ailable, a mon h 12. Classi ica ion o POI (Yes/no) was based on
FSH samples aken a mon hs 12. The dis ibu ion o FSH and E2 a
mon h 3 pos -ET washou was also examined. All FSH and E2 samples
aken du ing p egnancy o ou side he mens ual cycle days 2–5 we e
excluded om analysis, excep i he las mens ua ion occu ed >35
days be o e blood collec ion as indica i e o ameno hea.
Oligomeno hea was de ined as 120 consecu i e days wi hou
mens ua ion and wi hou p egnancy p io o he mon h 12 sample da e.
Ca ego ical da a was desc ibed as equency and pe cen , o e all,
Fig. 1. Se um collec ion o ho mone assessmen s and ans aginal ul asound (US) o endome ium hickness and an al ollicula coun (AFC) e alua ion in he
POSITIVE ial.
I. Demees e e e al.
The B eas 83 (2025) 104547
3
and by subg oups as app op ia e. Con inuous da a was summa ized as
median and in e qua ile ange (IQR) in he manusc ip , wi h ull dis-
ibu ions (mean, median, min, max, 25 h pe cen ile, and 75 h pe cen-
ile) p o ided in supplemen a y ables, o e all, and by subg oups as
app op ia e. Associa ion o ac o s wi h bina y endpoin s such as p eg-
nancy (yes/no) and low o a ian ese e (yes/no) we e e alua ed using
mul i a iable logis ic eg ession. Mul i a iable linea eg ession and
co ela ion es ima es we e u ilized when an ou come was con inuous.
De ails on s a is ical me hods implemen ed a e in he Supplemen a y
Ma e ial – Popula ions and Me hods.
3. Resul s
3.1. Assessmen o o a ian ese e
O 497 women in he seconda y analysis popula ion, 438 had useable
AMH measu emen s (Fig. 2), 209 (47.7 %) had low o a ian ese e,
de ined as AMH <0.5 ng/ml a mon h 3, o mon h 12 (Table 1). In a
mul i a iable logis ic eg ession model, younge age (<35 s. 35–39 o
40–42 yea s) and no p io chemo he apy ( s. p io chemo he apy) we e
associa ed wi h lowe odds o low o a ian ese e (Suppl Table 2).
Impo an ly, nei he he ype no he du a ion o ET we e associa ed
wi h low o a ian ese e.
3.2. P ema u e o a ian insu iciency (POI)
O 497 women in he seconda y analysis popula ion, 142 pa ien s
who we e no p egnan a mon h 12 we e eligible o POI analysis, all o
whom we e also eligible o low o a ian ese e analysis. The median
FSH and E2 alues a mon h 12 we e 9 IU/L (IQR: 7–14 IU/L) and 44 pg/
ml (IQR: 23–77 pg/ml), espec i ely (Suppl Table 3). O he 142 pa ien s
eligible o POI analysis, 15 (10.6 %) had POI. All 15 women wi h POI
Fig. 2. Flow Cha o he s udy popula ions.
Table 1
Pa ien and ea men cha ac e is ics acco ding o Low O a ian Rese e s a us
and acco ding o 12-mon h P ema u e O a ian Insu iciency (POI) s a us.
Low o a ian ese e POI
Pa ien s Numbe (%)
wi h LOR
Pa ien s Numbe (%)
wi h POI
Pa ien s Included in
Analysis
438 209 (47.7) 142 15 (10.6)
Age a en ollmen
(yea s)
<35 142 50 (35.2) 40 1 (2.5)
35–39 192 96 (50.0) 58 7 (12.1)
40–42 104 63 (60.6) 44 7 (15.9)
P io chemo he apy
No 165 38 (23.0) 52 0 (0.0)
Yes 273 171 (62.6) 90 15 (16.7)
P io Endoc ine
The apy
OFS±AI 72 34 (47.2) 26 4 (15.4)
SERM only 174 78 (44.8) 47 5 (10.6)
O he 192 97 (50.5) 69 6 (8.7)
OFS=O a ian Func ion Supp ession, AI=A oma ase Inhibi o s; SERM=Se-
lec i e es ogen ecep o modula o .
* Low o a ian ese e is de ined as AMH<0.5 ng/ml a mon h 3, o , i mon h 3
AMH was no a ailable, AMH<0.5 ng/ml a mon h 12. Analysis was based on 3-
mon h AMH o 422 non-p egnan pa ien s, and 12-mon h AMH o 16 non-
p egnan pa ien s. POI was de ined as FSH le el>25 IU/L a mon h 12.
I. Demees e e e al.
The B eas 83 (2025) 104547
4
had ecei ed p io chemo he apy (Table 1) and had low o a ian ese e,
whe eas 46.5 % o hose wi hou POI had low o a ian ese e (Suppl
Table 4).
As expec ed, a highe p opo ion o POI was obse ed in olde pa-
ien s, wi h 2.5 % e sus 15.9 % POI in pa ien s aged below 35 yea s and
be ween 40 and 42 yea s, espec i ely (Table 1). The du a ion o ET use
was simila be ween POI and non-POI g oups (Suppl Table 5). The
p opo ion o POI was 15.4 % in pa ien s who had p io o a ian unc ion
supp ession (OFS) wi h/wi hou a oma ase inhibi o s (OFS ±AI), 10.6
% o hose who ecei ed selec i e es ogen ecep o modula o (SERM)
only, 8.7 % o hose wi h o he ET (Table 1).
The FSH alues we e a ailable a bo h mon hs 3 and 12 o 111 o
142 pa ien s. The median 3-mon h FSH alue was 31 IU/L (IQR: 6–45
IU/L) and 7 IU/L (IQR: 6–12 IU/L) in POI (n =10) and non-POI pa ien s
(n =101) (Suppl Table 6). The Spea man co ela ion coe icien o FSH
alues a mon hs 3 and 12 was 0.37 (95 % CI: 0.19–0.52) (Suppl Fig. 1).
An uni a iable logis ic eg ession model showed a modes associa ion
be ween ele a ed FSH le el a mon h 3 and he occu ence o POI (OR:
1.07; 95 %CI: 1.03 o 1.12).
AFC, an addi ional ma ke o o a ian ese e, was a ailable in 57 o
he 142 pa ien s eligible o low o a ian ese e and POI analysis. As
expec ed, AFC alues we e nega i ely associa ed wi h olde age and
p io chemo he apy. The median AFC was also lowe in pa ien s wi h
low o a ian ese e s pa ien s wi hou low o a ian ese e, and in
pa ien s wi h POI s wi hou POI (Suppl Table 7).
