REVIEW
published: 04 Sep embe 2018
doi: 10.3389/ med.2018.00248
F on ie s in Medicine | www. on ie sin.o g 1Sep embe 2018 | Volume 5 | A icle 248
Edi ed by:
Venancio A ancini Al es,
Uni e sidade de São Paulo, B azil
Re iewed by:
Da io De Biase,
Uni e si à Degli S udi di Bologna, I aly
Luca Quaglia a,
Uni e si ä sspi al Basel, Swi ze land
*Co espondence:
Fe nando Schmi
[email p o ec ed]
Special y sec ion:
This a icle was submi ed o
Pa hology,
a sec ion o he jou nal
F on ie s in Medicine
Recei ed: 26 Ap il 2018
Accep ed: 15 Augus 2018
Published: 04 Sep embe 2018
Ci a ion:
Viei a AF and Schmi F (2018) An
Upda e on B eas Cance Mul igene
P ognos ic Tes s—Eme gen Clinical
Bioma ke s. F on . Med. 5:248.
doi: 10.3389/ med.2018.00248
An Upda e on B eas Cance
Mul igene P ognos ic
Tes s—Eme gen Clinical Bioma ke s
And é Filipe Viei a1,2 and Fe nando Schmi 1,2,3*
1IPATIMUP - Epi helial In e ac ions in Cance G oup, Ins i u o de Pa ologia e Imunologia Molecula , Uni e sidade do Po o,
Po o, Po ugal, 2Ins i u o de In es igação e Ino ação em Saúde, Uni e sidade do Po o, Po o, Po ugal, 3Faculdade de
Medicina, Uni e sidade do Po o, Po o, Po ugal
Mul igene signa u es gene a e c ucial p ognos ic in o ma ion pa icula ly use ul o cance
pa ien s whe e clinical pa ame e s and adi ional immunohis ochemical ma ke s alone
lead o equi ocal p ognosis. Clinicians a e now p o ided wi h molecula ools ha
assis in he ou line o adju an he apies, namely helping decide on he ex ension o
adju an endoc ine he apy o on supp essing adju an chemo he apy in pa ien s we e
oxic e ec s a e pa icula ly dele e ious o when his ea men is undamen ally no
needed. The impo ance o cance mul igene p ognos ic signa u es is well elucida ed
in he guidelines o adju an sys emic he apy in ea ly-s age b eas cance and
he guidelines on disease s aging ha a e p og essi ely in eg a ing gene exp ession
assays as classi ica ion bioma ke s. In addi ion o he p edic i e and p ognos ic alue,
some gene ic es s p o ide in insic sub yping classi ica ion. He ewi h, we compa e
he molecula es s Onco ypeDX, MammaP in , P osigna, EndoP edic , B eas Cance
Index, Mammos a , and IHC4 and epo he eligibili y o each one in he sui able
se ing. Th ough o now, he e is no a comme cially a ailable mul igene es ha makes
ecommenda ions ega ding adju an ea men o HER-2 and iple nega i e b eas
cance s. Thus, hese pa ien s s ill ecei e adju an chemo he apy. Impo an ly, iple
nega i e ca cinomas a e e y he e ogeneous ega ding p ognosis and new molecula
signa u es ha deciphe his e y he e ogeneous subg oup o b eas cance may imp o e
he clinical managemen o he disease.
Keywo ds: molecula signa u es, gene ic assays, p ognos ic es s, b eas cance , bioma ke s
INTRODUCTION
The clinical cou se o b eas cance may be di icul o p edic as his malignancy is composed
o many biological sub ypes ha in u n exhibi in a umo he e ogenei y, and pa ien s o en
p esen a di e en s ages o pa hological de elopmen . In spi e o his, a limi ed numbe o
p ognos ic ac o s ha e a c ucial ole oday o assess po en ial ecu ence o dea h om b eas
cance . Pa ien age, umo size, como bidi y, umo g ade, and numbe o me as asized axilla y
lymph nodes a e he s onges p ognos ic ac o s. One alida ed algo i hm-based model o
es ima e o e all su i al (OS) and 10-yea disease- ee su i al (DFS) ha inco po a es mos
o he a o emen ioned p ognos ic ac o s is Adju an ! Online (www.adju an online.com) (1,2).
Clinicians a e occasionally aced by high- isk b eas cance pa ien s in an ea ly s age o disease,
Viei a and Schmi Molecula Signa u es in B eas Cance
wi h es ogen- ecep o (ER)-posi i e b eas cance , wi hou
axilla y lymph node in ol emen , o in ol emen o up o 3
lymph nodes. The decision o adminis e adju an chemo he apy
o ex ended adju an endoc ine he apy o hese pa ien s is
equi ocal. Thus, bioma ke s o imp o e he clinical bene i o
adju an he apies in pa ien s wi h la e ecu ence a e clinically
aluable. Today, b eas cance managemen is al eady changing
in ligh o he new molecula analysis ha is becoming mo e
accessible in day- o-day pa hology labs. Gene ic p ognos ic
es s a e bioma ke s comme cially a ailable in he o m o
medical de ices/ es s. The p ognosis o b eas cance disease, he
assessmen o pa ien s whe e chemo he apy will be bene icial,
as well as he iden i ica ion o he molecula sub ype can be
p o ided by such molecula es s.
This e iew ocuses on se en majo p ognos ic signa u es
o b eas cance (Onco ypeDX, Mammap in , P osigna,
EndoP edic , B eas Cance Index, Mammos a and IHC4)
alida ed h ough clinical ials, some o which a e al eady
app o ed by FDA and ecommended by Ame ican [Na ional
Comp ehensi e Cance Ne wo k (NCCN), Ame ican Socie y o
Clinical Oncology (ASCO)] and Eu opean [Eu opean Socie y
o Medical Oncology (ESMO)] guidelines commi ees. Fu he ,
we explo e he u u e in he de elopmen o no el molecula
p ognos ic es s, namely in subg oups o mixed beha io b eas
cance s, such as he iple-nega i e ca cinomas.
