D . Lesiba Te ance Khalo. (2025). Impac o p95HER2 Exp ession on Clinical Ou comes in HER2-Posi i e
B eas Cance s: A Li e a u e Re iew. MAR Oncology and Hema ology. (2025) 5:10
Impac o p95HER2 Exp ession on Clinical Ou comes in HER2-Posi i e
B eas Cance s: A Li e a u e Re iew
D . Lesiba Te ance Khalo *
*Co espondence o: D . Lesiba Te ance Khalo, Mili a y Hospi al, P e o ia, Gau eng P o ince, Sou h
A ica.
Copy igh .
© 2025 D . Lesiba Te ance Khalo This is an open access a icle dis ibu ed unde he C ea i e Commons
A ibu ion License, which pe mi s un es ic ed use, dis ibu ion, and ep oduc ion in any medium, p o ided
he o iginal wo k is p ope ly ci ed.
Recei ed: 08 Oc 2025
Published: 17 Oc 2025
MAR Oncology and Hema ology (2025) 5:10
Li e a u e Re iew
D . Lesiba Te ance Khalo, MAR Oncology and Hema ology (2025) 5:10.
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D . Lesiba Te ance Khalo. (2025). Impac o p95HER2 Exp ession on Clinical Ou comes in HER2-Posi i e
B eas Cance s: A Li e a u e Re iew. MAR Oncology and Hema ology. (2025) 5:10
In oduc ion
Human epide mal g ow h ac o ecep o 2 (HER2), is one o a amily o 4 memb ane y osine kinases (TKs),
which was i s disco e ed 25 yea s ago, and shown o be o e exp essed in a human b eas cance cell (5) wi h
i s p e alence shown o be impo an in pa hogenesis and disease p og ession in b eas cance pa ien s (6).
The HER2 pa hway was desc ibed in sys ems biology e ms as a complex biological ne wo k composed o 3
laye s: 1) An inpu laye o memb ane ecep o s, alongside hei ligands, whose unc ion is o ac i a e signal
ex acellula cascades, 2) A co e sys em p ocessing laye o p o ein kinases (PKs) who’s oles a e signal
ansmission o he nucleus, ollowed by 3) An ou pu laye o ansc ip ion ac o s, which unc ion by
egula ing genes ha e ec a ious cellula unc ions, such as p oli e a ion, mig a ion, apop osis as well as
angiogenesis (1).
The inpu laye is composed o 4 memb ane ecep o s/kinases (HER1–4) and hei many ligands, including
endo helin g ow h ac o (EGF), ans o ming g ow h ac o alpha (TGF-α), and he egulin. Howe e , in b eas
cance , HER2 is he dominan kinase ecep o , o e exp essed in 20% o cases (6). Upon ligand binding, he
HER ecep o s unde go con o ma ional changes ha enable homo- o he e odime iza ion, ollowed by
ansphospho yla ion o he ecep o s. HER2 does no ha e ligand- binding capabili ies, bu i s open
con o ma ion allows o dime iza ion. When o e exp essed, he ac i a ed o m he e odime izes wi h o he
HER membe s ha ha e ligand-binding capabili ies o unde goes homo-dime iza ion (1). This dime iza ion
leads o he ac i a ion o he PI3K/AKT an i- apop osis pa hway (Figu e 1), he eby s imula ing he ac i a ion
o ansc ip ion ac o s and exhibi ing a p oli e a i e, mig a o y, angiogenic, and di e en ia ion cance
pheno ypes. The es ogen ecep o (ER) and he HER2 signaling pa hways a e he dominan d i e s o cell
p oli e a ion and su i al in mos (85%) b eas cance s (1).
D . Lesiba Te ance Khalo, MAR Oncology and Hema ology (2025) 5:10.
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D . Lesiba Te ance Khalo. (2025). Impac o p95HER2 Exp ession on Clinical Ou comes in HER2-Posi i e
B eas Cance s: A Li e a u e Re iew. MAR Oncology and Hema ology. (2025) 5:10
Figu e 1: HER-2 signaling pa hway (24).