3.3. AMH and FSH as p edic o s o p egnancy
A o al o 368 (74 %) o he 497 pa ien s in he seconda y analysis
popula ion epo ed a leas one p egnancy du ing he s udy pe iod [7];
while 72 % o pa ien s in he low o a ian ese e analysis popula ion
epo ed a leas one p egnancy (316/438). As p e iously epo ed [7],
younge age and emb yo ans e s. no ART we e posi i ely associa ed
wi h p egnancy, whe eas p io chemo he apy and ET ype and du a ion
showed no associa ion (Table 2). A mul i a iable logis ic eg ession
model showed ha lowe AMH alues we e associa ed wi h lowe odds
o p egnancy (Suppl Table 8). A simila model con i med ha he odds
o p egnancy we e lowe by 48 % o pa ien s wi h low o a ian ese e
(OR: 0.52; 95 % CI: 0.31 o 0.87) (Table 2).
We obse ed simila p egnancy a es among women wi h low
o a ian ese e, ega dless whe he ART was used (Table 3). Al hough
di e en p egnancy a es we e obse ed o pa ien s wi h and wi hou
low o a ian ese e acco ding o ART use (Table 3), his in e ac ion was
no s a is ically signi ican (p- alue: 0.170). Among 209 pa ien s wi h
low o a ian ese e (AMH <0.5 ng/mL), 49 % u ilized ART, compa ed
o 43 % o pa ien s wi h highe o a ian ese e (AMH ≥1.5 ng/mL); and
43 % o hose in be ween (Suppl Table 9).
Finally, he mul i a iable logis ic eg ession model, including 187 o
282 pa ien s who did no use ART and had mon h 3 FSH le els, e ealed
a e y modes associa ion be ween FSH a mon h 3 and spon aneous
p egnancy (OR: 0.96; 95 %CI 0.93–1.00.) (Suppl Tables 10–11).
3.4. Mens ual cycle cha ac e is ics
Among he 127 o 142 pa ien s who did no ha e POI, 31.5 % (40/
127) had expe ienced oligomeno hea be o e mon h 12 (Suppl
Table 12). The dis ibu ions o AMH and FSH le els a 3 and 12 mon hs
we e simila ega dless o hei oligomeno hea s a us du ing his pe iod
(Suppl Table 13).
O 93 non p egnan pa ien s a mon h 6 who had useable samples o
p oges e one and did no use ART, 60.2 % we e o ula o y. Mul i a iable
logis ic eg ession showed ha o ula o y s a us a mon h 6 was no
p edic i e o subsequen spon aneous p egnancy (OR: 1.41; 95 % CI:
0.53–3.74) (Suppl Tables 14–15).
3.5. P olac in and TSH
P olac in (PRL) and TSH we e e alua ed a mon h 3 pos -ET washou
in 444 and 450 pa ien s, espec i ely. No mal alues we e epo ed in
mos pa ien s (Suppl Table 16). Sepa a e mul i a iable logis ic eg es-
sion models did no show a nega i e associa ion wi h p egnancy (Suppl
Tables 17–18).
Table 2
Odds a ios o p egnancy (yes s no) om mul i a iable logis ic model
including low o a ian ese e (AMH<0.5 ng/ml), among 438 pa ien s in low
o a ian ese e analysis popula ion, o whom 316 became p egnan .
Odds Ra io Es ima es
Fac o Poin
Es ima e
95 % Wald
Con idence
Limi s*
Low o a ian ese e: Yes s No 0.523 0.314 0.873
ART: O a ian s imula ion by IVF/ICSI on ial s
No ART
1.096 0.576 2.084
ART: Emb yo ans e s No ART 2.518 1.220 5.195
ART: O he ART s No ART 1.355 0.716 2.567
Age: <35 s 40-42 4.641 2.444 8.812
Age: 35–39 s 40-42 2.708 1.605 4.569
P io chemo he apy: No s Yes 0.717 0.423 1.216
P io ET: SERM only s OFS±AI 1.066 0.553 2.054
P io ET: O he s OFS±AI 1.170 0.608 2.251
Du a ion p io ET (mon hs) 0.958 0.906 1.013
No e an in e ac ion es (no p o ided) o he in e ac ion be ween ART (Yes s.
No) and low o a ian ese e was no s a is ically signi ican (p- alue: 0.170).
*Fac o s a e conside ed associa ed wi h p egnancy i he 95 % Wald Con idence
Limi s do no include 1.000.
ART =Assis ed Rep oduc i e Technology; IVF/ICSI=In Vi o Fe iliza ion/
In acy oplasmic Spe m Injec ion; OFS=O a ian Func ion Supp ession, AI=
A oma ase Inhibi o s; SERM=Selec i e Es ogen Recep o Modula o ; ET =
Endoc ine The apy.
Table 3
Pa ien and ea men cha ac e is ics by use o ART, and p egnancy a es.
ART
a
No ART
Pa ien s Numbe (%)
p egnan
Pa ien s Numbe (%)
p egnan
O a ian ese e analysis
popula ion (n =438)
200 150 (75.0) 238 166 (69.7)
Low o a ian ese e
(AMH<0.5 ng/ml)
a
Yes 102 67 (65.7) 107 70 (65.4)
No 98 83 (84.7) 131 96 (73.3)
Age a en ollmen
(yea s)
<35 52 42 (80.8) 90 78 (86.7)
35-39 94 73 (77.7) 98 69 (70.4)
40-42 54 35 (64.8) 50 19 (38.0)
P io chemo he apy
No 70 53 (75.7) 95 61 (64.2)
Yes 130 97 (74.6) 143 105 (73.4)
P io ET
OFS±AI 33 26 (78.8) 39 26 (66.7)
SERM only 81 57 (70.4) 93 65 (69.9)
O he 86 67 (77.9) 106 75 (70.7)
ART =Assis ed Rep oduc i e Technology; IVF/ICSI=In Vi o Fe iliza ion/
In acy oplasmic Spe m Injec ion; OFS=O a ian Func ion Supp ession; AI=
A oma ase Inhibi o s; SERM=Selec i e es ogen ecep o modula o ; ET =
Endoc ine The apy.
a
Al hough he di e ence in p egnancy success pe cen age be ween low
o a ian ese e coho s (no e sus yes) was g ea e o pa ien s who used ART
(19.0 % highe o no low o a ian ese e) han o pa ien s who did no use ART
(7.9 % highe o no low o a ian ese e), he in e ac ion es yielded p =0.170.
The co a ia es in he in e ac ion model o p egnancy we e: age, p io chemo-
he apy, p io ET, du a ion p io ET, low o a ian ese e (yes/no), and ART
(yes/no).
I. Demees e e e al.
The B eas 83 (2025) 104547
5
4. Discussion
In his seconda y endpoin analysis om he POSITIVE ial ha
assessed he ho mone p o iles a 3, 6 and 12 mon hs a e in e up ing
ET, we obse ed ha a ound hal o he eligible coho expe ienced low
o a ian ese e a e he 3-mon h ET washou . As expec ed, low o a ian
ese e was mo e equen in olde pa ien s and pa ien s who ecei ed
p io chemo he apy; howe e , i was simila ac oss ype and du a ion o
ET. No ably, low o a ian ese e was associa ed wi h lowe odds o
p egnancy. Su p isingly, only 10.6 % o pa ien s who we e no al eady
p egnan a mon h 12 expe ienced POI, despi e 63.4 % o hem ha ing
ecei ed chemo he apy. Among hose who ecei ed chemo he apy,
16.7 % expe ienced POI. Finally, FSH le el a mon h 3 was associa ed
wi h POI, bu only modes ly wi h p egnancy a es. O he pa ame e s,
such as o ula o y s a us, oligomeno hea, PRL o TSH we e no p e-
dic i e o spon aneous p egnancy.