BREAST CANCER MOLECULAR
SUBTYPES
DNA mic oa ays and Nex Gene a ion Sequencing (NGS)
ep esen a g ea ad ance in molecula echnology. The
cha ac e iza ion o b eas cance by DNA mic oa ay analysis
has e ealed c ucial classi ica ion sys ems by gene exp ession
p o ile (3). Fi e majo sub ypes o b eas ca cinomas we e
iden i ied: ER-posi i e/HER2-nega i e (luminal A and luminal
B sub ypes); ER-nega i e/HER2-nega i e (basal sub ype); HER2-
posi i e; and ca cinomas ha ha e ea u es simila o no mal
b eas issue (4–6). Di e ing elapse- ee su i al (RFS) and
OS ha e been ound o hese in insic molecula sub ypes in
se e al e ospec i e s udies. Fu he , o he b eas ca cinomas
ha e been iden i ied as a molecula ly dis inc disease, as is
he case o claudin-low cance s (7), me aplas ic (8), molecula
apoc ine (9), and in asi e lobula ca cinomas (10). T iple
nega i e ca cinomas, which a e ERα-nega i e, PgR-nega i e and
HER2 nega i e by immunohis ochemis y, ha e been shown o
be he e ogeneous ega ding esponse o ea men (11) and we e
ecen ly subdi ided in o molecula sub ypes (12).
Abb e ia ions: AJCC, Ame ican join commission o cance ; ASCO, Ame ican
socie y o clinical oncology; DFS, disease- ee su i al; DMFS, dis an me as asis-
ee su i al; ER, es ogen ecep o ; ESMO, Eu opean socie y o medical oncology;
FDA, Food and d ug adminis a ion; FFPE, Fo malin- ixed pa a in embedded;
HER2, Epide mal g ow h ac o ecep o 2; HR, ho mone ecep o ; NCCN,
Na ional comp ehensi e cance ne wo k; NGS, Nex gene a ion sequencing; OS,
o e all su i al; PCR, Pa hologic comple e esponse; PgR, p oges e one ecep o ;
RFS, elapse- ee su i al; ROR, isk o ecu ence sco e; RS, ecu ence sco e;
RT-PCR, e e se ansc ip ion polyme ase chain eac ion; TNM, umo , node,
me as asis (s aging sys em).
DEVISING MULTIGENE PROGNOSTIC
SIGNATURES FROM GENE EXPRESSION
ANALYSIS
Big da a p o ided by DNA mic oa ay echnologies and
RNA sequencing o b eas ca cinomas in combina ion wi h
bioin o ma ics p o ide unpa alleled oppo uni ies o s udying
b eas ca cinomas. In he pas decade, algo i hms ha e
been gene a ed es ima ing he a es o cance ecu ence
and/o su i al ha comp ise a educed se o genes ha
cons i u es he gene signa u e. The gene ic signa u e is
ob ained by compu e -based models, alida ed in clinical
s udies and, in some cases, ansla ed o comme cial p ognos ic
assays (13).
To de elop a molecula gene signa u e, gene exp ession
a ia ions a e de e mined wi hin he candida e exp ession
da ase . High a iance genes o genes ha a e ound
di e en ially exp essed be ween selec ed pheno ypically
di e se g oups (e g., good p ognosis s. bad p ognosis)
a e selec ed. Pa ien s a e g ouped in o he ca ego ies based
on so ed gene exp ession p o iles, usually ansla ed in o
a sco e. The Kaplan-Meie es ima o , logis ic eg ession,
and Cox p opo ional haza ds model a e well-es ablished
s a is ical app oaches o es he su i al unc ions ha
measu e dis an ecu ence- ee su i al (DRFS), DFS o
OS du ing ime in la ge-scale da a se s o gene exp ession
wi h clinical da a, such as su i al o he apeu ic esponse.
When assembling a p edic i e signa u e, he exp ession
alues o he genes p esen in he signa u e a e weigh ed o
imp o e i s p edic i e success. A ma hema ical equa ion is
buil ha p edic s 5-yea o 10-yea pos diagnosis isk o
ecu ence/dea h. These s a egies allow o ind a small subse
o gene al e a ions ha a e mos in o ma i e o su i al
p edic ion (14).
In he Kaplan Meie me hod, an es ima ion o he su i al
unc ion du ing ime is analyzed by log- ank s a is ics and he
ac ion o pa ien s su i ing a each ime a e su ge y and/o
ea men is plo ed (15,16). In logis ic eg ession, a s a is ical
eg ession me hod is applied whe e he independen a iable
de e mines an ou come in which he e a e only wo possible
ou comes (ali e o deceased; elapse, o no elapse). I was
demons a ed ha he p edic i e accu acy could be ma kedly
enhanced by he applica ion o logis ic eg ession analysis, in
compa ison o con en ional Kaplan Meie app oaches, which
a e o en based upon incomple e o g ea ly igh -censo ed
clinical da a (17,18). The Cox p opo ional haza ds model
is a s a is ical eg ession model ha allows in es iga ing he
e ec o se e al a iables ha may impac pa ien ou come
and i assumes a cons an isk o dea h/ elapse du ing ime,
known as he haza d/odds a io (19), in con as o he Kaplan
Meie es ima o ha assesses he impac o a single ac o
in a a ying p opo ion o deceased/ elapsed pa ien s du ing
ime (16).
The gene signa u e has o be alida ed in clinical assays, whe e
a isk sco e can s a i y pa ien s, acco ding wi h he p obabili y
o su i al gi en by he su i al unc ions. In gene al, pa ien s
a e assigned o a low- isk g oup when he isk o ecu ence
F on ie s in Medicine | www. on ie sin.o g 2Sep embe 2018 | Volume 5 | A icle 248
Viei a and Schmi Molecula Signa u es in B eas Cance
is abou 10% (10-yea su i al p obabili y a ound 90%) (13).
The gene signa u e can be es ed o he in e ac ion be ween
he ea men bene i (e.g., chemo he apy) and he isk sco e
in Cox p opo ional haza ds and/o Kaplan-Meie models. In
addi ion o he assessmen o he ea men e ec in su i al,
models can be c ea ed adding he isk sco e o clinical a iables,
such as umo size, age, and g ade. The pe o mance o su i al
ma hema ical models can g ea ly imp o e wi h he combina ion
o bo h he gene signa u e plus clinical and pa hological da a.
Some molecula signa u es ha e been ansla ed o a sho
lis o p o ein bioma ke s ha can be eadily es ed h ough
immunohis ochemis y o immuno luo escence (20,21). This
is use ul in pa hology labo a o ies whe e ou ine molecula
echniques a e being slowly implemen ed. An algo i hm is
calcula ed based on he su i al eg ession models o assess he
coe icien s and he es ablishmen o a p ognos ic sco e/index in
issues.
The implemen a ion o high- h oughpu echniques like ee
ci cula ing DNA p o iling and mic o-RNA analysis will pe mi
he de elopmen o mul i a ia e models and open a enues
o new gene exp ession signa u es o be o mula ed and
implemen ed.