Some HER2 posi i e b eas cance s ha e been shown o exp ess he unca ed o m o HER2, known as
p95HER2, which lacks he ex acellula domain. This lack o he ex acellula domain has been a ibu ed o
esis ance o d ugs such as as uzumab, as i wo ks h ough domain-binding mechanisms (7, 8).
This s udy ocuses on he exp ession o p95HER2, a unca ed o m o HER2, and i s po en ial impac on
b eas cance pa ien s ecei ing as uzumab. The objec i e is o de e mine whe he high le els o p95HER2
in hese pa ien s a e associa ed wi h a wo se disease p ognosis compa ed o pa ien s wi hou hese mu a ions.
The w i e will conduc a comp ehensi e li e a u e e iew o explo e his issue in he con ex o Sou h A ica.
Hypo hesis
Ele a ed exp ession o P95HER2 in HER2-posi i e b eas cance s is associa ed wi h poo e clinical ou comes,
including p og ession- ee su i al (PFS) and o e all su i al (OS), due o i s ole in media ing esis ance o
as uzumab he apy.
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D . Lesiba Te ance Khalo. (2025). Impac o p95HER2 Exp ession on Clinical Ou comes in HER2-Posi i e
B eas Cance s: A Li e a u e Re iew. MAR Oncology and Hema ology. (2025) 5:10
P ojec objec i es
A comp ehensi e li e a u e e iew delinea ing he impac o p95HER2 exp ession on clinical ou comes in
HER2-posi i e b eas cance s has was unde aken, o assess he co ela ion be ween p95HER2 exp ession
le els and clinical ou comes such as o e all su i al (OS), p og ession- ee su i al (PFS), ecu ence- ee
su i al (RFS), pa hologic comple e esponse (pCR) as well as examining he he apeu ic implica ions o
p95HER2 exp ession on he e icacy o HER2 a ge ed he apies in as uzumab.
Me hodology
We conduc ed comp ehensi e li e a u e e iew; 1) To gain a be e unde s anding on he opic, by iden i ying
ecen li e a u e e iews on he a o emen ioned, ollowed by selec ion o ele an o iginal pape s, 2) The
sea ch s a egy and selec ion c i e ia o na ow down he sea ch, 3) App op ia e me hods o selec ing ele an
and up- o-da e pape s we e unde aken; such include, bu a e no limi ed o he sea ch language, p ominen
au ho s, pape s wi h mo e ci a ions, as well as c edible pee - e iewed jou nals wi h highe impac ac o s, 4)
The sea ch was no limi ed o pee - e iewed pape s and books, bu ex ended o published con e ence
p oceedings and hesis. Below, in Figu e 2 is a g aphical depic ion o he e iew s a egy and wo k low.
Figu e 2: The g aphical depic ion o he me hodology wo k low. A selec ion o 16 pee e iewed a icles
speci ically looking a clinical da a depic ing he impac o p95HER2 exp ession, and i s associa ion wi h
disease se e i y we e ca e ully selec ed o his e iew.
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D . Lesiba Te ance Khalo. (2025). Impac o p95HER2 Exp ession on Clinical Ou comes in HER2-Posi i e
B eas Cance s: A Li e a u e Re iew. MAR Oncology and Hema ology. (2025) 5:10
Schola ly da abases and sea ch engines, such as PubMed, Scopus, Google Schola , Else ie , and
ScienceDi ec , we e used o de elop a comp ehensi e sea ch s a egy. The esea che used he ollowing
keywo ds in he sea ch: p95HER2, HER2-posi i e b eas cance , clinical ou comes, as uzumab, ea men
esponse, and esis ance. The Medical Subjec Headings (MeSH) keywo ds and Boolean ope a o s we e used
o na ow he sea ch. S udies published 10-15 yea s ago, o da e, we e included. Bo h clinical s udies and
o iginal esea ch a icles we e included in he c i e ia. S udies ha included he use o he ollowing scien i ic
echniques —immunohis ochemis y, FISH, and sequencing o HER2- posi i e issue/cells — we e included.