This s udy con i med ha olde age and p io chemo he apy a e
associa ed wi h highe likelihood o low o a ian ese e, consis en wi h
o he s udies [22–24]. The ela i ely modes incidence o low o a ian
ese e in he POSITIVE coho may be a ibu ed o he young age o he
POSITIVE popula ion (coho ’s median age was 37 yea s) [6] and
a ia ion in ea men s. The impac o he ype o chemo he apy
egimen was no assessed in his s udy. No ably, nea ly 40 % o pa ien s
did no ecei e chemo he apy, and among hese, only 23 % had low
o a ian ese e. While p e ious s udies ha e epo ed a dec ease in
AMH le els in women using amoxi en [22], i s impac on e ili y e-
mains con o e sial [25]. Reassu ingly, he ype and du a ion o ET,
including SERMs, we e no associa ed wi h ho monal ac o s o e ili y
in he POSITIVE coho .
The low POI a e is consis en wi h he p e ious POSITIVE analysis
epo ing a mens ua ion eco e y a e o nea ly 95 % wi hin one yea
ollowing ET in e up ion [7]. Howe e , p e ious s udies assessing
ea men - ela ed ameno hea in p emenopausal BC su i o s showed
lowe a es o o a ian unc ion eco e y a e ea men [26–29]. The
low POI a e in he POSITIVE ial should be in e p e ed wi h cau ion.
No all pa ien s ecei ed chemo he apy, and pa ien s we e younge han
in mos p e ious s udies, being his a ial popula ion who sough
p egnancy. Mo eo e , POI was de ined solely based on FSH alues,
wi hou including oligomeno hea in he de ini ion [19]. No ably, no
all pa ien s wi h POI expe ienced oligomeno hea wi hin he i s yea ,
al hough i may be in luenced by he use o ART, in oducing a po en ial
bias. P e ious s udies demons a ed ha p egnancy is possible in young
cance su i o s wi h POI, wi h a spon aneous concep ion a e o 4–10
% [30–32]. Finally, only pa ien s who we e no p egnan a mon h 12
( hose likely acing mo e e ili y issues) we e included in he POI
analysis. These indings sugges ha POI is no he p ima y eason o
no being p egnan a mon h 12 in he POSITIVE coho .
We p e iously showed ha 74 % o pa ien s in he POSITIVE ial
had a leas one p egnancy, mos being spon aneous [7]. Al hough
younge age and emb yo ans e we e he p ima y ac o s associa ed
wi h p egnancy, ou cu en analysis demons a ed ha low o a ian
ese e was also associa ed wi h lowe p egnancy a es. While AMH has
been adi ionally conside ed a poo p edic o o p egnancy, da a in
cance su i o s emain limi ed [14]. In pa ien s who ecei e ART, AMH
is associa ed wi h lowe esponse o o a ian s imula ion and, conse-
quen ly educed p egnancy success [33]. Howe e , among 215 pa ien s
who pe o med ART, only 18 unde wen o a ian s imula ion o IVF. A
o al o 68 pa ien s unde wen c yop ese ed emb yo ans e , and 17
ecei ed emb yo/egg dona ion [7], o which p egnancy success does
no depend upon AMH le el. In ac , we did no ind a signi ican
in e ac ion be ween ART and low o a ian ese e on p egnancy success.
Mo eo e , he use o ART may be biased by he ac ha all pa ien s we e
ac i ely ying o concei e as soon as possible and may ha e used hei
ozen ma e ial e en when spon aneous concep ion migh ha e been
possible. O e all, hese da a sugges ha a emp a spon aneous
concep ion could also be ecommended o pa ien s wi h low o a ian
ese e be o e ART p ocedu es in his popula ion.
We also assessed FSH le el a mon h 3 as a po en ial p edic o o
spon aneous p egnancy. In women wi h no mal mens ual cycle, high
FSH le els a e conside ed a ma ke o sub- e ili y in pa ien s using ART,
bu i s p edic i e alue dec eases o pa ien s no using ART [34].
Al hough FSH le els a mon h 3 we e sligh ly highe in pa ien s who did
no achie e p egnancy compa ed o hose who did, median FSH alues
emained low (<10 IU/L) in bo h g oups. This may explain why FSH a
mon h 3 showed only a modes associa ion wi h p egnancy ou comes.
While o ula ion is necessa y o unassis ed concep ion, we did no
ind a co ela ion be ween o ula o y s a us a mon h 6 and he likeli-
hood o subsequen spon aneous p egnancy. O a ian unc ion eco e y
o en occu s wi hin he i s yea a e chemo he apy, bu olde age is
mo e likely o be associa ed wi h lack o o la e eco e y [35]. Since
o ula o y s a us was de e mined based on a single lu eal p oges e one
le el a mon h 6, some pa ien s may ha e esumed o ula o y cycles a e
ou assessmen . Howe e , we p e iously showed ha only an addi ional
4 % o pa ien s esumed menses be ween mon hs 6 and 12 [7]. This
con i ms ha ano ula o y cycles a mon h 6, as well as oligomeno hea,
did no p edic la e spon aneous p egnancy in pa ien s who in e up ed
ET. Likewise, hy oid disease and hype p olac inemia a e bo h ac o s
associa ed wi h o ula o y dys unc ion [36] and lowe e ili y. Howe -
e , we ound ha abno mal TSH and PRL alues we e no associa ed
wi h lowe p egnancy a es. These esul s should be cau iously in e -
p e ed gi en wide con idence in e als and he small p opo ion o pa-
ien s wi h abno mal TSH and PRL alues.
Ou indings should be conside ed in he con ex o ce ain limi a-
ions. Fi s , ime poin s analyses we e limi ed o 3, 6 and 12 mon hs a e
ET in e up ion. Mo eo e , we included samples collec ed >35 days
wi hou mens ua ion based on no mal menses de ini ion [37]. Pa ien s
wi h longe mens ual cycles may ha e had an inapp op ia ely imed
assessmen . The o ula o y cycle may be unde es ima ed in pa ien s wi h
i egula cycles due o eliance on a single p oges e one measu emen
du ing p esumed lu eal phase a mon h 6 in non-p egnan women. This
limi a ion may accoun o obse ed low o ula o y cycle a e. O he
po en ial causes o in e ili y, including male ac o s, and o a ian
ese e be o e ea men we e no epo ed in he POSITIVE ial.
Finally, he seconda y endpoin s analysis was pe o med on a ela i ely
small numbe o eligible pa ien s.
