Vol.:(0123456789)
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Clinical and T ansla ional Oncology (2019) 21:31–45
h ps://doi.o g/10.1007/s12094-018-02010-w
CLINICAL GUIDES INONCOLOGY
SEOM clinical guidelines inad anced and ecu en b eas cance
(2018)
J.I.ChacónLópez‑Muñiz1,2 · L.delaC uzMe ino3· J.Ga iláG ego i4· E.Ma ínezDueñas5· M.Oli ei a6·
M.A.SeguíPalme 7· I.Ál a ezLópez8· S.An olinNo oa9· M.Belle Ezque a10· S.López‑Ta uellaCobo11
Recei ed: 3 Decembe 2018 / Accep ed: 5 Decembe 2018 / Published online: 8 Janua y 2019
© The Au ho (s) 2019
Abs ac
Al hough he me as asic b eas cance is s ill an incu able disease, ecen ad ances ha e inc eased signi ican ly he ime o
p og ession and he o e all su i al. Howe e , oo much in o ma ion has been p oduced in he las 2 yea s, so a well-based
guideline is a aluable documen in ea men decision making. The SEOM guidelines a e in ended o make e idence-based
ecommenda ions on how o manage pa ien s wi h ad anced and ecu en b eas cance o achie e he bes pa ien ou comes
based on a a ional use o he cu en ly a ailable he apies. To assign a le el o ce ain y and a g ade o ecommenda ion he
Uni ed S a es P e en i e Se ices Task Fo ce guidelines me hodology was selec ed as e e ence.
Keywo ds Ad anced· Loco- egional ecu ence· B eas cance · SEOM· Guidelines
* J. I. Chacón López-Muñiz
[email p o ec ed]
L. dela C uz Me ino
[email p o ec ed]
J. Ga ilá G ego i
jga[email p o ec ed]g
E. Ma ínez Dueñas
edua do.ma inez@hospi alp o incial.es
M. Oli ei a
moli [email p o ec ed]
M. A. Seguí Palme
[email p o ec ed]
I. Ál a ez López
ISABELMANUELA.ALV[email p o ec ed]
S. An olin No oa
sil ia.an olin.no [email p o ec ed]
M. Belle Ezque a
[email p o ec ed]
S. López-Ta uella Cobo
slopez a [email p o ec ed]
1 Se icio de Oncología Médica, Hospi al Vi gen de la Salud,
A da. de Ba be , 30, 45004Toledo, Spain
2 GEICAM, Mad id, Spain
3 Se icio de Oncología Médica, Medicine Depa men ,
Hospi al Vi gen Maca ena, Uni e si y o Se illa, Se ille,
Spain
4 Se icio de Oncología Médica, Fundación Ins i u o
Valenciano de Oncología, Valencia, Spain
5 Se icio de Oncología Médica, Hospi al P o incial de
Cas ellón, Cas ellón, Spain
6 Vall d’Heb on Uni e si y Hospi al andVall d’Heb on
Ins i u e o Oncology, Ba celona, Spain
7 Se icio de Oncología Médica, Co po ació Sani a ia Pa c
Tauli, Sabadell, Ba celona, Spain
8 Se icio de Oncología Médica, Hospi al Uni e si a io
Donos ia/Donos iako Unibe si a e Ospi alea, Donos ia,
Spain
9 Se icio de Oncología Médica, Hospi al Uni e si a io
ACo uña, ACo uña, Spain
10 Vall d’Heb on Uni e si y Hospi al andVall d’Heb on
Ins i u e o Oncology (VHIO), Ba celona, Spain
11 Se icio de Oncología Médica, Hospi al Gene al
Uni e si a io G ego io Ma añón,Ins i u o de In es igación
Sani a ia G ego io Ma añón (IiSGM), Uni e sidad
Complu ense,Cibe Onc, GEICAM, Mad id, Spain
32 Clinical and T ansla ional Oncology (2019) 21:31–45
1 3
In oduc ion
B eas cance (BC) ep esen s he i s cause o in asi e can-
ce in he Spanish women, accoun ing o 29% o all emale
cance s. Acco ding o ecen da a, 26,730 new cases and
6477 dea hs a e es ima ed annually in Spain [1].
Me as a ic BC (MBC) emains i ually an incu able dis-
ease, wi h epo ed median o e all su i al (OS) o app oxi-
ma ely 2yea s. Howe e , imp o ed OS (up o 5yea s) has
been obse ed ecen ly o ce ain sub ypes, pa icula ly in
HER2-posi i e disease. De no o me as a ic disease has be -
e 5-yea OS ha ecu en MBC and p ognosis appea o
imp o e o e ime [2].
Pa ien s wi h loco- egional ecu ence (LRBC) may o
may no be amenable o adical local ea men . O e all,
acco ding o a Spanish s udy, an inc ease in OS has been
obse ed in he ecen yea s in LRBC pa ien s [3].
Me hodology
The SEOM guidelines ha e been de eloped wi h he con-
sensus o en b eas cance oncologis s om he coope a i e
g oups GEICAM (Spanish B eas Cance Resea ch G oup)
and SOLTI (Spanish Collabo a i e G oup o he S udy,
ea men and o he expe imen al s a egies in solid umo s).
To assign a le el o ce ain y (LC) and a g ade o ecom-
menda ion (GR) o he di e en s a emen s desc ibed in he
clinical guidelines, he Uni ed S a es P e en i e Se ices
Task Fo ce (USPSTF) guidelines me hodology was selec ed
as e e ence, as he p e iously adop ed o he o me e sion
o SEOM ecommenda ions [4] (Table1).