P e e ence was gi en o au ho s whose esea ch was p ima ily conduc ed wi hin he Sou h A ican con ex ,
pa icula ly in clinical s udies. P e-clinical (animal) s udies we e excluded om he sea ch, alongside a icles
ha we e olde han 15 yea s
Resul s
Following a comp ehensi e li e a u e sea ch using he abo e da abases (PubMed, Scopus, Google Schola ,
Else ie , ScienceDi ec ), a as body o li e a u e was e ie ed. Followed by a manual pick o o iginal a icles,
hus excluding li e a u e e iews. The ocus was on clinical s udies, whe he e ospec i e o Phase 1, 2, o 3
clinical ials. He e, we picked e y ew a icles ha speci ically ouched on p95HER2-posi i e b eas cance
pa ien s on as uzumab ea men . Below is an accoun o he selec ed a icles ha depic he co ela ion
be ween p95HER2 exp ession in b eas cance pa ien s and clinical ou comes, speci ically PFS and OS (Table
1). O he endpoin clinical ou comes in his li e a u e, such as ecu ence- ee su i al (RFS), disease- ee
su i al (DFS), and pa hological comple e esponse (pCR), we e also included.
Table 1: S udies ha depic he co ela ion be ween p95HER2 exp ession in b eas cance pa ien s and clinical
ou comes, speci ically he PFS and OS, as well as second-line ea men s udies.
Au ho
S udy ype
(clinical)
Pa ien
sample ype
(Numbe o
pa icipan s)
Majo indings
Re e ence
Goh e al.,
2024
Re ospec i e
FFPE (59)
P e alence o p95HER2 in
p emenopausal women, wi h
wo sening DFS.
14
Rigakos e
al., 2021
Re ospec i e
FFPE (114)
An agg essi e cance pheno ype was
associa ed wi h high exp ession o
p95HER2, as pe high CNVs, as well
as exp ession o Ki67.
15
D . Lesiba Te ance Khalo, MAR Oncology and Hema ology (2025) 5:10.
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D . Lesiba Te ance Khalo. (2025). Impac o p95HER2 Exp ession on Clinical Ou comes in HER2-Posi i e
B eas Cance s: A Li e a u e Re iew. MAR Oncology and Hema ology. (2025) 5:10
Lip on e al.,
2013
Re ospec i e
FFPE (89)
Bo h HER3 and p95HER2
exp essing pa ien s exhibi ed poo
clinical ou comes.
16
Chums i e
al., 2018
Re ospec i e
FFPE (91)
The a io o p95HER2/HER2 was
signi ican ly associa ed wi h
wo sening PFS.
17
Duchnowska
e al., 2017
Re ospec i e
FFPE (189)
Second-line Lapa inib ea ed
pa ien s wi h high p95HER2
exp essions may ha e he bes
clinical ou comes while on ea men .
20
Han e al.,
2012
Re ospec i e
FFPE (52)
Wi h combina ion he apy o
Lapa inib plus Capeci abine, he e
was no signi ican associa ion
be ween p95 iso o m and PFS/OS.
21
Cao e al.,
2023
Single-a m,
mul icen e phase
2 ial
Clinical ial
(100
pa ien s)
Wi h a combina ion o py o inib and
capeci abine, he median
PFS inc eased om 8 o 11 mon hs
pos ea men .
22
Se e al s udies ha e shown ha he inc eased exp ession o a unca ed e sion o HER2, p95HER2, is a
c i ical de e minan o poo p ognosis and he apeu ic esponse in HER2-posi i e b eas cance . I has also
been shown ha he median su i al a e o hese pa ien s can be as low as 8 mon hs. To be e unde s and
hese unde lying esis ance mechanisms, con en ionally, 2D umo cell cul u e models ha e been used.