In conclusion, low o a ian ese e was obse ed in hal o he pop-
ula ion and was associa ed wi h lowe p egnancy a es. Ne e heless,
a ound 65 % o pa ien s wi h low o a ian ese e achie ed p egnancy,
ega dless o he use o ART. As expec ed, main ac o s associa ed wi h
low o a ian ese e we e age and chemo he apy, bu no he ype and
du a ion o ET. Reassu ingly, we epo ed a low incidence o POI in
young BC pa ien s who did no achie e p egnancy 12 mon hs a e ET
in e up ion. These indings unde sco e he impo ance o p o iding
comp ehensi e e ili y counseling o young women who in e up ET o
pu sue p egnancy, emphasizing he need o collabo a ion wi h ep o-
duc i e heal hca e specialis s o op imize concep ion op ions. Such
counseling ensu es bo h cance ea men and amily planning can be
mos e ec i ely in eg a ed.
CRediT au ho ship con ibu ion s a emen
Isabelle Demees e e: W i ing – e iew & edi ing, W i ing – o iginal
d a , Valida ion, Resou ces, P ojec adminis a ion, In es iga ion,
Funding acquisi ion, Concep ualiza ion. Samuel M. Niman: W i ing –
e iew & edi ing, W i ing – o iginal d a , Visualiza ion, Valida ion,
Me hodology, Fo mal analysis, Da a cu a ion. Ann H. Pa idge:
W i ing – e iew & edi ing, Supe ision, Resou ces, Funding acquisi ion,
Concep ualiza ion. Daniela S. Diego: W i ing – e iew & edi ing,
W i ing – o iginal d a . Roswi ha Kammle : W i ing – e iew & edi -
ing, Valida ion, Supe ision, P ojec adminis a ion, Da a cu a ion.
Monica Rugge i: W i ing – e iew & edi ing, Visualiza ion, Supe i-
sion, P ojec adminis a ion, Funding acquisi ion, Concep ualiza ion.
I. Demees e e e al.
The B eas 83 (2025) 104547
6
Ma co Colleoni: W i ing – e iew & edi ing, Resou ces. Chikako Shi-
mizu: W i ing – e iew & edi ing, Resou ces. C is ina Sau a: W i ing –
e iew & edi ing, Resou ces. Ka en A. Gelmon: W i ing – e iew &
edi ing, Resou ces. Anna B. Sae e sdal: W i ing – e iew & edi ing,
Resou ces. Judi h R. K oep: W i ing – e iew & edi ing, Resou ces.
Aud ey Mailliez: W i ing – e iew & edi ing, Resou ces. F ede ic
Aman : W i ing – e iew & edi ing, Resou ces. Manuel Ruız-Bo ego:
W i ing – e iew & edi ing, Resou ces. Jeong Eon Lee: W i ing – e iew
& edi ing, Resou ces. Akemi Ka aoka: W i ing – e iew & edi ing,
Resou ces. Janice M. Walshe: W i ing – e iew & edi ing, Resou ces.
Junko Takei: W i ing – e iew & edi ing, Resou ces. Simona Bo s na :
W i ing – e iew & edi ing, Resou ces. Vi ginia F. Bo ges: W i ing –
e iew & edi ing, Resou ces. Ch is obel Saunde s: W i ing – e iew &
edi ing, Resou ces. Snezana Susnja : W i ing – e iew & edi ing, Re-
sou ces. Vesna Bjelic-Radisic: W i ing – e iew & edi ing, Resou ces.
Fa ima Ca doso: W i ing – e iew & edi ing, Resou ces. Jane Lowe
Meisel: W i ing – e iew & edi ing, Resou ces. Jenni e F. Kawwass:
W i ing – e iew & edi ing. Tanja Spanic: W i ing – e iew & edi ing,
Resou ces. Sa a El-Abed: W i ing – e iew & edi ing, Resou ces.
Ma ine Picca : W i ing – e iew & edi ing, Funding acquisi ion.
La issa A. Ko de: W i ing – e iew & edi ing, Concep ualiza ion. A on
Goldhi sch: W i ing – e iew & edi ing, Concep ualiza ion. Richa d D.
Gelbe : W i ing – e iew & edi ing, W i ing – o iginal d a , Visualiza-
ion, Valida ion, Supe ision, Me hodology, Funding acquisi ion,
Fo mal analysis, Da a cu a ion, Concep ualiza ion. Oli ia Pagani:
W i ing – e iew & edi ing, Supe ision, Resou ces, Funding acquisi ion,
Concep ualiza ion. Ha em A. Azim: W i ing – e iew & edi ing, Su-
pe ision, Concep ualiza ion. Fed o A. Pecca o i: W i ing – e iew &
edi ing, Supe ision, Resou ces, Concep ualiza ion.
P io p esen a ion
An abs ac o his wo k has been accep ed o o al p esen a ion a
he 2025 ESMO B eas Cance Annual Cong ess.
E hical app o al s a emen
The s udy was sponso ed by he IBCSG in acco dance wi h he In-
e na ional Council o Ha moniza ion Good Clinical P ac ice guide-
lines, he Decla a ion o Helsinki, and local clinical esea ch egula ions.
The p o ocol was app o ed by he ins i u ional e iew boa d a each
pa icipa ing cen e . All pa ien s ga e w i en in o med consen .
Da a sha ing s a emen
A e publica ion, access o de-iden i ied pa icipan da a may be
eques ed by esea che s by submi ing a p oposal ( o s a _cen e @ibcsg.
o g), which will be e iewed o scien i ic me i and easibili y in
acco dance wi h IBCSG guidelines o collabo a i e esea ch and da a
sha ing policy (h ps://www.ibcsg.o g/en/pa ien s-p o essionals/ es
ea ch-collabo a ion).
Funding
The B eas Cance Resea ch Founda ion and Roche Diagnos ics In-
e na ional p o ided inancial suppo o IBCSG o ansla ional
esea ch sample logis ics and cen aliza ion, and Roche Diagnos ics also
p o ided eagen s o se um es ing a he cen al labo a o y in B ussels.
The Fonds de la Reche che Scien i ique (FNRS-CRD) p o ided addi ional
suppo o ho mone analysis and biobanking a he cen al labo a o y in
B ussels. (Isabelle Demees e e is a Senio Resea che Associa e a he
FNRS).
The POSITIVE ial is suppo ed by he ETOP IBCSG Pa ne s Foun-
da ion (globally) and he Alliance o Clinical T ials in Oncology (in
No h Ame ica), in collabo a ion wi h he B eas In e na ional G oup
(BIG), he BIG coope a i e g oups, and he Na ional Clinical T ials
Ne wo k o he Na ional Cance Ins i u e.
Globally, he ial ecei es g an suppo o cen al o local ial
conduc om he ollowing: he In e na ional B eas Cance S udy
G oup (IBCSG), F on ie Science and Technology Resea ch Founda ion,
Sou he n Eu ope (F on ie Sou he n Eu ope), Rising Tide Founda ion o
Clinical Cance Resea ch (CCR-15-120; CCR-20-200; CCR-24-150), Pink
Ribbon Swi ze land, Swiss Cance League (KLS-3361-02), San Sal a o e
Founda ion, Swiss G oup o Clinical Cance Resea ch, Clinical Cance
Resea ch Founda ion o Eas e n Swi ze land, Ms. Elisabe a Pa esi,
Ve ein Ba gu , Swiss Cance Founda ion, Ms. Ch is ine Ha ne and M .