Gene al o e iew o ad anced b eas cance
Goals o  ea men
The wo main goals o he ea men o MBC pa ien s a e
o imp o e su i al and o op imize he quali y o li e [5].
Fo LRBC pa ien s o whom a adical app oach is no ea-
sible, he aims o he ea men a e simila o ha in MBC
pa ien s. Con e sely, o hose LRBC amenable o a local
ea men he objec i es will be o e adica e all mac oscopic
diseases and o imp o e bo h disease- ee su i al and o e -
all su i al.
• Since he diagnosis o ad anced o ecu en BC is made,
pa ien s should also be o e ed app op ia e mul idisci-
Table 1 S eng h o ecommenda ion and le el o ce ain y acco ding o he Uni ed S a es P e en i e Se ices Task Fo ce (USPSTF) a e July
2012 [4]
Ca ego y De ini ion
S eng h o ecommenda ions (g ade)
A The USPSTF ecommends he se ice. The e is high ce ain y ha he ne bene i is subs an ial
B The USPSTF ecommends he se ice. The e is high ce ain y ha he ne bene i is mode a e o he e is mode a e ce ain y ha
he ne bene i is mode a e o subs an ial
C The USPSTF ecommends selec i ely o e ing o p o iding his se ice o indi idual pa ien s based on p o essional judgmen and
pa ien p e e ences. The e is a leas mode a e ce ain y ha he ne bene i is small
D The USPSTF ecommends agains he se ice. The e is mode a e o high ce ain y ha he se ice has no ne bene i o ha he
ha ms ou weigh he bene i s
I The USPSTF concludes ha he cu en e idence is insu icien o assess he balance o bene i s and ha ms o he se ice. E i-
dence is lacking, o poo quali y, o con lic ing, and he balance o bene i s and ha ms canno be de e mined
Le els o ce ain y ega ding ne bene i
High The a ailable e idence usually includes consis en esul s om well-designed, well-conduc ed s udies in ep esen a i e p ima y
ca e popula ions. These s udies assess he e ec s o he p e en i e se ice on heal h ou comes. This conclusion is he e o e
unlikely o be s ongly a ec ed by he esul s o u u e s udies
Mode a e The a ailable e idence is su icien o de e mine he e ec s o he p e en i e se ice on heal h ou comes, bu con idence in he
es ima e is cons ained by such ac o s as he numbe , size, o quali y o indi idual s udies; inconsis ency o indings ac oss
indi idual s udies; limi ed gene alizabili y o indings o ou ine p ima y ca e p ac ice; lack o cohe ence in he chain o e i-
dence. As mo e in o ma ion becomes a ailable, he magni ude o di ec ion o he obse ed e ec could change, and his change
may be la ge enough o al e he conclusion
Low The a ailable e idence is insu icien o assess e ec s on heal h ou comes. E idence is insu icien because o : he limi ed numbe
o size o s udies; impo an laws in s udy design o me hods.; inconsis ency o indings ac oss indi idual s udies; gaps in he
chain o e idence; indings no gene alizable o ou ine p ima y ca e p ac ice; lack o in o ma ion on impo an heal h ou -
comes. Mo e in o ma ion may allow es ima ion o e ec s on heal h ou comes
33Clinical and T ansla ional Oncology (2019) 21:31–45
1 3
plina y ca e, as i may ha e an impac in OS, including
symp om- ela ed in e en ion (LC high; GR A).
• Resea ch is a p io i y in his se ing. Pa icipa ion in
well-designed, independen , p ospec i e ials should be
o e ed o all eligible pa ien s, whene e possible (LC
high; GR A).
Fo all indica ions and b eas cance ypes, pallia i e
ea men is s ongly ecommended when indica ed.
Diagnosis o  ecu ence andme as a ic disease
• Clinical loco- egional ecu ence should be con i med
by biopsy in all LRBC be o e planning any he apeu ic
s a egy (LC high; GR A).
• Bo h in LRBC and in MBC (p ima y o elapsed) he
his ologic analyses should be pe o med i possible. In
ecu ences, i will se e o con i m neoplas ic ecu ence
and o echeck his ologic sub ype, as changes in ho mone
ecep o s (HR) and HER2 be ween p ima y umo and
ecu ences ha e been epo ed [6] (LC high; GR A).
S aging
• Fo bo h MBC and LRBC clinical e alua ion should
include medical his o y and physical examina ion. Mini-
mal s aging wo kup should include imaging echniques
o ches , abdomen and bone, hema ology and biochemis-
y. The ecommended imaging echniques a e body TC
and bone scin ig aphy (LC mode a e; GR B).
• The ole o umo ma ke s (TM) in he ollow-up o ea ly
BC pa ien is con o e sial [7] (LC low; GR C). Once
ecu ence is diagnosed, basal TM (CEA, CA15.3 and/
o Ca 27.4) may be pe o med. Because, i ele a ed, may
help o moni o disease esponse o he apy, especially in
he p esence o non-measu able disease (LC low; GR C).
Howe e , ea men decisions should no be based only
on he a ia ion o TM le els (LC mode a e; GR A).
• O e all, he use o sys ema ic b ain image in all pa ien s
in he absence o suspicious symp oms is no ecom-
mended, e en in HER2-posi i e disease (LC mode a e;
GR B).
• The use o Posi on emission omog aphy (PET) is con-
o e sial in MBC, bu can be used ins ead o TC and
bone scan, i a ailable (le el o e idence low, GR B) [8].