Howe e , hese models, due o hei monolaye na u e, canno ully ecapi ula e he umo mic o-en i onmen ,
he eby wa an ing he de elopmen o mo e biologically complex, ye clinically ele an models o disease.
Sca old (ma ix)- ee sel -assembled agg ega es o cance cells (sphe oids), pa icula ly known as o ganoids,
a e sui able in i o models o disease (9-12). They ha e he e o e been ex ensi ely used in a ious se ings o
s udy umo p og ession and mechanisms o esis ance (12).
This li e a u e e iew aims o assess he co ela ion be ween p95HER2 exp ession le els and clinical
ou comes, including p og ession- ee su i al (PFS) and o e all su i al (OS). In addi ion, i examined he
he apeu ic implica ions o p95HER2 exp ession on he e icacy o HER2- a ge ed he apies in as uzumab.
T as uzumab (He cep in) and pe uzumab a e wo o he HER-2 ecep o -binding humanized monoclonal
an ibodies ha ha e been app o ed by he FDA as he apeu ic agen s o HER2-posi i e b eas cance s (13).
Howe e , some b eas cance s ha e been shown o exp ess an abe an o m o HER2, missing he ex acellula
domain. This unca ed iso o m o HER2 is commonly e e ed o as p95HER2, which has been a ibu ed o
esis ance o d ugs such as as uzumab. Below is an accoun o his esis ance mechanism, alongside he
esul ing clinical ou comes in pa ien s ha bo ing such mu a ions.
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B eas Cance s: A Li e a u e Re iew. MAR Oncology and Hema ology. (2025) 5:10
A ecen s udy by Goh e al. (2024) showed a highe ecu ence and me as asis a e in pa ien s wi h p95HER2-
posi i e umo s compa ed o hose wi h no p95HER2 exp ession. This was a e ospec i e s udy whe ein
o malin- ixed pa a in-embedded (FFPE) issue sec ions we e s ained wi h he p95HER2 an ibody o e alua e
exp ession. This s udy was designed o include samples om 30 non- elapsed b eas cance pa ien s, alongside
29 p ima y as uzumab- esis an pa ien samples. In hei s udy, he g oup demons a ed ha p95HER2
posi i i y was associa ed wi h wo se disease- ee su i al (DFS) in pa ien s unde going as uzumab ea men
(14). Simila ly, a s udy by Rigakos e al. (2021) showed an associa ion be ween he P95-iso o m and esis ance
o as uzumab. He e, he au ho s ound ha high p95-iso o m exp essing pa ien s had a g ea e isk o dea h,
and ha his iso o m was co ela ed o inc eased exp ession le els o p oli e a ion ma ke (ki-67) as well as
gain o HER2 copy numbe a ia ions (CNVs), hus indica i e o a mo e agg essi e cance pheno ype (15).
In hei ques o u he elucida e he “ as uzumab escape” bioma ke s, a s udy by Lip on e al. (2013 designed
a dual an ibody p oximi y-based assay o he p ecise quan i a ion o HER3 o al p o ein (H3T). He e, 89 FFPE
sec ions o me as a ic b eas pa ien s p e iously on as uzumab ea men we e assessed o clinical ou comes
such as OS and PFS using a Ve aTag H3T assay. The da a was analyzed ia Kaplan–Meie and decision ee
analysis. This s udy also showed ha pa ien s on he ea men exhibi ed poo clinical ou comes (16). He e,
pa ien s wi h high exp ession le els o H3T showed a lowe PFS compa ed o hose wi h low exp ession le els.
Howe e , he e we e no signi ican di e ences in OS be ween he high- and low-exp essing samples.
Fu he mo e, o alida e he esul s, IHC, ELISA, and FACS we e also pe o med, and he esul s co ela ed
(16).