Ma c Wyss, Piajoh Fondazione di Famiglia, G uppo Gio ani Pazien i
“Anna dai Capelli Co i”, and Schweize F auenlau Be n — all in
Swi ze land; BIG Agains B eas Cance and he Baille La ou Fund,
Belgium; Ga eway o Cance Resea ch (G-15-1900), Uni ed S a es;
Fondazione Umbe o Ve onesi, I aly; C & A, Ge many; Du ch Cance
Socie y, he Ne he lands; No wegian B eas Cance Socie y and Pink
Ribbon — bo h in No way; ELGC K.K. and Pink Ring — bo h in Japan;
M . Yong Seop Lee, Ms. Sun Hee Kang, and Ko ean B eas Cance
Founda ion — all in Sou h Ko ea; and o he p i a e dono s.
In No h Ame ica, he Alliance o Clinical T ials in Oncology e-
cei es suppo om he Na ional Cance Ins i u e o he Na ional In-
s i u es o Heal h (NIH) (Alliance o Clinical T ials in Oncology
Na ional Cance Ins i u e Communi y Oncology Resea ch P og am
[NCORP] g an UG1CA189823) and he bio eposi o y esou ce g an
U24CA196171; he Eas e n Coope a i e Oncology G oup–Ame ican
College o Radiology Imaging Ne wo k (ECOG-ACRIN) ecei es suppo
unde g an UG1CA189828; SWOG Cance Resea ch Ne wo k ecei es
suppo unde NIH g an s UG1CA189974 and U10CA180888; and NRG
Oncology ecei es suppo unde NIH g an U10CA180868 and NCORP
g an UG1CA189867. Canadian Cance T ials G oup (CCTG) pa icipa-
ion in he ial is suppo ed h ough i s g an om he Na ional Cance
Ins i u e o he NIH (CA180863). Funding suppo om he Du ch
Cance Socie y, The Ne he lands (KaWeFis Ba ch7/7723). Addi ional
p og amma ic unding suppo o he CCTG is p o ided by he Cana-
dian Cance Socie y (707213) and he Canada Founda ion o Inno a-
ion. In addi ion, he ial ecei es suppo om RETHINK B eas
Cance , Canada, and he Gilson Family Founda ion, Uni ed S a es.
Decla a ion o compe ing in e es
I. Demees e e epo ed in i ed speake hono a ia om Fe ing and
suppo o a ending cong ess om The amex, O ganon; Resea ch
G an om ROCHE diagnosis, Fe ing, The amex (Ins .). A.H.Pa idge
epo ed Royal ies o au ho ship o UpToDa e: Wol e s Kluwe ; and
non-Financial In e es s as co-Chai o B eas Commi ee: Alliance o
Clinical T ials, Na ional Cance Ins i u e; and Chie Scien i ic Ad iso :
Susan G. Komen Founda ion. M.Colleoni: epo ed Resea ch Funding
om Roche (Ins ), and non- inancial in e es as Co-Chai o he In e -
na ional B eas Cance S udy G oup Scien i ic Commi ee. C. Shimizu
epo ed hono a ia om As aZeneca, Kyowa Hakko Ki in, Chugai
Pha ma, Taiho Pha maceu ical, P ize , Daiichi Sankyo/UCB Japan,
MSD; and esea ch g an om Lilly. C. Sau a epo ed Consul ing o
Ad iso y Role o As aZeneca, Daiichi Sankyo, Eisai, MediTech,
No a is, P ize , Philips Heal hca e, Pie e Fab e, Puma Bio echnology,
Roche, SeaGen, Gilead Sciences, Pin Pha ma, Syn hon, Zymewo ks,
Pha maLex;
Speake s’ Bu eau o As aZeneca, Daiichi Sankyo/As a Zeneca,
P ize , Pie e Fab e, Puma Bio echnology, Seagen, Exe e Pha maceu-
icals, Lilly; Resea ch Funding om Puma Bio echnology (Ins ), Roche
(Ins ), As aZeneca (Ins ), Baye (Ins ), Boeh inge Ingelheim (Ins ),
B is ol Mye s Squibb (BMS) (Ins ), Cy omX The apeu ics (Ins ), Daiichi
Sakyo (Ins ), Roche (Ins ), Genen ech (Ins ), GlaxoSmi hKline (Ins ),
InnoUp (Ins ), Lilly (Ins ), Mac oGenics (Ins ), Mena ini (Ins ), Me us
(Ins ), No a is (Ins ), P ize (Ins ), Sano i/A en is (Ins ), Seagen (Ins );
T a el, Accommoda ions, expenses om P ize , No a is, Roche,
As aZeneca, Puma Bio echnology, Daiichi Sankyo, Eisai Eu ope and
I. Demees e e e al.
The B eas 83 (2025) 104547
7
o he Rela ionship: Resea ch unding in he o m o hi d-pa y medical
w i ing suppo , u nished by Eleano Po eous, MSc, o Nucleus Global,
an Inizio Company, was p o ided by F. Ho mann-La Roche L d; K.A.
Gelmon epo ed hono a ia om As aZeneca, P ize , Lilly, No a is,
Me ck, Gilead, Seagen, Ci y o Hope, Celcui y; As aZeneca, P ize , BMS.
A.B. Sae e sdal epo ed Consul ing o Ad iso y Role: Takeda Science
Founda ion. Judi h R. K oep epo ed he ollowing ins i u ional
esea ch g an s om: KWF, As aZeneca, No a is, and Philips;
ecei ing consul ing ees om As aZeneca, Daiichi, Eisa, GSK, Lilly,
MSD, and No a is; ecei ing suppo o a ending mee ings and/o
a el om: Daiichi; pa icipa ing on a da a sa e y moni o ing boa d o
ad iso y boa d o : Alison and TEIPP ials; and se es in a leade ship o
iducia y ole (in o he boa d, socie y, commi ee, o ad ocacy g oup,
paid o unpaid) o EORTC-GCG. A. Mailliez epo ed hono a ia as
in i ed speake o ad iso y ole om As a Zeneca, MSD oncology,
No a is, Roche; Mena ini, Oseus, Seagen, P ize , Daiichi Sankyo; and
Expe Tes imony o GSK. F. Aman epo ed hono a ia om ROCHE
and Ad iso y ole o MiMARK Diagnos ics; un es ic ed esea ch g an
om Es ´
ee Laude ; M. Ruiz-Bo ego epo ed Hono a ia om Roche/
Genen ech, P ize , No a is and Consul ing o Ad iso y Role o Roche,
Puma Bio echnology. J.E.Lee: epo ed ecei ing consul ing ees om:
MSD; ecei ing paymen o hono a ia ( o lec u es, p esen a ions,
speake s bu eaus, manusc ip w i ing o educa ional e en s) om:
Exac Science and Takeda Ko ea; and se ing in a leade ship o iducia y
ole (in o he boa d, socie y, commi ee, o ad ocacy g oup, paid o
unpaid) o : he Ko ean B eas Cance Socie y.