In he pos ope a i e su eillance PET/TC is ecom-
mended only in cases o equi ocal and con lic ing ind-
ings [9] (LC low; GR C).
Loco‑ egional ecu ence managemen
Local he apy
Local only ecu ence
Pa ien s wi h local and egional disease a e di ided in o
h ee g oups.
• Ini ial ea men wi h lumpec omy + adia ion he apy
(RT): ea ecu ence wi h o al mas ec omy + axilla y
lymph node s aging i le el II/III axilla y dissec ion no
p e iously done [10] (LC mode a e; GR B). Limi ed
da a sugges ha a epea ed sen inel node biopsy may
be success ully pe o med in pa ien s who ha e p e i-
ously unde gone b eas -conse ing he apy and sen inel
node biopsy [11] (LC low; GR C). Fo isola ed ipsila e al
b eas cance ecu ences, b eas conse a i e su ge y
plus pa ial b eas i adia ion is an al e na i e op ion [12]
(LC mode a e; GR B).
• Ini ial ea men wi h mas ec omy and no p io RT: ea
ecu ence wi h su gical esec ion i possible + RT [13,
14] (LC low; GR B).
• Ini ial ea men wi h mas ec omy + le el I/II axilla y
dissec ion and p io RT: su gical esec ion i possible
[13] (LC low; GR B). Limi ed da a ega ding addi ional
i adia ion [15] (LC low; GR C).
Regional onlyo local and egional ecu ence
• Axilla y ecu ence: su gical esec ion i possible + RT
i possible [16] (LC mode a e; GR B).
• Sup acla icula and in e nal mamma y node ecu ence:
RT i possible [17] (LC mode a e; GR B).
Pa ien s wi h disease no amenable o adical local ea -
men should be ea ed wi h induc ion chemo he apy (CT),
endoc ine o an i-HER2 he apy when indica ed, and hen
pallia i e adia ion, which is manda o y i he pa ien is
adia ion naï e [14, 18] (LC low; GR B).
Sys emic he apy
CT a e i s local o egional ecu ence imp o es long-
e m ou comes p ima y in ER nega i e disease. Endoc ine
he apy in his se ing imp o es long- e m ou comes o
ER posi i e disease [19] (LC mode a e; GR B). In case o
HER2-posi i e disease and he absence o p e ious an i-
HER2 adju an ea men , as uzumab is indica ed [20]
(LC mode a e; GR B). Howe e , he op imal s a egy in case
34 Clinical and T ansla ional Oncology (2019) 21:31–45
1 3
o p e ious adju an an i-HER2 ea men is unknown. CT
is indica ed o endoc ine- esis an disease, as i s line in
iple-nega i e disease and combined wi h an i-HER2 d ugs
in HER2-posi i e disease.
In pa ien s wi h disease no amenable o adical local
ea men , he choice o pallia i e sys emic he apy should
be made acco ding o he p inciples de ined o me as a ic
BC (LC high; GR A).
Endoc ine he apy inad anced HR‑posi i e/
HER2‑nega i e b eas cance
Since he las SEOM guideline o MBC on 2015 se e al
ad ances ha e occu ed in he ea men o endoc ine he -
apy (ET) o luminal MBC [21]. Endoc ine he apy includes
ER- a ge ing d ugs as single agen s o in combina ion wi h
d ugs a ge ing pa hways in ol ed in ho mone esis ance
such as he mTOR inhibi o , e e olimus (PIK3/AKT/mTOR
pa hway) and CDK4/6 inhibi o s (cell cycle pa hway). ER-
a ge ing d ugs can ac by lowe ing he le els o ci cula ing
es ogens o hose ac ing di ec ly in he ER (Table2).
Gene al conside a ions
The p e e ed ea men o luminal ABC is ET in he majo -
i y o cases. Sequen ial ET should be used as long as he
pa ien seems o be bene i ing om ET and does no ha e
e idence o immedia ely li e- h ea ening disease o apid
p og ession o isce al disease wi h o gan dys unc ion
( isce al c isis), o when he e is an e idence o endoc ine
esis ance. The p esence o isce al in ol emen alone is
no a con aindica ion o he use o ET (LC high; GR A).
The choice o which ET o use in each si ua ion should
ake in o conside a ion: (1) p io (neo) adju an ET s “de
no o” ABC; (2) Disease- ee in e al; (3) esponse o p io
ET; (4) bu den o disease and symp oms; (5) menopausal
s a us; (6) como bidi ies; (7) pa ien p e e ences and (8)
cos s and a ailabili y.
Since e en ually all pa ien s de elop esis ance o p ima -
ily esis an o ET, his mus be conside ed be o e s a ing
any he apy ( i s o nex lines). Al hough a clea and con-
sis en de ini ion o esis ance o ET is lacking, endoc ine
esis ance has been de ined by consensus (Table3), as well
as he ype o ET ha should be used in i s and second lines
(Table4) [5, 22].