THE CLINICAL APPLICATION OF GENETIC
TESTS: PROGNOSTIC INFORMATION,
THERAPY DECISION, MOLECULAR
SUBTYPING, AND PATIENT STAGING
Ideally, gene ic es s mus be able o accu a ely measu e he
gene p o ile o in e es in di e en ce i ied labo a o ies. This
equisi e is known as analy ic alidi y o he assay and i mus
be main ained as p ognos ic es s become decen alized, i.e.,
adap ed in house o each labo a o y, p e e ably using o malin–
ixed pa a in embedded (FFPE) issue samples. Gene ic es s
mus also p o ide clinical alidi y, as hey should be able o
clea ly s a i y a popula ion in o wo o mo e g oups o pa ien s
ha ha e di e en clinical beha io ega ding pa ien ou come—
usually RFS, DRFS, o OS. Finally, he clinical u ili y o gene ic
es s is shown in app op ia ely designed clinical ials ha
dic a e whe he using gene ic es s leads o op imized clinical
decision-making wi h a con iden deg ee o e idence. Gene ic
es s pa ien p ognos ic assessmen should be demons a ed
in e ospec i e o p ospec i e s udies. Fu he mo e, gene ic
es s should be assessed o p edic i e alue h ough he
e alua ion o ea men bene i , ideally in p ospec i e s udies
(13).
Today, he applica ions o gene exp ession signa u es in he
clinic a e di e se and hese assays ha e he p opensi y o assume
a p ominen o e en c i ical signi icance in e e y pa hology
labo a o y (Figu e 1).
In 2017, AJCC ecognized he need o inco po a e
gene exp ession p ognos ic panels in o he TNM s aging
sys em (eigh h edi ion) (22). Al hough he expe panel
does no endo se any pa icula assay, i is clea ha
genomic assay ecu ence sco es can al e p ognosis and
s age. Low isk sco es gi en by Onco ypeDX, Mammap in ,
Endop edic , PAM50/P osigna, o B eas Cance Index (BCI)
can be used ega dless o he umo size, o downs age
ho mone ecep o -posi i e, HER2 nega i e and lymph node-
nega i e umo s, placing hem in o he same p ognos ic
ca ego y as T1a-T1b N0 M0 ca cinomas. As o his ime,
no ups aging is ecommended based on mul igene panel
es ing (22).
In 2016, ASCO guidelines (addi ional upda e in 2017) made
se e al ecommenda ions ega ding he decision o supp essing
adju an sys emic he apy o women wi h ea ly-s age in asi e
luminal b eas cance (23,24). Impo an ly, his he apy has a
c ucial impac in educing umo g ow h and pa ien cance
mo ali y, hus clinicians should be cau ious when deciding o op
ou o his he apy. In addi ion o he clinician, he pa ien is also
in ol ed in heal h ca e decision-making and he la e should be
in o med o he isks and bene i s o any ea men modi ica ion.
S ill, o some women he oxici y associa ed wi h adju an
chemo he apy may no jus i y he clinical bene i s ob ained wi h
such he apy. None o he gene exp ession o p o ein assays a e
ecommended by ASCO, NCCN, o ESMO ega ding decision-
making on HER2-posi i e b eas cance o iple nega i e b eas
cance s (23–27).
Ano he po en ial applica ion o mul ipa ame e gene
exp ession assays is he decision o ex end endoc ine he apy in
pa ien s wi h ER/PgR-posi i e, HER2-nega i e, node-nega i e
b eas cance and wi h 5 yea s o endoc ine he apy wi hou
disease ecu ence. No ewo hy, ASCO does no make any
ecommenda ion as o a speci ic assay o make decisions on
ex ended endoc ine he apy (23).
Fu he mo e, ce ain gene signa u es we e de ised o iden i y
b eas cance molecula sub ypes, which may help in accessing
p ognosis. PAM50/P osigna (28) and BlueP in (29) a e an
example o such es s. O no e, mul igene es s and molecula
sub ype classi ica ion do no in o m us abou he mu a ions and
epigene ic e en s ha ha e impac in cance p og ession. Some
au ho s a gue in a o o assays ha a e based in he combina ion
o mu a ion p o iling wi h he gene exp ession analysis (30)
because he p esence o speci ic d i e gene ic abe a ions can
p edic he esponse o speci ic a ge ed he apies (30,31). Thus,
one impo an app oach is o assess he comple e spec um
o cance mu a ions and ind he speci ic ac ionable molecules
ha a e c ucial in o de o pe o m ailo ed he apy. Today,
wo companies comme cialize molecula es s ha e alua e
dis inc gene mu a ional p o iles and p edic ac ionable a ge s
o he clinic. These es s a e no ocused in he iden i ica ion
o a simple gene o p o ein signa u e. Speci ically, Founda ion
One CDx (Founda ion Medicine, Camb idge, Massachusse s,
US and Roche, Basel, Swi ze land) is a FDA app o ed NGS-
based in i o diagnos ic assay ha gi es an in o ma i e
comp ehensi e genomic p o ile o he pa ien ’s umo , analyzing
all classes o gene mu a ions known o be soma ically al e ed
in solid ca cinomas and allowing he ma ching wi h a ge ed
he apies. I de ec s base subs i u ions, inse ion and dele ion
e en s (indels), copy numbe al e a ions and selec gene
ea angemen s in 324 genes, as well as genomic pheno ypes
including mic osa elli e ins abili y and umo mu a ional bu den,
using DNA isola ed om FFPE umo issue specimens. Ano he
F on ie s in Medicine | www. on ie sin.o g 3Sep embe 2018 | Volume 5 | A icle 248
Viei a and Schmi Molecula Signa u es in B eas Cance
FIGURE 1 | Clinical applica ions o mul igene/p o ein signa u es in b eas cance . Di e en mul igene/p o ein assays may ha e dis inc i e applica ions. Molecula
signa u es can be used o es p ognosis, p edic ea men bene i , de e mine umo sub ype o downs age selec pa ien s.
es p o iding p ecision medicine is Ca is Molecula In elligence
(Ca is Li e Sciences, Phenix, A izona, US) ha uses mul iple
umo p o iling echnologies o e ie e in o ma ion om
pa ien ’s DNA (base subs i u ions, indels and copy numbe
al e a ions), RNA (gene usions and a ian ansc ip s) and
p o ein (immunohis ochemis y). Like he a o emen ioned assay,
Ca is Molecula In elligence umo p o iling includes umo
mu a ional bu den and mic osa elli e ins abili y es ing ia NGS
(32).