Janice M. Walshe epo ed Hono a ia om No a is, Consul ing o
Ad iso y Role om Gilead Sciences; T a el, Accommoda ions, Ex-
penses: No a is. Junko Takei epo ed Speake s’ Bu eau ole o
As aZeneca. S. Bo s na epo ed hono a ia om As aZeneca, Lilly,
P ize , No a is, Roche, MSD Oncology, Sandoz, Gilead Sciences,
Consul ing o Ad iso y Role: No a is, As aZeneca, Roche, P ize , MSD,
Oncology, Lilly. V. F. Bo ges epo ed S ock and O he Owne ship In-
e es s: Pe la The apeu ics, Consul ing o Ad iso y Role o Seagen,
As aZeneca, Gilead Sciences, Resea ch Funding: Seagen (Ins ), Olema
Oncology (Ins ), As aZeneca (Ins ). C Saunde s: epo s se ing in a
leade ship o iducia y ole (in o he boa d, socie y, commi ee, o
ad ocacy g oup, paid o unpaid) o Pa hWes Labo a o y Medicine and
B eas Cance T ials. S. Susnja epo ed Consul ing o Ad iso y Role
o As aZeneca, Lilly, No a is, Roche, P ize ; Speake s’ Bu eau ole o
Amicus The apeu ics, No a is, P ize , Resea ch Funding: Roche (Ins );
T a el, Accommoda ions, Expenses om Amicus The apeu ics, Roche.
V. Bjelic-Radisic epo ed consul ing ees ( o he ins i u ion) om:
P ize , Roche, and Lilly; ecei ing paymen o hono a ia ( o he ins i-
u ion, o lec u es, p esen a ions, speake s bu eaus, manusc ip w i ing
o educa ional e en s) om: P ize and Lilly; ecei ing suppo o
a ending mee ings and/o a el om: P ize ; pa icipa ing on a da a
sa e y moni o ing boa d o ad iso y boa d o P ize ; and se ing in a
leade ship o iducia y ole (in o he boa d, socie y, commi ee, o
ad ocacy g oup, paid o unpaid) o AWOgyn.
F. Ca doso: epo ed consul ing ees om: Amgen, As ellas/Medi-
a ion, As aZeneca, Baye , Celgene, Daiichi-Sankyo, Eisai, GE
Oncology, Genen ech, Gilead, GlaxoSmi hKline, Iq ia, Mac ogenics,
Medscape, Me ck-Sha p, Me us BV, Mylan, Mundipha ma, No a is,
P ize , Pie e-Fab e, p IME Oncology, Roche, Sano i, Samsung, Bioepis,
Seagen, Te a, and Touchime; ecei ing paymen o hono a ia ( o lec-
u es, p esen a ions, speake s bu eaus, manusc ip w i ing o educa-
ional e en s) om: P ize , Roche, Gilead, As aZeneca, No a is, and
Me ck; ecei ing suppo o a ending mee ings and/o a el om:
P ize , Roche, Gilead, As aZeneca, and No a is; and se ing in a
leade ship o iducia y ole (in o he boa d, socie y, commi ee, o
ad ocacy g oup, paid o unpaid) o ABC Global Alliance (P esiden ),
ABC Consensus Con e ence and Guidelines (Chai ), Eu opean Academy
o Cance Sciences (Fellow), and ESMO, ESO, ASCO, AACR, ECO,
AORTIC, UICC, EORTC, IBCSG, SOLTI, EACR, SIS, ASPIC, SPO, and E i a
(membe /commi ee membe ).
T. Spanic: epo ed hono a ia om P ize , MSD, Roche; Conseling
and ad iso y ole o Roche, In i ed Speake o Regional Mee ing by
As a Zeneca; O he , Podcas Gues : No a is; Un es ic ed G an o
Eu opa Donna Slo enija: No a is, Roche, MSD, As aZeneca, Lenis; and
Non-Financial In e es s as membe o Boa d o Di ec o s, S a ing Jan
2025: ABC Global Alliance. S. El-Abed: epo ed he ollowing ins i u-
ional esea ch g an s om: As aZeneca, Sano i, Roche, Genen ech,
GlaxoSmi hKline, P ize , and No a is. M. Picca : epo ed he
ollowing ins i u ional esea ch g an s om: As aZeneca, Lilly,
Mena ini, MSD, No a is, P ize , Roche-Genen ech, Se ie , and Gilead;
ecei ing consul ing ees om: As aZeneca, Gilead, Lilly, Mena ini,
Me sana, MSD, No a is, P ize , Roche-Genen ech, Sea le Gene ics,
Seagen, NBE The apeu ics, and Summi The apeu ics; ecei ing paymen
o hono a ia ( o lec u es, p esen a ions, speake s bu eaus, manusc ip
w i ing o educa ional e en s) om: As aZeneca, Gilead, Lilly,
Mena ini, Me sana, MSD, No a is, P ize , Roche-Genen ech, Seagen,
NBE The apeu ics, and Summi The apeu ics; and pa icipa ing on a
da a sa e y moni o ing boa d o ad iso y boa d o Oncoly ics. R.D.
Gelbe : epo ed esea ch unding om As aZeneca, Roche, Me ck. O.
Pagani: epo ed counsul ing o ad iso y ole o Debiopha m. H.A.
Azim: epo ed hono a ia om Pie e Fab e, eme gence he apeu ics,
Diaccu a e, PEP The apy, Linkin ax; In i ed Speake and a el ac-
commoda ion expense om As a Zeneca, No a is S ocks/Sha es:
Inna e Pha ma; Fa ima Ca doso and Ka en Gelmon a e Edi o -in-Chie
and Depu y Edi o in The B eas , espec i ely, and ha e no in ol e-
men in he pee - e iew o his a icle and no access o in o ma ion
ega ding i s pee e iew. Ann Pa idge, Fed o Alessand o Pecca o i
and Ha em A Azim J a e pa o he Edi o ial Boa d o The B eas and
we e no in ol ed in he edi o ial e iew o he decision o publish his
a icle.
No o he con lic o in e es we e epo ed.
Acknowledgemen s
The POSITIVE ial esul ed om he collabo a ion o he Endoc ine
Wo king G oup o he B eas In e na ional G oup (BIG)-No h Ame ican
B eas Cance G oup (NABCG), and was collabo a i ely designed and
conduc ed by he In e na ional B eas Cance S udy G oup (IBCSG; he
sponso and coo dina ing g oup), and coope a i e g oups a ilia ed wi h
BIG, and he Alliance o Clinical T ials in Oncology ( he sponso in
No h Ame ica), including he Na ional Clinical T ials Ne wo k o he
Na ional Cance Ins i u e and o he s.