The op imal sequence o endoc ine-based he apy is
unce ain. A ailable op ions o p e- and pe imenopausal
women wi h o a ian unc ion supp ession (OFS)/o a ian
Table 2 Common classes o
endoc ine he apy
Mechanism o ac ion
SERM selec i e es ogen ecep o modula o , SERD selec i e es ogen ecep o down egula o (Ful es an
500mg/mon h wi h loading dose is he ecommended dosage), GnRH gonado opin-ho mone eleasing-
ho mone, NSAI non-s e oideal a oma ase inhibi o s (3 d gene a ion), SAI s e oidal a oma ase inhibi o s
(3 d gene a ion)
Mechanism o ac ion Class Agen
Es ogen ecep o blockage SERM Tamoxi en, o emi en
SERD Ful es an
Es ogen dep i a ion O a ian abla ion Su ge y, adia ion
O a ian supp ession wi h GnRH
analogs
Gose elin
T ip o elin
Leup olide
NSAI Anas ozole
Le ozole
SAI Exemes ane
Unknown P oges ins Meges ol ace a e
Med oxyp oges e one ace a e
High-dose es ogens Die hyls ilbes ol (DES)
Table 3 De ini ion o endoc ine esis ance le els [5, 22]
P ima y endoc ine esis ance Relapse while on he i s 2yea s o adju an endoc ine he apy (ET), o p og essi e disease (PD) wi hin i s
6mon hs o i s -line ET o ABC, while on ET
Seconda y endoc ine esis ance Relapse while on adju an ET bu a e he i s 2yea s, o elapse wi hin 12mon hs o comple ing adju an
ET, o PD ≥ 6mon hs a e ini ia ing ET o ABC, while on ET
35Clinical and T ansla ional Oncology (2019) 21:31–45
1 3
unc ion abla ion (OFA), and pos -menopausal women
include a oma ase inhibi o (AI), amoxi en, ul es an , AI/
ul es an plus CDK 4/6 inhibi o , and ET plus e e olimus.
In la e lines, also meges ol ace a e and oes adiol, as well
as epe i ion o p e iously used agen s, may be used.
Besides he ER/PR posi i i y, as de ined by in e na ional
guidelines [23], we do no ha e ano he use ul bioma ke
o selec ET.
As he blockage o he es ogen signal is he mains ay o
he ea men and he es ogen le el a ies depending on he
menopausal s a us, i is impo an o de ine he si ua ion o
each pa ien (Table5) [24].
Pos menopausal women
Fi s ‑line se ing
• Thi d gene a ion AIs Anas ozole, le ozole (non-
s e oidal a oma ase inhibi o s, NSAI) and exemes-
ane (s e oidal a oma ase inhibi o , SAI) a e supe-
io o amoxi en. The e a e no di e ences in
e icacy be ween he h ee AIs [25] (LC high; GR A).
• Ful es an 500mg has be e p og ession ee su i al
(PFS) han anas ozol (18 s 13mon hs), wi hou di -
e ences in OS in pa ien s wi hou p io exposu e o ET,
pa icula ly in hose wi h non- isce al disease [26].
• The combina ion o an NSAI o ul es an plus CDK4/6
inhibi o has consis en ly shown o inc ease PFS in abou
10mon hs compa ed o ET alone, al hough wi h mo e
oxici y, and he e ec is consis en in all ials and in all
clinical subg oups.
The h ee op ions (AI, ul es an 500mg and AI/ ul-
es an + CDK4/6 inhibi o ) a e alid o he i s line.
Tamoxi en is also an op ion, i o he s canno be used. The
combina ion o ET plus CDK4/6 inhibi o is he p e e ed
one i no o he con aindica ions a e p esen . [5, 22, 25, 26]
(LC high; GR A).
• Fo pa ien s ha ecei ed chemo he apy as i s line
o ea men , main enance ET is a easonable op ion,
al hough no assessed in clinical ials [5, 22]. The e
is somewha less e idence o combina ion o ET wi h
CDK4/6 inhibi o s in his si ua ion; so, ou ecommen-
da ion is o conside he use o ET alone, aking in o
accoun he oxici y and QoL a iables (LC low; GR B).
Second‑line se ing
The second line will depend on whichd ughas been used
as i s line.
• AI is be e han p oges in, and simila o ul es an
250mg. In second line ul es an 500mg is be e han
250mg [21].
• Fo hose pa ien s ea ed wi h p io AIs, ul es an 500
would be he op imal op ion. [27]. Also, he al e na e
Table 4 Consensus de ini ion o 1s and 2nd lines o endoc ine he apy (ET) [5, 22]
1s line ET: (endoc ine sensi i e pa ien s) Newly diagnosed (de no o) ABC
Relapse > 12mon hs om comple ion o (neo) adju an endoc ine he apy wi h no ea -
men o ad anced o me as a ic disease ( ea men naï e in he ad anced se ing)
2nd line ET Relapse on o wi hin 12mon hs om comple ion o (neo) adju an endoc ine he apy
wi h no ea men o ad anced o me as a ic disease (ea ly elapse)
P og ession a e 1s line o endoc ine he apy o ad anced disease (as desc ibed be o e)
Table 5 De ini ions and menopausal s a us [24]
Menopause Is he pe manen cessa ion o menses
Reasonable c i e ia o de e mining menopause include any o he ol-
lowing
P io bila e al oopho ec omy
Age ≥ 60yea s
Age < 60yea s and ameno heic o 12 o mo e mon hs in he absence
o chemo he apy, amoxi en, o emi ene, o o a ian supp ession and
ollicle-s imula ing ho mone (FSH) and es adiol in he pos meno-
pausal ange
I aking amoxi en o o emi ene, and age < 60yea s, hen FSH and
plasma es adiol le el mus be in pos menopausal anges
I is no possible o assign menopausal s a us o women who a e ecei ing an LHRH agonis o an agonis
In he apy-induced ameno hea, oopho ec omy o se ial measu emen o FSH and/o es adiol a e needed o ensu e pos menopausal s a us i
he use o a oma ase inhibi o s is conside ed as a componen o endoc ine he apy

36 Clinical and T ansla ional Oncology (2019) 21:31–45
1 3
class o AI can be conside ed. Swi ching be ween s e-
oidal and non-s e oidal AIs p oduces modes addi ional
clinical bene i s, sugges ing pa ial non-c oss- esis ance
be ween he classes o inhibi o . Howe e in hese ci -
cums ances, he esponse a es o he second AI ha e
gene ally been low [28].