Up o now, he e is no molecula es ha p edic s he si e o
dis an me as asis o ma ion. Fo example, luminal b eas umo s
equen ly dissemina e o he bone, whe eas, he b ain is an o gan
p e e en ially a ge ed by HER2 and basal-like umo s cells. A
gene signa u e ha p edic s he si e o elapse could lead o close
igilance o po en ially implica ed o gans.
MOLECULAR SIGNATURES AND THEIR
VALIDATION IN EVIDENCE-BASED
CLINICAL TRIALS
ASCO and NCCN make speci ic ecommenda ions based on
clinical s udies and he le el o e idence hey p o ide on he use
o gene ic assays o help clinicians decide on adju an he apy o
women wi h ea ly s age in asi e b eas cance (Table 1).
Onco ype DX
Onco ype DX (Genomic Heal h, Redwood, CA) is a 21-gene
signa u e ha is one o he bes - alida ed b eas cance mul igene
es s. I is inco po a ed in he s aging guidelines o AJCC 8 h
edi ion (22), as well as in ASCO he apy guidelines o ea ly
s age b eas cance ea men (23,24), NCCN clinical p ac ice
F on ie s in Medicine | www. on ie sin.o g 4Sep embe 2018 | Volume 5 | A icle 248
Viei a and Schmi Molecula Signa u es in B eas Cance
TABLE 1 | Clinical ials implica ed in he de elopmen o mul igene p ognos ic signa u es.
Numbe o
genes/p o eins
Candida e pa ien s o
adju an chemo he apy
assessmen
( ecommended by guidelines)
ASCO / NCCN
ecommenda ions
AJCC s aging Molecula
sub yping
Clinical ial Combina ion wi h
clinical pa ame e s
in sco e
assessemen
Re e ences
Onco ypeDX 21 genes
(16 genes +5
e e ence genes)
ER/PgR+, HER2, node –
ER/PgR+, HER2, node +
Yes
(s ong)
Yes No NSABP B14
( e opec i e)
NSABP B20
( e ospec i e)
SWOG 8814
( e ospec i e)
T ansATAC
( e ospec i e)
TAILORx
(p ospec i e)
RxPonde
(p ospec i e)
No (33)
(34)
(35)
(36)
(37,38)
(39)
MammaP in 70 genes ER/PgR+, HER2, node –
ER/PgR+, HER2, node +
Yes
(s ong)
Yes Yes
(BlueP in )
TRANSBIG
( e ospec i e)
RASTER
(p ospec i e)
MINDACT
(p ospec i e)
Yes
(Adju an ! Online)
(40)
(41)
(42)
P osigna/PAM50 50 genes
(+5 e e ence genes)
ER/PgR+, HER2-, node - Yes
(mode a e)
Yes Yes ABCG8
( e ospec i e)
ATAC
( e ospec i e)
Yes (P oli e a ion sco e,
umo size)
(43)
(36)
EndoP edic 12 genes
(8 genes +3 RNA
e e ence genes +1
DNA e e ence gene)
ER/PgR+, HER2-, node - Yes
(mode a e)
Yes No GEICAM 9906
ABCSG6
( e ospec i e)
ABCSG8
( es ospec i e)
Yes ( umo size and
nodal s a us (EPclin))
(44)
(45)
(46)
B eas Cance Index 7 genes
(5 genes +2 genes
a io)
ER/PgR+, HER2-, node - Yes
(mode a e)
Yes No
T ansATAC
( e ospec i e)
S ockholm ial
( e ospec i e)
No
(47)
(48)
Mammos a 5 p o eins – No No No NSABP B14
( e ospec i e)
B20
( e ospec i e)
No (49)
IHC4 4 p o eins – No No No T ansATAC
( e ospec i e)
Yes
(nodal s a us, umo
size, g ade, and age)
(21)
(50)
Molecula assays can be used o de e mine he bene i s o ea ly s age b eas cance chemo he apy (ASCO and NCCN guidelines) and o op imize he s aging o pa ien s (AJCC TNM s aging 8 h edi ion guidelines).
F on ie s in Medicine | www. on ie sin.o g 5Sep embe 2018 | Volume 5 | A icle 248

Viei a and Schmi Molecula Signa u es in B eas Cance
guidelines in oncology (26), ESMO clinical p ac ice guidelines o
diagnosis, ea men , and ollow-up o p ima y b eas cance (25)
and S . Gallen consensus panel guidelines (51). Onco ype DX is
based on RNA isola ion om FFPE b eas cance issue ollowed
by RT-PCR, p o iding a s a i ica ion o he 5-yea o 10-yea isk
o dis an elapse in o isk g oups: low isk whe e he clinical
bene i o chemo he apy is expec ed o be small [ ecu ence
sco e (RS <18)], in e media e isk whe e i is unce ain whe he
he bene icial e ec o chemo he apy ou balance he isks and
complica ions media ed by i s oxic la e al e ec s (RS 18–31), and
high isk whe e he e is a high p obabili y o cance o ecu ence,
and he bene i s o chemo he apy a e should su pass he isks
o side e ec s (RS >31). O no e, in he la es clinical ials
isk sco es cu o s ha e been op imized, e lec ing a o hcoming
adjus men in he assay (37).
The assay is FDA clea ed and i was ini ially es ed in node
nega i e pa ien s using samples om he NSABP B14 clinical
ial (33). The assessmen o chemo he apy bene i was done in
NSABP B20 s udy (34) and in he la ge s udies SWOG 8814 (35)
and T ansATAC (36).
In he e ospec i e analysis pe o med on he SWOG
8814 s udy, a andomized clinical ial in pos -menopausal,
axilla y lymph node-posi i e, ER-posi i e b eas cance women,
Onco ype DX deli e ed p edic i e e idence o chemo he apy
bene i in amoxi en ea ed pa ien s (35).
The TAILORx s udy is a p ospec i e phase III ial designed
o HR-posi i e, HER-2 nega i e and node nega i e b eas cance
(38,52). The RS bounda ies ha we e ini ially de e mined
o Onco ype DX we e modi ied in his s udy o a oid
unde ea men , wi h he lowe limi going om 18 o 11 and he
uppe end was ede ined om 31 o 25. The ini ial esul s om
TAILORx showed ha women wi h HR posi i e, HER2 nega i e,
and node-nega i e b eas cance in he low RS g oup ha e a
e y low isk o ecu ence a 5 yea s (<10%) wi h endoc ine
he apy alone, and he e o e, can sa ely omi chemo he apy (37).