We since ely hank he pa ien s and hei amilies, he abo e-
men ioned ial pa ne s, he suppo e s (all na ional unding bodies,
cha i ies, and p i a e dono s), he collabo a o s, he cu en and o me
membe s o he ial’s Commi ees and he In es iga o s.
We hank Julie Dech`
ene and Mi iam Ch is o el o hei in aluable
assis ance wi h blood sample logis ics and cen aliza ion.
Appendix A. Supplemen a y da a
Supplemen a y da a o his a icle can be ound online a h ps://doi.
o g/10.1016/j.b eas .2025.104547.
Re e ences
[1] Elling on TD, Mille JW, Henley SJ, Wilson RJ, Wu M, Richa dson LC. T ends in
b eas cance incidence, by ace, e hnici y, and age among women aged >/=20
yea s - uni ed S a es, 1999-2018. MMWR Mo b Mo al Wkly Rep 2022;71(2):43–7.
h ps://doi.o g/10.15585/mmw .mm7102a2.
[2] Cance ac s and igu es 2018 - es ima ed numbe o new cases o he ou majo
cance s by sex and age g oup. h ps://www.cance .o g/con en /dam/cance -o
g/ esea ch/cance - ac s-and-s a is ics/annual-cance - ac s-and- igu es/2018/es i
ma ed-numbe -o -new-cases- o - he- ou -majo -cance s-by-sex-and-age-g oup-20
18.pd .
[3] P ac ice Commi ee o he Ame ican Socie y o Rep oduc i e Medicine. Elec onic
add ess aao: e ili y p ese a ion in pa ien s unde going gonado oxic he apy o
gonadec omy: a commi ee opinion. Fe il S e il 2019;112(6):1022–33. h ps://
doi.o g/10.1016/j. e ns e .2019.09.013.
I. Demees e e e al.
The B eas 83 (2025) 104547
8
[4] Ame ican College o O, Gynecologis s Commi ee on Gynecologic P, P ac ice C.
Female age- ela ed e ili y decline. Commi ee opinion no. 589. Fe il S e il 2014;
101(3):633–4. h ps://doi.o g/10.1016/j. e ns e .2013.12.032.
[5] Na ional Comp ehensi e Cance Ne wo k. B esa Cance . [h ps://www.nccn.
o g/p o essionals/physician_gls/pd /b eas .pd ].
[6] Pa idge AH, Niman SM, Rugge i M, Pecca o i FA, Azim J HA, Colleoni M, e al.
In e up ing endoc ine he apy o a emp p egnancy a e b eas cance . N Engl J
Med 2023;388(18):1645–56. h ps://doi.o g/10.1056/NEJMoa2212856.
[7] Azim J HA, Niman SM, Pa idge AH, Demees e e I, Rugge i M, Colleoni M, e al.
Fe ili y p ese a ion and assis ed ep oduc ion in pa ien s wi h b eas cance
in e up ing adju an endoc ine he apy o a emp p egnancy. J Clin Oncol 2024:
2822–32. h ps://doi.o g/10.1200/JCO.23.02292.
[8] Lambe ini M, Pecca o i FA, Demees e e I, Aman F, Wyns C, S ukenbo g JB, e al.
Fe ili y p ese a ion and pos - ea men p egnancies in pos -pube al cance
pa ien s: ESMO clinical p ac ice Guidelines(dagge ). Ann Oncol 2020;31(12):
1664–78. h ps://doi.o g/10.1016/j.annonc.2020.09.006.
[9] Eu opean Socie y o Human R, Emb yology Guideline G oup on POI, Webbe L,
Da ies M, Ande son R, Ba le J. ESHRE guideline: managemen o women wi h
p ema u e o a ian insu iciency. Hum Rep od 2016;31(5):926–37. h ps://doi.
o g/10.1093/hum ep/dew027.
[10] Ande son RA, Aman F, B aa D, D’Angelo A, Chu a de Sousa Lopes SM,
Demees e e I, e al. ESHRE guideline: emale e ili y p ese a ion. Hum Rep od
Open 2020;2020(4):hoaa052. h ps://doi.o g/10.1093/h open/hoaa052.
[11] La Ma ca A, Sighinol i G, Radi D, A gen o C, Ba aldi E, A enisio AC, e al. An i-
Mulle ian ho mone (AMH) as a p edic i e ma ke in assis ed ep oduc i e
echnology (ART). Hum Rep od Upda e 2010;16(2):113–30. h ps://doi.o g/
10.1093/humupd/dmp036.
[12] Poseidon G, Al iggi C, Ande sen CY, Buehle K, Con o i A, De Placido G, e al.
A new mo e de ailed s a i ica ion o low esponde s o o a ian s imula ion: om a
poo o a ian esponse o a low p ognosis concep . Fe il S e il 2016;105(6):
1452–3. h ps://doi.o g/10.1016/j. e ns e .2016.02.005.
[13] Peigne M, Be na d V, Dijols L, C eux H, Robin G, Hocke C, e al. Using se um An i-
Mulle ian ho mone le els o p edic he chance o li e bi h a e spon aneous o
assis ed concep ion: a sys ema ic e iew and me a-analysis. Hum Rep od 2023;38
(9):1789–806. h ps://doi.o g/10.1093/hum ep/dead147.
[14] Ande son RA, Came on D, Cla o F, Demees e e I, Lambe ini M, Nelson SM, e al.
An i-Mulle ian ho mone as a ma ke o o a ian ese e and p ema u e o a ian
insu iciency in child en and women wi h cance : a sys ema ic e iew. Hum
Rep od Upda e 2022;28(3):417–34. h ps://doi.o g/10.1093/humupd/dmac004.
[15] Bala J, Se h S, Dhankha R, Ghalau VS. Chemo he apy: impac on an i-mulle ian
ho mone le els in b eas ca cinoma. J Clin Diagn Res 2016;10(2):BC19–21.
h ps://doi.o g/10.7860/JCDR/2016/15933.7328.
[16] Dezellus A, Ba ie e P, Campone M, Lemanski C, Vanlemmens L, Migno L, e al.
P ospec i e e alua ion o se um An i-Mulle ian ho mone dynamics in 250 women
o ep oduc i e age ea ed wi h chemo he apy o b eas cance . Eu J Cance
2017;79:72–80. h ps://doi.o g/10.1016/j.ejca.2017.03.035.
[17] Lambe ini M, Pecca o i FA, Demees e e I, Aman F, Wyns C, S ukenbo g JB, e al.
Fe ili y p ese a ion and pos - ea men p egnancies in pos -pube al cance
pa ien s: ESMO clinical p ac ice guidelines. Ann Oncol 2020. h ps://doi.o g/
10.1016/j.annonc.2020.09.006.
[18] Pa idge AH, Niman SM, Rugge i M, Pecca o i FA, Azim J HA, Colleoni M, e al.
Who a e he women who en olled in he POSITIVE ial: a global s udy o suppo
young ho mone ecep o posi i e b eas cance su i o s desi ing p egnancy.