• The combina ion o CDK4/6 inhibi o s + ul es an has
p o en o be be e han ul es an alone in pa ien s wi h-
ou p io exposu e o CDK4/6 inhibi o s a e p og es-
sion o AIs, wi h inc ease in PFS [29–31] (LC high; GR
A).
• Also, he combina ion o he mTOR (mammalian a ge
o apamycin) inhibi o e e olimus wi h ET (exemes-
ane in a phase III ial, and also wi h amoxi en and
ul es an in phase II ials) a e p og ession o an AI
leads o an inc eased PFS compa ed wi h ET alone, bu
wi h wo se ole ance (see e iew in nex sec ion).
The e a e no da a o de ine he bes choice o ea men
a e p og ession o a CDK4/6 inhibi o in i s line.
Subsequen lines o  he apy
The e is e y limi ed in o ma ion om p ospec i e ials
in pa ien s wi h p io exposi ion o mo e han wo lines
o ET. In cases whe e a posi i e e ec has been achie ed
wi h p io ET, hose ET no p e iously used and p oges ins
and o he ET (Table2) can be es ed [5, 22] (LC mode -
a e; GR B).
P emenopausal women
• The e a e less da a o p emenopausal women ea ed
wi h endoc ine he apy alone, as many ials wi h ET
ha e included mainly pos menopausal women. Howe e ,
he old da a wi h OFS in combina ion wi h amoxi en,
small ials wi h OFS and AI o ul es an and da a o
p emenopausal pa ien s included in new ials o ET wi h
CDK4/6 inhibi o s ha e p o en ha he bene i in p e-
menopausal women is compa able o ha ob ained in
pos menopausal [32, 33]. Fo all hese easons he in e -
na ional consensus is ha he op imal managemen o
p e/pe imenopausal pa ien s wi h luminal ABC consis s
o he induc ion o OFS o OFA in combina ion wi h
ano he endoc ine agen . Once he pa ien has been en-
de ed pos menopausal, ecommenda ions o pos meno-
pausal apply (LC high; GR A).
• Adequa e OFS o ABC p emenopausal pa ien s can be
ob ained h ough bila e al o a iec omy, con inuous use o
LHRH agonis s o OFA h ough pel ic RT ( his la e is
no always e ec i e, and he e o e is he leas p e e ed
op ion) [5, 22] (LC high; GR A).
• Fo hose pa ien s ha do no desi e o a ian supp ession,
amoxi en is a easonable op ion (LC high; GR B).
Endoc ine he apy inmen
The e a e ew da a in hese popula ions. In e na ional guide-
lines ecommenda ions a e ha ea men should be chemi-
cal cas a ion wi h GnRH analogs and hen combina ion
wi h ET as in pos menopausal women. Also, o hose ha
do no wan cas a ion amoxi en is a easonable op ion [5]
(LC mode a e; GR A).
Chemo‑endoc ine he apy
The e is no clea e idence ha concomi an use o ET plus
chemo he apy esul s in imp o emen in OS. The e o e,
his combina ion should be discou aged ou side a clinical
ial [34] (LC low; GR D).
Du a ion o ET
ET should be con inued un il p og essi e disease o ox-
ici y. Fo hose pa ien s ea ed wi h combined he apy
(CDK4/6 inhibi o s o e e olimus) who ha e se e e ox-
ici y o he non-ho mone componen o he combina ion
ET alone can be used un il p og ession (LC high; GR A).
Ta ge ed he apy inad anced b eas cance
CDK4/6 inhibi o s: palbociclib, ibociclib
andabemaciclib
The combina ion o a CDK 4/6 inhibi o wi h an AI is
he p e e ed i s -line op ion o mos pa ien s wi h endo-
c ine-sensi i e HR-posi i e/HER2-nega i e me as a ic
b eas cance (Table2) [35–37] (LC high; GR A).
Recen e idence sugges s he e icacy o he combina-
ion o CDK4/6 inhibi o wi h ul es an in i s -line se -
ing and endoc ine-sensi i e disease [30] (LC high; GR A).
The op ion o CDK4/6 inhibi o wi h an AI would also
be app op ia e o hose pa ien s who ha e no ecei ed
p io ea men wi h a CDK4/6 inhibi o (LC mode a e;
GR B).
Fo pa ien s wi h endoc ine- esis an HR-posi i e/
HER2-nega i e disease (Table2) ABC, he combina ion o
a CDK4/6 inhibi o wi h ul es an is he p e e ed op ion.
[29–31, 38] (LC high; GR A).
37Clinical and T ansla ional Oncology (2019) 21:31–45
1 3
Bo h combina ions (CDK/AI and CDK/ ul es an ) a e
applicable ega dless o he pa ien ’s menopausal s a us,
al hough p e/pe imenopausal pa ien s addi ionally will
equi e o a ian unc ion abla ion o supp ession.