Due o he a ying da a ega ding he co ela ion be ween p95HER2 exp ession and poo clinical ou comes,
Chums i e al. (2018 sough o e alua e he a io o p95HER2/HER2 in b eas cance pa ien s. He e, wo Phase
II clinical ials we e conduc ed o e alua e he co ela ion be ween quan i a i e le els o HER2, p95HER2,
and p95HER2/HER2, and clinical ou comes ollowing as uzumab-based chemo he apy in me as a ic HER2-
posi i e b eas cance pa ien s (17). The s udy concluded ha wo sening PFS and OS a e signi ican ly
co ela ed wi h p95HER2/HER2 a io (17).
Fu he mo e, he s udies desc ibed mechanisms unde lying he co ela ion be ween he p96-iso o m and poo
clinical ou comes we e limi ed in he clinical se ing. Mos simila s udies a e in i o (9-12). Recen clinical
s udies ha e indica ed ha he e may be speci ic co-exp essed bioma ke s co ela ing o he pa hological and
clinical pa ame e s o poo p ognosis in HER2-posi i e b eas cance (18), as well as speci ic mu a ions (19).
A s udy by He gue a-Redondo e al. (2016 showed ha he HER2 co- ampli ied and co-exp essed Gasde min
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(encoded by he gene GSDMB is a po en ial c i ical de e minan o poo p ognosis and he apeu ic esponse
in HER2-posi i e b eas cance (23).
To elucida e he genome al e a ions in his cance pheno ype, a ecen s udy by Ma e al. (2024 pe o med a
gene- a ge ed genome sequencing in HER2+ b eas cance pa ien s. In his s udy, app oxima ely 650 mu a ions
we e epo ed. Two mu a ions o no e we e hose in he umo supp esso genes NF1 and ATM, which we e
associa ed wi h as uzumab esis ance (19). Speci ically, he NFI mu a ion was associa ed wi h a highe isk
o ea ly pa ien elapses (19). This is he i s s udy o iden i y he unique cance - ela ed gene mu a ion p o ile,
hus laying a ounda ion o p ospec i e s udies aimed a u he elucida ing esis ance mechanisms o
as uzumab.
Due o he na u e o esis ance o ea men in pa ien s wi h posi i e p95HER2 exp ession, second-line
ea men op ions ha e been made a ailable o hese pa ien s o inc ease hei PFS and OS a es. In hei
e ospec i e s udy, Duchnowska e al. (2017) quan i ied he exp ession le els o HER2, HER3, and p95HER2
p o eins, hus allowing o a mo e in-dep h analysis o hei po en ial p edic i e ele ance in de e mining
pa ien s’ PFS and OS. This s udy showed ha pa ien s ea ed wi h Lapa inib (a HER1 and HER2 y osine
kinase inhibi o (TKI)) who ha e high p95HER2 exp ession may ha e he bes clinical ou comes while on
ea men (20).
The Lapa inib Expanded Access P og am (a combina o y ea men egimen o Lapa inib and capeci abine)
u ilized Ve aTag assays o quan i y he exp ession le els o HER2, HER3, and p95HER2 p o eins om FFPE
issue samples om b eas cance pa ien s who showed esis ance o as uzumab. He e, he e was no
signi ican co ela ion be ween clinical ou comes and p95 exp ession le els in hei coho o HER2-posi i e,
as uzumab- e ac o y me as a ic b eas cance pa ien s (21). On he con a y, a ecen in es iga o -ini ia ed,
single-a m, phase 2 ial conduc ed in China a 16 si es e ealed ha bo h combina ions o py o inib and
capeci abine can be a ea men op ion o HER2-posi i e ad anced b eas cance pa ien s exhibi ing
as uzumab esis ance (22). In his s udy, he p ima y endpoin was he in es iga o -ini ia ed PFS. This s udy
showed ha he median PFS inc eased om 8 o 11 mon hs pos - ea men (22).