Recen ly, Spa ano and colleagues epo ed he de ini i e esul s
om TAILORx, cla i ying he e ec o chemo he apy o women
conside ed o be a in e media e isk o ecu ence. Pa ien s
in his g oup we e andomized o ecei e endoc ine he apy
wi h o wi hou chemo he apy. The au ho s es ablished ha
chemo he apy may be spa ed in all women olde han 50 wi h
RS esul s o 11 o 25 and all women age 50 o younge wi h RS
esul s o 11–15 (52).
In e e ence o he 21-gene signa u e, ASCO guidelines epo
ha “chemo he apy is indica ed in ea ly s age pa ien s ha ha e
ER/PgR–posi i e, HER2-nega i e, node-nega i e b eas cance
wi h a high RS and i is no indica ed in pa ien s wi h a low
RS.” In pa ien s wi h an in e media e RS, he assessmen is no
di ec and ecommenda ions may be de e mined by TAILORx. In
hese cases, he likelihood o dis an ecu ence and bene i om
chemo he apy inc eases wi h an inc ease in he RS esul . Fo
ER/PgR–posi i e node-posi i e b eas cance , ASCO guidelines
a e cau ious abou using Onco ype DX assay. Addi ional s udies
a e equi ed o iden i y pa ien s wi h di e en ex en o axilla y
nodal s a us and RS whe e chemo he apy is in ac bene icial
(23). An ongoing ial (RxPONDER, ClinicalT ials.go iden i ie :
NCT01272037) is ying o iden i y he cu o o he RS o
which adju an chemo he apy is ad an ageous o axilla y lymph
node posi i e pa ien s. Acco ding wi h NCCN guidelines, “ he
21-gene RT-PCR assay can be conside ed in pa ien s wi h 1–3
in ol ed ipsila e al axilla y lymph nodes o guide he addi ion
o combina ion chemo he apy o s anda d ho mone he apy”
(26). A e ospec i e analysis o p ospec i e andomized ials
(NSABP B14 and B20, SWOG 8814 and T ansATAC) sugges s
ha Onco ype DX as a simila p edic ion abili y in hese pa ien s
as in he pa ien s lacking lymph node in ol emen (26). Bo h
ecommenda ion guidelines indica e ha he 21-gene RS should
no be used o guide ea men decision in HER2-posi i e b eas
cance o iple-nega i e b eas cance (23,24,26).
Mammap in
MammaP in is a 70-gene signa u e endo sed in he s aging
guidelines o AJCC 8 h edi ion (22), as well as in ASCO guidelines
o ea ly s age b eas cance ea men (23,24), NCCN clinical
p ac ice guidelines in oncology (26), ESMO clinical p ac ice
guidelines o diagnosis, ea men , and ollow-up o p ima y
b eas cance (25) and S . Gallen consensus panel guidelines (51).
MammaP in is a p ognos ic es clea ed by he FDA o s a i y
pa ien s wi h ER-posi i e o ER-nega i e b eas ca cinomas in o
a high s. low isk o elapse (53).
In he TRANSBIG conso ium s udy, he Mammap in gene
sco e p o ed o be be e a s a i ying low isk s. high isk
pa ien s han he clinical isk assessed wi h he Adju an !
Online ool (40). P ospec i e alida ion in node nega i e pa ien s
was ob ained in he RASTER ial, whe e clinical high isk
pa ien s bu wi h a low MammaP in gene ic isk wi hou
chemo he apy did no nega i ely impac in DMFS (41). Recen ly,
p ospec i e indica ion o he p edic i e abili y o MammaP in
in ea ly-s age luminal b eas cance o adju an chemo he apy
became a ailable in he MINDACT ial (le el1A e idence).
The MINDACT s udy included 6,693 women wi h ea ly s age
b eas cance (lymph node nega i e o 1-3 lymph node posi i e).
This s udy showed ha chemo he apy could be spa ed in
women who had a low genomic isk o ecu ence acco ding
o MammaP in and who we e a high clinical isk o elapse
de ined using Adju an ! (42). In a subse o same clinical ial,
a s udy p esen ed a ESMO 2017 showed ha he 70-gene
signa u e MammaP in could de ec agg essi e small umo s
[ umo size <1 cm (pT1abpN0)]. The au ho s ound ha
a ound 25% o small umo s we e agg essi e and pa ien s
bene i ed om chemo he apy (54). The MINDACT s udy u he
p o ided he pla o m o MammaP in o be included in ASCO
guidelines o clinicians o di ec chemo he apy in node posi i e
ea ly s age b eas cance pa ien s (23,24). Acco ding wi h he
ecen ly upda ed ASCO guidelines o b eas cance ea men ,
i a pa ien has HR–posi i e, HER2-nega i e, bea ing a node
nega i e ca cinoma, bu wi h high clinical isk, MammaP in
can be used o guide he apy decisions. ASCO s a es ha
“MammaP in assay may also be used in pa ien s wi h one o
h ee posi i e nodes and a high clinical isk o in o m decisions
on wi hholding adju an sys emic chemo he apy. Howe e , such
pa ien s should be in o med ha a bene i om chemo he apy
canno be excluded.” Fu he , “i a pa ien has iple nega i e
b eas cance , he clinician should no use he MammaP in assay
F on ie s in Medicine | www. on ie sin.o g 6Sep embe 2018 | Volume 5 | A icle 248
Viei a and Schmi Molecula Signa u es in B eas Cance
o guide decisions on adju an sys emic chemo he apy” (24).
O no e, he MammaP in index is posi i ely associa ed wi h
he likelihood o PCR, i e., high index pa ien s bene i om
neoadju an chemo he apy (29). In e es ingly, MammaP in
could p o ide p ognos ic alue in HER2-posi i e b eas cance .
Howe e , he 10-yea dis an DFS is 84%, a alue ha is no
a o able o supp ess adju an chemo he apy. Thus, he use o
he MammaP in p ognos ic es o decide he adminis a ion o
adju an chemo he apy in HER2-posi i e b eas cance pa ien s
is no ecommended and addi ional s udies a e equi ed (55).