Conside ing all hese da a, a CDK4/6 inhibi o should be
added o endoc ine he apy, a he la es when s a ing sec-
ond-line endoc ine he apy. Because he side e ec p o ile o
he CDK4/6 inhibi o s appea s subs an ially mo e ole able
han ha seen wi h e e olimus, he panel o expe s ecom-
mends using CDK4/6 inhibi o s a he han e e olimus as
he ini ial- a ge ed he apy o pa ne wi h ET.
Wi h he excep ion o HR s a us, a p esen he e a e no
alida ed p edic i e bioma ke s o iden i y hose women
who could bene i om endoc ine-based he apy wi h a
CDK4/6 inhibi o (Table6).
mTOR inhibi o s: e e olimus
The combina ion o an AI wi h e e olimus, an mTOR inhibi-
o , can be a alid ea men op ion o pa ien s wi h endo-
c ine- esis an HR-posi i e/HER2-nega i e me as a ic b eas
cance , since hey a e likely o ob ain a signi ican ly longe
median PFS compa ed o a oma ase inhibi o mono he apy
(7.8 s 3.2mon hs) [39, 40].
Howe e , as an OS bene i could no be p o ed [41], when
conside ing his a ge ed he apy, special a en ion mus be
paid o he inc eased oxici y including po en ially se e e
side e ec s (e.g., non-in ec ious pneumoni is) (LC high; GR
B). P ima y p ophylac ic measu es (e.g. mou hwashes wi h
dexame hasone and me iculous o al hygiene) a e ecom-
mended o p e en oublesome side e ec s [42]. Elde ly
pa ien s should be closely moni o ed du ing ea men wi h
p oac i e managemen o side e ec s.
Wi h he excep ion o HR s a us, a p esen he e a e no ali-
da ed p edic i e ma ke s o iden i y hose women who could
bene i om endoc ine-based he apy wi h a mTOR inhibi o .
PARP inhibi o s: olapa ib and alazopa ib
The poly-(ADP- ibose)-polyme ase (PARP) inhibi o s
olapa ib and alazopa ib a e bo h use ul ea men op ions
o pa ien s wi h ad anced ge mline BRCA1/2-mu a ed
iple-nega i e b eas cance (TNBC) o HER2-nega i e
luminal-like b eas cance [43, 44]. Speci ically, olapa ib
has been ecen ly app o ed by EMA o ea me as a ic
b eas cance a e p og ession on chemo he apy. Pa ien s
should ha e ecei ed p e ious ea men in he o m o (neo)
adju an he apy o up o wo lines o chemo he apy wi h
an h acyclines and axanes o me as a ic disease, and mus
no ha e pla inum- esis an disease.
This ecommenda ion is based on longe PFS (app oxi-
ma ely 3mon hs), highe o e all esponse a e, good side
e ec p o ile and an imp o ed quali y o li e wi h bo h PARP
inhibi o s compa ed o physician’s choice o s anda d chem-
o he apy (capeci abine, e ibulin, o ino elbine) in wo an-
domized phase III ials (OlympiAD and EMBRACA ials)
[43, 44] (LC high; GR A).
T ea men o HER2‑posi i e ad anced b eas
cance
Fi s ‑line he apy
The ini ial ea men app oach o HER2-posi i e MBC mus
include a combina ion o chemo he apy and an i-HER2 he -
apy [45]. The same HER2 a ge ing agen should con inue
beyond p og ession h ough subsequen lines o ea men
[46] (LC high; GR A).
Dual-blockade wi h as uzumab, pe uzumab and axanes
is he ea men o choice in he i s -line se ing ollowing he
esul s o phase III CLEOPATRA ial ha demons a es a s a-
is ical signi ican imp o emen in PFS and OS om adding
pe uzumab o as uzumab and doce axel [47] (LC high; GR
A).
Replacing axane wi h ino elbine may be conside ed in
ce ain ci cums ances [48] (LC low; GR C).
O no e, only 10% o CLEOPATRA pa ien s we e p e i-
ously exposed o as uzumab. In he PHEREXA ial es ing
as uzumab plus capeci abine wi h o wi hou pe uzumab, a
smalle bene i om addi ion o pe uzumab o as uzumab-
exposed MBC pa ien s in second-line se ing was epo ed [49].
T as uzumab em ansine (T-DM1) was non-in e io o
as uzumab- axane in he phase III i s -line MARIANNE
s udy. Howe e , he e a e no da a ega ding a head- o-head
compa ison be ween T-DM1 and dual HER2-blockade wi h
Table 6 Compa ison o he s a us o au ho iza ion o CDK4/6 inhibi-
o s
HR +/HER2 − ABC ho mone ecep o -posi i e and HER2-nega i e
Ad anced B eas Cance , AI a oma ase inhibi o , ET endoc ine he apy
a Endoc ine he apy mus be combined wi h a lu einizing ho mone–
eleasing ho mone (LH–RH) agonis in p e o pe imenopausal women
EMA Indica ion
PALBOCICLIB HR +/HER2 − ABC in combina ion wi h:
An AIa
Ful es an , in women p e iously ea ed wi h
ETa
RIBOCICLIB Women wi h HR +/HER2 − ABC, in combina-
ion wi h an AI o Ful es an as ini ial ET o in
women who ha e ecei ed p io ETa
ABEMACICLIB Women wi h HR +/HER2 − ABC in combina ion
wi h an AI o Ful es an , as ini ial ET o in
women p e iously ea ed wi h ETa
38 Clinical and T ansla ional Oncology (2019) 21:31–45
1 3
as uzumab, pe uzumab and a axane. Consis en ly, T-DM1
is gene ally ese ed o second-line se ing [50]. One excep-
ion could be in cases o as p og ession on/a e adju an
as uzumab (6–12mon hs) o i he pa ien is no sui able
o axanes and dual blockade [51, 52] (LC mode a e; GR B).