B eas 2021;59:327–38. h ps://doi.o g/10.1016/j.b eas .2021.07.021.
[19] Esh e AC, Imsggo POI, Panay N, Ande son RA, Bennie A, Ceda s M, e al. E idence-
based guideline: p ema u e o a ian insu iciency. Fe il S e il 2025;123(2):
221–36. h ps://doi.o g/10.1016/j. e ns e .2024.11.007.
[20] P ac ice commi ees o he Ame ican socie y o ep oduc i e M, he socie y o
ep oduc i e E, in e ili y: diagnosis and ea men o lu eal phase de iciency: a
commi ee opinion. Fe il S e il 2021;115(6):1416–23. h ps://doi.o g/10.1016/j.
e ns e .2021.02.010.
[21] Tsepelidis S, De eke F, Demees e e I, Flahau A, Ge y C, Engle Y. S able se um
le els o An i-Mulle ian ho mone du ing he mens ual cycle: a p ospec i e s udy
in no mo-o ula o y women. Hum Rep od 2007;22(7):1837–40.
[22] Pa idge AH, Ruddy KJ, Gelbe S, Schapi a L, Abusie M, Meye M, e al. O a ian
ese e in women who emain p emenopausal a e chemo he apy o ea ly s age
b eas cance . Fe il S e il 2010;94(2):638–44.
[23] Pecca o i FA, Azim J HA, O ecchia R, Hoeks a HJ, Pa lidis N, Kesic V, e al.
Cance , p egnancy and e ili y: ESMO clinical p ac ice guidelines o diagnosis,
ea men and ollow-up. Ann Oncol 2013;24(Suppl 6): i160–70. h ps://doi.o g/
10.1093/annonc/md 199.
[24] Mailliez A, Pigny P, Boga E, Kelle L, D’O azio E, Vanseymo ie M, e al. Is
o a ian eco e y a e chemo he apy in young pa ien s wi h ea ly b eas cance
in luenced by con olled o a ian hype s imula ion o e ili y p ese a ion o
umo cha ac e is ics? Resul s o a p ospec i e s udy in 126 pa ien s. In J Cance
2022;150(11):1850–60. h ps://doi.o g/10.1002/ijc.33933.
[25] Shandley LM, Spence JB, Fo he gill A, Me ens AC, Mana unga A, Paploma a E,
e al. Impac o amoxi en he apy on e ili y in b eas cance su i o s. Fe il
S e il 2017;107(1):243–252 e245. h ps://doi.o g/10.1016/j.
e ns e .2016.10.020.
[26] Jacobson MH, Me ens AC, Spence JB, Mana unga AK, Howa ds PP. Menses
esump ion a e cance ea men -induced ameno hea occu s ea ly o no a all.
Fe il S e il 2016;105(3):765–772 e764. h ps://doi.o g/10.1016/j.
e ns e .2015.11.020.
[27] Poo u PD, Hu J, Zheng Y, Gelbe SI, Ruddy KJ, Tamimi RM, e al. T ea men -
ela ed ameno hea in a mode n, p ospec i e coho s udy o young women wi h
b eas cance . NPJ B eas Cance 2021;7(1):99. h ps://doi.o g/10.1038/s41523-
021-00307-8.
[28] Lambe ini M, Campbell C, Bines J, Ko de LA, Izquie do M, Fumagalli D, e al.
Adju an An i-HER2 he apy, ea men - ela ed ameno hea, and su i al in
p emenopausal HER2-Posi i e ea ly b eas cance pa ien s. J Na l Cance Ins
2018. h ps://doi.o g/10.1093/jnci/djy094.
[29] T app E, S eidl J, Rack B, Kupka MS, Ande gassen U, Jucks ock J, e al. An i-
Mulle ian ho mone (AMH) le els in p emenopausal b eas cance pa ien s ea ed
wi h axane-based adju an chemo he apy - a ansla ional esea ch p ojec o he
SUCCESS A s udy. B eas 2017;35:130–5. h ps://doi.o g/10.1016/j.
b eas .2017.07.007.
[30] Demees e e I, B ice P, Pecca o i FA, Ken os A, Dupuis J, Zachee P, e al. No
e idence o he bene i o gonado opin- eleasing ho mone agonis in p ese ing
o a ian unc ion and e ili y in lymphoma su i o s ea ed wi h chemo he apy:
inal long- e m epo o a p ospec i e andomized ial. J Clin Oncol 2016;34(22):
2568–74. h ps://doi.o g/10.1200/JCO.2015.65.8864.
[31] Chabu M, Schneide P, Cou bie e B, Saul ie P, Be and Y, Tabone MD, e al.
O a ian unc ion and spon aneous p egnancy a e hema opoie ic s em cell
ansplan a ion o leukemia be o e pube y: an L.E.A. coho s udy. T ansplan
Cell The 2023;29(6):378 e371–9. h ps://doi.o g/10.1016/j.j c .2023.02.019.
[32] Pod igu na-S opa A, Czyzyk A, G ymowicz M, Smola czyk R, Ka ulski K,
Czajkowski K, e al. P ema u e o a ian insu iciency: he con ex o long- e m
e ec s. J Endoc inol In es ig 2016;39(9):983–90. h ps://doi.o g/10.1007/
s40618-016-0467-z.
[33] Bosch E, B oe S, G iesinge G, G ynbe g M, Humaidan P, Kolibianakis E, e al.
ESHRE guideline: o a ian s imula ion o IVF/ICSI. Hum Rep od Open 2020;2020
(2):1–13. h ps://doi.o g/10.1093/h open/hoaa009.
[34] an Mon ans JM, Hoek A, an Hoo MH, de Koning CH, Tonch N, Lambalk CB.
P edic i e alue o basal ollicle-s imula ing ho mone concen a ions in a gene al
sub e ili y popula ion. Fe il S e il 2000;74(1):97–103. h ps://doi.o g/10.1016/
s0015-0282(00)00560-4.
[35] Kabi ian R, F anzoi MA, Ha as J, Cou an C, T edan O, Le y C, e al.
Chemo he apy- ela ed ameno hea and quali y o li e among p emenopausal
women wi h b eas cance . JAMA Ne w Open 2023;6(11):e2343910. h ps://doi.
o g/10.1001/jamane wo kopen.2023.43910.
[36] P ac ice Commi ee o he Ame ican Socie y o Rep oduc i e Medicine. Elec onic
add ess aao: cu en e alua ion o ameno hea: a commi ee opinion. Fe il S e il
2024;122(1):52–61. h ps://doi.o g/10.1016/j. e ns e .2024.02.001.
[37] Commi ee on P ac ice B-G. P ac ice bulle in no. 128: diagnosis o abno mal
u e ine bleeding in ep oduc i e-aged women. Obs e Gynecol 2012;120(1):
197–206. h ps://doi.o g/10.1097/AOG.0b013e318262e320.
I. Demees e e e al.
The B eas 83 (2025) 104547
9