Likewise o ASCO guidelines, he 2017 S . Gallen In e na ional
B eas Cance panel (ESMO) expanded i s guidelines o
ecommend he use o MammaP in o help guide chemo he apy
decision-making o pa ien s wi h ea ly-s age b eas cance , wi h
HR-posi i e and lymph-node posi i e b eas cance . Onco ype
DX gene-exp ession es was also ecommended o guiding
ea men decisions in hese pa ien s (27). Rega ding he
ecen NCCN guidelines, he la es esul s om he MINDACT
s udy ha e no been included. None heless, NCCN s a es ha
p ognos ic mul igene assays a e o be conside ed o es ima e isk
o ecu ence o dea h and bene i s o adju an chemo he apy in
hese pa ien s (26).
BlueP in is a molecula classi ica ion sys em based on 80
genes ha allows b eas cance sub yping classi ica ion in o low-
isk luminal- ype, high- isk luminal- ype, HER-2- ype and basal-
like- ype. I enables pa ien selec ion o ei he chemo he apy
o endoc ine ea men (29). Also, he e is a good associa ion
be ween BlueP in sub yping and chemosensi i i y PCR, wi h
basal-like and HER2 sub ypes ha ing a highe PCR a es (29,56).
BlueP in di e s om he PAM50 classi ie as only 9 genes a e
p esen in bo h gene se s: ESR1, PGR, ERBB2, GRB7, BCL2,
NAT1, FOXA1, FOXC1, MLPH bu he classi ica ion o pa ien s
in o luminal, HER2, and basal subg oups by PAM50 o BlueP in
is expec ed o ha e g ea simila i y, since he ag eemen wi h
he o iginal in insic gene se om Pe ou and colleagues is
>90%. O no e, oday he e is no s anda dized me hod o
molecula sub yping o b eas cance , hence, i is unce ain
which me hodology is ideal a classi ying b eas cance molecula
sub ypes (29).
P osigna/Pam50
P osigna/PAM50 (P osigna B eas Cance P ognos ic Gene
Signa u e Assay; NanoS ing Technologies, Sea le, WA) is a 50
genes molecula signa u e ha was de eloped in p emenopausal
and pos menopausal women ea ed wi hou any adju an
sys emic he apy (36,43). I encompasses he NanoS ing
nCoun e echnology in pa ien analysis. This es p o ides a
isk o ecu ence sco e (ROR) ha akes in o accoun he
PAM50 p o ile desc ibed by Pa ke e al. (28) and clinical
ea u es o he pa ien , such as umo size and p oli e a ion
sco e (33). ROR is s a i ied in o low (10-yea dis an ecu ence
<10%), in e media e (10-yea dis an ecu ence 10–20%) and
high sco es (10-yea dis an ecu ence >20%). Analogously o
Mammap in /BlueP in , P osigna/PAM50 p o ides b eas cance
in insic sub ype classi ica ion.
ASCO guidelines indica e ha he clinician may use
his signa u e “in conjunc ion wi h o he clinicopa hologic
a iables o guide decisions on adju an sys emic he apy in
ER/PgR-posi i e, HER2-nega i e, node-nega i e b eas cance :
chemo he apy should be conside ed o pa ien s in he PAM50
high- isk g oup and i is no indica ed o pa ien s in he
low- isk g oup.” Addi ional s udies a e needed o suppo
ecommenda ions abou adju an chemo he apy in pa ien s wi h
an in e media e P osigna/PAM50 ROR sco e. Rega ding node
posi i e ER/PgR-posi i e, HER2-nega i e b eas cance , ASCO
wa ns ha “mo e da a a e equi ed o de e mine whe he
PAM50-ROR can be used wi h con idence in guiding he use o
adju an sys emic he apy.” Fu he , no da a suppo he use o
PAM50-ROR in HER2-posi i e b eas cance o in iple nega i e
b eas cance (23).
The ABCG8 s udy and he ATAC ials p o ided e idence o
he p ognos ic use o his molecula es , wi h subse s comp ising
he e ospec i e analysis o he PAM50 signa u e in endoc ine-
ea ed pa ien s wi h ER-posi i e, node-nega i e disease (36,43).
The P osigna/PAM50 ROR sco e added s a is ically signi ican
p ognos ic in o ma ion beyond he s anda d clinical ea men
sco e, which was de i ed om s anda d clinical co a ia es,
including age, g ade, umo size, nodal s a us, and adju an
he apy (43). In he s udy by Dowse and colleagues ha
compa ed P osigna/PAM50 wi h Onco ype DX in he same FFPE
samples o endoc ine- ea ed pa ien s wi h ER-posi i e, node-
nega i e disease, he au ho s showed ha mo e in o ma ion was
added by P osigna/PAM50 ROR han by Onco ype DX RS, i.e.,
mo e pa ien s we e sco ed as high isk and ewe as in e media e
isk by ROR han by RS (50). Al hough he p ognos ic alue o
P osigna/PAM50 has been cla i ied, he e is a lack o p ospec i e
clinical s udies ha show he p edic i e alue o his signa u e.
Endop edic
EndoP edic (My iad Gene ics, Inc) is a wel e gene molecula
signa u e. I comp ises he measu emen o he exp ession o
eigh cance ela ed genes, h ee RNA e e ence genes and one
DNA e e ence gene. Endop edic calcula es a isk sco e (EP,
endop edic sco e), which can be used oge he wi h umo size
and nodal s a us o allow he calcula ion o a comp ehensi e isk
sco e (EPclin) (45). I s applica ions include guiding ea men
decisions o chemo he apy as well as ex ended an i-ho monal
he apy.
Clinical e idence o he use o his signa u e came om
he GEICAM ial ha showed ha EP is an independen
p ognos ic pa ame e in node-posi i e, ER+/HER2– b eas
cance pa ien s ea ed wi h adju an chemo he apy ollowed
by ho mone he apy (44). EP and EPclin we e also endo sed
in wo andomized phase III ials (ABCSG6 and ABCSG8)
ha comp ised mo e han 1700 pos menopausal b eas cance
pa ien s ea ed wi h endoc ine he apy alone, indica ing ha
bo h EP and EPclin could be employed o s a i y subg oups
displaying no able di e ences in 10-yea dis an ecu ence
su i al in pa ien s wi h node-nega i e and node-posi i e disease
(45).
Al hough he s eng h o ecommenda ion is lowe han ha
wi h Onco ype DX o MammaP in s udies, ASCO guidelines
indica e ha EP sco e may also be employed in he decision-
making p ocess ega ding he adminis a ion o adju an
F on ie s in Medicine | www. on ie sin.o g 7Sep embe 2018 | Volume 5 | A icle 248
Viei a and Schmi Molecula Signa u es in B eas Cance
sys emic chemo he apy in pa ien s wi h ER/PgR–posi i e, HER2-
nega i e, node-nega i e b eas cance . Fo node posi i e pa ien s,
he le el o e idence o he p esen EndoP edic s udies is
insu icien o ASCO o make a s ong ecommenda ion (23).