Second‑line he apy
T-DM1 is he ecommended egimen o second-line he apy,
as in he phase III EMILIA ial. I demons a ed supe io i y
o e lapa inib and capeci abine in e ms o PSF and OS [53]
(LC high; GR A). Howe e , i should be no ed ha he e a e
limi ed da a abou T-DM1 e icacy in pe uzumab exposed
pa ien s.
Pe uzumab, as uzumab and chemo he apy may be con-
side ed as second line in pa ien s p e iously no exposed
o pe uzumab, and lapa inib and capeci abine a e sui able
op ions i T-DM1 was used as i s line o i is con aindica ed
[51, 52] (LC mode a e; GR B).
Thi d‑line he apy andbeyond
Regimens cu en ly ecommended o i s o second line
should be conside ed o he la e lines, i no used p e iously
[5] (LC low; GR C).
T-DM1 demons a ed supe io i y o e ea men o physi-
cian’s choice in hi d and la e lines in phase III TH3RESA
ial [54] (LC high; GR A).
Despi e he p o en ac i i y o lapa inib and capeci abine in
he second line [55], his combina ion was in e io o T-DM1
in EMILIA ial, so i p e e ably should be used a e wa ds
(LC mode a e; GR B).
T as uzumab plus di e en chemo he apies ( ino elbine,
capeci abine, gemci abine) may be an op ion i no used p e i-
ously (LC low; GR C).
T as uzumab and lapa inib a e also an op ion [56] (LC mod-
e a e; GR B).
The numbe and du a ion o each ea men line wi h
HER2- a ge ed he apy and chemo he apy combina ions
canno be es ablished. The chemo he apy should con inue
o app oxima ely 6mon hs (o longe ) and/o o he ime o
maximal esponse, depending on oxici y and in he absence o
p og ession. When chemo he apy is s opped, clinicians should
con inue he HER2- a ge ed he apy. A ailable da a sugges
ha he bene i is main ained in hi d line and u he he apy
[51, 52] (LC mode a e; GR B).
HR‑posi i e HER2‑posi i e MBC
The i s ea men app oach in his popula ion is HER2- a -
ge ed he apy plus chemo he apy (LC high; GR A).
In selec ed cases (including hose wi h con aindica ions
o chemo he apy, pa ien ’s wi h a s ong p e e ence agains
chemo he apy o hose wi h a long disease- ee in e al, mini-
mal disease bu den, in pa icula in e ms o isce al in ol e-
men , and/o s ong ER/PR exp ession) ET plus as uzumab
o lapa inib can be an op ion [57, 58] (LC mode a e; GR B).
I a egimen o HER2- a ge ing he apy and chemo he apy
is s a ed, ET may be added o he HER2- a ge ed he apy
when chemo he apy ends [51, 52] (LC low; GR C).
T ea men o  iple‑nega i e ad anced
b eas cance
TNBC is cha ac e ized by he absence o exp ession o
ER, PR, and HER2. TNBC is a he e ogeneous en i y.
The e is a signi ican o e lap o TNBC wi h basal-like
sub ype by PAM50, al hough hey a e no synonyms [59].
Chemo he apy (CT) is he s anda d ea men o
pa ien s wi h TNBC [60]. The choice o he s a egy and
cy o oxic agen s is condi ioned by a la ge numbe o
ac o s and mus be conside ed indi idually. In gene al,
sequencing single agen chemo he apy is p e e ed [61],
limi ing combina ion he apies o pa ien s wi h agg es-
si e, symp oma ic o li e- h ea ening disease [51] (LC
high; GR A).
The op imal du a ion o CT is no well es ablished, bu
gene ally a gi en egimen should be used un il p og es-
sion o disease o unaccep able oxici y [62] (as de ined
oge he wi h he pa ien ) (LC mode a e; GR B).
Gi en he agg essi eness o he disease and he limi ed
e ec i e ea men op ions, pa ien s wi h me as a ic TNBC
should always be o e ed pa icipa ion in well designed,
p ospec i e, independen ials whene e such ials a e
a ailable, and he pa ien is willing o pa icipa e (LC
high; GR A).
Fi s ‑line ea men
• In pa ien s ha a e CT-naï e, an h acyclines o axanes,
ei he alone o in combina ions a e conside ed as i s -
line ea men [63] (LC high; GR A). This ecommen-
da ion is also alid o pa ien s wi h la e ecu ences
(> 1yea ) a e comple ing (neo) adju an an h acy-
clines and/o axanes.
• In pa ien s wi h axane-naï e and an h acycline- esis -
an MBC, o wi h an h acycline cumula i e dose o ox-
ici y who a e being conside ed o u he CT, axane-
based he apy, p e e ably as single agen would usually
be conside ed as he he apy o choice (LC high; GR
A). In pa ien s p e ea ed wi h adju an axanes and
an h acyclines, o he op ions such as ino elbine [64,
65] and capeci abine [66] a e also a ailable (LC mode -
a e; GR B).