Fu he , numbe s a e no a ailable backing he use o EP o EPclin
in HER2-posi i e b eas cance o iple nega i e b eas cance .
B eas Cance Index
B eas Cance Index (BCI, Bio he anos ics, Inc.) combines he
exp ession o 5 p oli e a ion genes known as molecula g ade
index (MGI) wi h he 2-gene a io HOXB13:IL17BR (H:I) in
a linea model. This sco e was de eloped in pos menopausal
pa ien s wi h ER-posi i e, lymph node–nega i e b eas cance
as a p edic i e es o he likelihood o bene i om ex ended
adju an endoc ine he apy (57).
The T ansATAC and he S ockholm ials p o ided he
clinical alida ion and he indica ion o p ognos ic u ili y o
his molecula signa u e (47,48,58). Re ospec i e analysis
o umo samples om hese andomized ials allowed he
BCI assay (H:I+MGI) o independen ly iden i y pa ien s on
5- o 10 yea endoc ine he apy wi h isk o la e-dis an
ecu ence (58). Fu he , al hough s udies demons a e ha BCI
has clinical use ega ding decision making abou he ex ension
o adju an endoc ine he apy beyond i e yea s in pa ien s
wi h ER/PgR-posi i e, HER2-nega i e, node-nega i e b eas
cance (58), he applica ion o his es is no ecommended
by ASCO guidelines, due o insu icien e idence. Fu he ,
da a a e no a ailable o suppo he use o BCI in luminal
node posi i e b eas cance , in HER2-posi i e o in iple
nega i e b eas cance o guide decisions on adju an sys emic
he apy (23).
Mammos a
Mammos a es (Cla ien Diagnos ic Se ices, a GE Heal hca e
company, CA) is a i e-p o ein based assay ha p o ides
a sco e o low- isk, mode a e- isk, and high- isk pa ien s.
Mammos a is no a ue gene ic es . Ra he , i is a i e-
an ibody immunohis ochemis y p ognos ic es . This es uses
he ma ke s CEACAM5, HTF9C, NDRG1, SLS7A5, and TP53
o g oup pa ien s on amoxi en he apy in o isk g oups o
in o m abou p ognosis and pu a i e ea men choices, namely
ega ding he likelihood o bene i o adju an sys emic he apy
(20). Mammos a was de eloped o ER/PgR-posi i e, ea ly s age
in asi e b eas cance pa ien s. S udies showing he suppo he
use o he i e-p o ein assay in HER2-posi i e b eas cance o
TN b eas cance a e lacking.
The e is e idence based s udies showing ha Mammos a
has p ognos ic alue in amoxi en- ea ed pa ien s, being able o
ecognize hose pa ien s who ha e supe io bene i om adju an
chemo he apy (20,59). S ill, he p opo ion o pa ien s who we e
ecu ence ee a 10 yea s was only 85% in he low- isk subg oup
(59). Thus, ASCO does no make a s ong ecommenda ion
o he assessmen o adju an chemo he apy bene i in ea ly
s age pa ien s wi h luminal b eas cance (node posi i e o node
nega i e) (23).
IHC4
IHC4 is an index de i ed om e alua ion o ER, PgR, HER2,
and Ki67 by immunohis ochemis y, which a e ansla ed using
an algo i hm in o a disease ecu ence isk. These ou ma ke s
a e al eady b oadly used in he clinical se ing o de ine
su oga e molecula sub ypes. The clinical ial T ansATAC was
e ospec i ely e alua ed o he ou p o ein ma ke s (21). Since
he alida ion and es ing o IHC4 is limi ed o e y ew s udies
and i has no been shown o be su icien ly ep oducible, ASCO
does no ecommend i s gene al clinical applica ion. IHC4 is
no ecommended o be used in iple nega i e o HER2 b eas
ca cinomas (21,23).
COMPARISON OF MULTIGENE
PROGNOSTIC TESTS
Despi e p ognos ic es s ha ing di e en se s o genes/p o eins,
some o hem a e sha ed be ween di e en signa u es (Table 2
and Supplemen a y Table 1). Onco ype DX sha es he highes
amoun o genes/p o eins wi h o he signa u es, 9 genes
being common wi h P osigna/PAM50 (BIRC5, CCNB1, MYBL2,
MMP11, GRB7, ESR1, PGR, BCL, BAG1), 1 gene wi h
EndoP edic (BIRC5), and 4 genes/p o eins wi h IHC4 (ESR1,
PGR, HER2, Ki67). MammaP in signa u e (60) sha es one gene
wi h Onco ype DX (SCUBE2), h ee genes wi h P osigna/PAM50
(KNTC2, MELK, ORC6L) and one gene wi h BCI (CENPA).
P osigna/PAM50 signa u e has wo genes ha a e p esen in
EndoP edic signa u e (BIRC5, UBE2C), one gene ha is p esen
in BCI (RRM2), and wo genes/p o eins ha a e p esen in IHC4
(ESR1, PGR). Mammos a does no ha e any genes/p o ein in
common wi h he o he signa u es. In ligh o he abo e, he
numbe o sha ed genes/p o eins be ween molecula signa u es
is e y small, bu hey a e able o s a i y pa ien DFS none heless.
In ac , al hough he gene se s being es ed in he di e en
signa u es is di e en , some biological unc ions and molecula
pa hways a e sha ed. In e es ingly, p oli e a ion genes and
ho mone ecep o ela ed genes a e epea edly ound in di e en
b eas cance p ognos ic signa u es. In ac , i has been sugges ed
ha mos o he su i al eadou ob ained om b eas cance
signa u es is de i ed om a p oli e a ion pheno ype (61). O
no e, despi e ha cu en gene ic es s ha e been op imized o
p o ide he bes p ognos ic in o ma ion, wo k by Vene e al.
sugges ed ha a signa u e made om a andom selec ion o genes
om he genome has a high chance o be signi ican ly associa ed
wi h ou come, mo e so when he andom signa u es a e made o
mo e han 100 genes (61).
The ac ha molecula p ognos ic es s a e no alike means
ha wo es s pe o med on he same sample may gi e dis inc
esul s. Fu he , es s ha ha e an “in e media e” isk sco e lead
o an inconclusi e esul . When applying mo e han one gene ic
es on he same sample, we ha e o cla i y which assay is be e
o guide ea men decisions. In a s udy by Fan and colleagues
he conco dance o MammaP in and Onco ype DX assays in
e ms o pa ien s assigned o he same isk ca ego y was 77%
o hose wi h ER-posi i e disease (62). Da a p esen ed in Miami
B eas con e ence in 2014 showed ha he conco dance be ween
F on ie s in Medicine | www. on ie sin.o g 8Sep embe 2018 | Volume 5 | A icle 248
Viei a and Schmi Molecula Signa u es in B eas Cance
TABLE 2 | Sha ed genes/p o eins be ween molecula signa u es.
Onco ype DX
21 genes
Mammap in
70 genes
P osigna/PAM50
50 genes
Endop edic
12 genes
BCI
7 genes
Mammos a
5 p o eins
IHC4
4 p o eins
Onco ype DX SCUBE2 BIRC5, CCNB1,
MYBL2, MMP11,
GRB7, ESR1, PGR,
BCL, BAG1
BIRC5 ESR1, PGR,
HER2, Ki67
MammaP in – – KNTC2, MELK, ORC6L CENPA
P osigna/PAM50 – – BIRC5, UBE2C RRM2 ESR1, PGR
EndoP edic – – – – – – –
BCI – – – – – – –
Mammos a – – – – – – –
IHC4 – – – – – – –
Fo he comple e gene/p o ein lis , see Supplemen a y Table 1.
MammaP in isk g oups and Onco ype DX ca ego ies was 85.7%
wi hin he pa ien s classi ied as high isk by Onco ype DX and
38.1% wi hin he pa ien s classi ied as high isk by MammaP in
(63). In ano he compa a i e s udy, Nunes and colleagues es ed
bo h gene signa u es in 29 pa ien s: wo had high isk bo h by
RS and MammaP in ; eigh had in e media e RS, wi h ou high
isk by MammaP in ; 19 had a low RS, wi h eigh high isk by
MammaP in . They concluded ha RS and MammaP in o e
di e en p ognos ic in o ma ion (64). Possible explana ions o
he obse ed a ia ion in isk s a i ica ion include di e ences in
baseline cha ac e is ics o he s udy coho s, di e ences in umo
biology and/o di e ences in assay echnology. In e es ingly,
among pa ien s who unde go he Onco ype DX 21-gene assay,
39–67% ecei e an in e media e isk esul . Recen ly, in he
PROMIS clinical ial i was shown ha 45% o in e media e isk
pa ien s ha e a low isk esul wi h MammaP in and 55% had
a high isk esul . The MammaP in 70-gene signa u e led o
change in physicians’ ea men decisions in his popula ion wi h
ea ly b eas cance (65).
Dowse and colleagues compa ed Onco ype DX wi h
P osigna/PAM50 and he la e assay p o ided supe io
p ognos ic esul on elapse isk, showing imp o ed s a i ica ion
in he in e media e and high- isk g oups o pa ien s (50).
Recen p elimina y esul s we e epo ed o he p ospec i e
phase III clinical ial OPTIMA, which will compa e Onco ype
DX, MammaP in , P osigna, IHC4, IHC4-Aqua (Nex Cou se
B eas ), and MammaType gene signa u es in he same g oup
o pa ien s (66). In his s udy, di e gences we e de ec ed in
pa ien s a ibu ed in o isk s a i ica ion g oups and molecula
sub ypes. The low- isk g oup o Onco ype DX showed a highe
numbe o pa ien s han he low/in e media e isk g oup in he
P osigna, Mammap in o IHC4 assays and disco dan molecula
sub yping was obse ed in 40.7% o umo s. The main OPTIMA
ial ini ia ed pa ien en olmen in Janua y 2017.
A deepe in es iga ion o T ansATAC s udy compa ing he
pe o mance o he p ognos ic mul igene signa u es Onco ype
DX, P osigna/PAM50, BCI, EPClin, IHC4, and he Clinical
T ea men Sco e showed ha in pa ien s wi h node nega i e
disease he P osigna/PAM50, BCI, and EPClin signa u es p o ide
supe io p ognos ic accu acy, whe eas BCI and EPClin p o ided
supe io p ognos ic accu acy o pa ien s wi h node posi i e
disease. O no e, pa icula ly in women wi h node-posi i e
disease, mul igene p ognos ic es s when combined wi h clinical
ea u es signi ican ly imp o ed p ognos ic alue o dis an
elapses and isk s a i ica ion. These esul s poin o he
impo ance o combining clinical and pa hological in o ma ion
wi h he use o genomic signa u es (13,67).
A MULTIGENE SIGNATURE FOR TRIPLE
NEGATIVE CARCINOMAS
Al hough gene ally seen as clinically e y agg essi e, iple
nega i e b eas ca cinomas ep esen a e y he e ogeneous
g oup o umo s ega ding p ognosis. Recen ly, iple nega i e
ca cinomas we e s a i ied in o molecula sub ypes. Lehmann
and colleagues subdi ided his g oup o b eas cance s in o
Basal-like (BL)-1, BL2, Mesenchymal-like (M), Mesenchymal
s em-like (MSL), Luminal and ogen ecep o (LAR), and
Imunnomodula o y (IM) (12,30). BL-1 and IM umo s in gene al
ha e a be e p ognosis, as hey espond well o an acyclin,
axanes, and cyspla in chemo he apy and immune checkpoin
ac i a ion he apy, espec i ely.
F om he se e al a emp s o design p ognos ic molecula
signa u es o iple nega i e cance s, i s ill emains o be
cla i ied i ob aining a “good” p ognosis g oup o iple nega i e
ca cinomas will make hem eligible o suspending o emo ing
he bene i s o chemo he apy. Ring and colleagues de eloped a
new classi ica ion signa u e based on 101 genes using Lehmann’s
gene exp ession da ase . Ring e al. (68) and a gene ic assay
is being de eloped on his algo i hm building on p edic ing
p ognosis and esponse o he apy (69). Al hough dis an
ecu ence high- isk and low- isk g oups can be o mula ed
based upon da a abou immune cell, in lamma ion esponse
and DNA damage/ epai mechanisms, he p ac ical u ili y o
his obse a ion is someway es ic ed because e en pa ien s
ca ego ized as “good p ognosis” ha e abou 20% isk o dis an
ecu ence in he absence o sys emic adju an he apy (70). O
no e, a highe han 10% isk o ecu ence in he low isk g oup
is oo high o mos pa ien s and physicians do no suppo ha
F on ie s in Medicine | www. on ie sin.o g 9Sep embe 2018 | Volume 5 | A icle 248