39Clinical and T ansla ional Oncology (2019) 21:31–45
1 3
• Be acizumab, a humanized an i-VEGF monoclo-
nal an ibody, imp o es PFS and o e all esponse
a e (ORR), bu no OS, when combined wi h axa-
nes o capeci abine in HER2-nega i e MBC pa ien s
[67–70] and may be conside ed o selec ed pa ien s
wi h agg essi e o symp oma ic disease (LC mode -
a e; GR C). In he absence o p edic i e bioma ke s,
his bene i mus be weighed agains i s oxici y p o ile
(hype ension, p o einu ia, and hemo hagic e en s)
[71]. Main enance he apy wi h be acizumab plus
capeci abine (compa ed o be acizumab alone) a e
induc ion i s -line ea men wi h be acizumab plus
doce axel imp o es PFS and OS o HER2-nega i e
MBC pa ien s (PFS 11.9 s 4.3mon hs) [72]. Gi en
hese esul s, capeci abine plus be acizumab may be
conside ed o selec ed cases a e ini ial CT wi h doc-
e axel plus be acizumab (LC low; GR C).
• The combina ion o ca bopla in and gemci abine has
been accep ed as con ol a m by EMA and FDA in an-
domized ials, and ac ually showed a signi ican ac i -
i y (PFS o a ound 5mon hs and median OS o a ound
1yea as i s -line he apy) [73]. The combina ion is
ac i e in pa ien s esis an o an h acyclines and axa-
nes, and i is an accep able op ion in young pa ien s wi h
agg essi e symp oma ic disease (LC mode a e; GR B).
• Ca bopla in as i s -line ea men o pa ien s wi h
TNBC and/o ge mline BRCA1- o BRCA2-associa ed
MBC (gBRCA) was as e ec i e as doce axel in he and-
omized phase III TNT ial [74]. Al hough he e we e no
di e ences in ORR o PFS in he unselec ed popula ion
(ORR, ca bopla in 31.4% s doce axel 34.0%), gBRCA
mu a ion ca ie s had an absolu e di e ence o 34.7% in
ORR (68% s 33%, p = 0.03; bioma ke , ea men in e -
ac ion p = 0.01), which also ansla ed in signi ican di -
e ences in PFS (6.8 s. 3.1mon hs, p = 0.04). Based on
hese esul s, ca bopla in can be conside ed as an op ion
bo h o unselec ed TNBC pa ien s (LC mode a e; GR B)
and o gBRCA MBC (LC high; GR A).
• A ezolizumab in combina ion wi h nab-pacli axel
has shown o imp o e PFS in pa ien s wi h me as a ic
TNBC when compa ed o nab-pacli axel alone [75].
This was achie ed bo h in he in en - o- ea popula ion
(7.2 s 5.5mon hs; HR 0.80) and among pa ien s wi h
PD-L1-exp essing umo s in he in il a ing immune
cells. In he in en ion- o- ea analysis, he median OS
was 21.3mon hs wi h a ezolizumab plus nab-pacli axel
and 17.6mon hs wi h placebo plus nab-pacli axel (HR
0.84; p = 0.08), and among pa ien s wi h PD-L1-pos-
i i e umo s, he median OS was 25.0mon hs and
15.5mon hs, espec i ely. Al hough encou aging, addi-
ional esul s o ials es ing immuno he apy agen s plus
chemo he apy mus be awai ed be o e a ecommenda ion
can be made o inco po a e immuno he apy in i s -line
ea men o TNBC.
Second and u he lines o  ea men
The e is no limi o he numbe o he apy lines o be p o-
posed o me as a ic TNBC pa ien s, as long as a good quali y
o li e is main ained [51].
In pa ien s p e ea ed wi h an an h acycline and a ax-
ane, and who do no need combina ion CT, single-agen
capeci abine, ino elbine (o al o IV), and e ibulin a e he
p e e ed choices [64, 65, 76, 77] (LC mode a e; GR B).
Addi ional choices include an al e na i e axane (s anda d
o nab-pacli axel), echallenge wi h an h acyclines (liposo-
mal o mula ion), gemci abine, o pla inum agen s [78] (LC
mode a e; GR B).
Chemo he apy inluminal‑ad anced b eas
cance
Chemo he apy should be he s anda d ea men o HR-pos-
i i e MBC pa ien s ha a e e ac o y o endoc ine he apy,
and o hose women wi h iple-nega i e MBC [5] (see ec-
ommenda ions in he TNBC sec ion).
An h acyclines, axanes, ino elbine, capeci abine, gem-
ci abine and e ibulin a e easonable and a ailable op ions.
The choice o he s a egy and cy o oxic agen s mus be con-
side ed indi idually, aking in o accoun p e ious he apies
and hei oxici ies, umo bu den, ime un il ecu ence a e
p io he apy, biological age, pe o mance s a us, como -
bidi ies, es ima e li e expec ancy, need o a apid disease/
symp om con ol and pa ien ’s p e e ences [5, 79]. No pa -
icula chemo he apeu ic agen o egimen has been able o
p o ide consis en gains in su i al in hese pa ien s [79]. In
gene al, sequencing single-agen chemo he apy is p e e ed
[61, 80], limi ing combina ion he apies o pa ien s wi h
agg essi e, symp oma ic o li e- h ea ening disease (a leas
same e icacy, less oxici y) [5] (LC high; GR A).
E alua ion o esponse o chemo he apy should gene ally
occu a e wo o ou cycles depending on he dynamics
o he disease, he loca ion and ex en o me as a ic in ol e-
men and ype o ea men . Imaging o a ge lesions may be
su icien in many pa ien s (LC mode a e; GR B) [5]. Subjec-
i e and objec i e oxici ies mus be e alua ed epea edly, as
well as he symp oms and pe o mance s a us. Du a ion o
each egimen and he numbe o egimens should be ailo ed
o each indi idual pa ien .