Discussion
This li e a u e e iew aimed o assess he co ela ion be ween p95HER2 exp ession le els and clinical
ou comes, including p og ession- ee su i al (PFS) and o e all su i al (OS). In addi ion, we examined he
he apeu ic implica ions o p95HER2 exp ession on he e icacy o HER2- a ge ed he apies in as uzumab.
D . Lesiba Te ance Khalo, MAR Oncology and Hema ology (2025) 5:10.
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D . Lesiba Te ance Khalo. (2025). Impac o p95HER2 Exp ession on Clinical Ou comes in HER2-Posi i e
B eas Cance s: A Li e a u e Re iew. MAR Oncology and Hema ology. (2025) 5:10
Se e al s udies ha e shown ha he inc eased exp ession o p95HER2 is a c i ical de e minan o poo
p ognosis and he apeu ic esponse in HER2-posi i e b eas cance , wi h he median su i al a e o hese
pa ien s as low as 8 mon hs.
S udies ha e shown a highe ecu ence and me as asis a e in pa ien s wi h p95HER2-posi i e umo s. The
esea ch disco e ed ha hese pa ien s had a g ea e isk o dea h. The p95HER2 exp ession co ela ed wi h
inc eased exp ession le els o p oli e a ion ma ke s, such as Ki-67, as well as he gain o HER2 copy numbe
a ia ions (CNVs), hus indica ing a mo e agg essi e cance pheno ype, which led o lowe PFS as well as OS
a es in pa ien s wi h high exp ession le els o p95HER2 in a clinical se ing.
While ou unde s anding o he mechanisms unde lying he co ela ion be ween he p95-iso o m and poo
clinical ou comes is g owing, he e is s ill much o be done. Mos esea ch in his a ea has been conduc ed in
i o, and he clinical se ing p esen s i s own limi a ions. Howe e , ecen clinical s udies ha e indica ed ha
he e may be speci ic co-exp essed bioma ke s and gene mu a ions ha co ela e wi h he pa hological and
clinical pa ame e s o poo p ognosis in HER2-posi i e b eas cance . Fo ins ance, a s udy by He gue a-
Redondo e al. (2016) iden i ied GSDMB as a co-exp essed bioma ke . This gene p oduc is a membe o a
amily o gasde mins ha egula e apop osis in epi helial cells and con ibu e o disease p og ession. Th ough
Rab7 ac i a ion, GSDMB is in ol ed in au ophagy and plays a pi o al ole in modula ing au ophagosome
ma u a ion. The p ocess, in u n, acili a es cance cell esis ance h ough he mechanism o au ophagy. Ma e
al. (2024) also iden i ied wo mu a ions in he umo supp esso genes NF1 and ATM, showing ha hese we e
associa ed wi h as uzumab esis ance. Bo h s udies highligh he need o u he esea ch o ully unde s and
he mechanisms unde lying he co ela ion be ween p95HER2 exp ession le els and poo clinical ou comes.
This wo k is u gen and o u mos impo ance in he igh agains p95HER2-posi i e b eas cance .
Due o he na u e o esis ance o ea men in pa ien s wi h p95HER2 exp ession, second-line ea men
egimens, as well as combina ion chemo he apies, ha e been made a ailable o hese pa ien s o inc ease hei
PFS and OS a es. D ugs ha a ge o he HER iso o ms, in place o HER2, ha e been used in he clinical
se ing— o ins ance, Lapa inib (a HER1 and HER3 inhibi o was used as a second- line d ug. Fu he mo e,
in a s udy by Han e al. (2012), Lapa inib, a small-molecule dual y osine-kinase inhibi o was used in
combina ion he apies, whe e i was pai ed wi h capeci abine, which is ac i a ed o 5'- luo ou acil (5FU) and
inhibi s hymidine syn hesis. Howe e , he e ha e been con adic o y clinical ou comes, wi h a ia ions in
pa ien PFS. Some s udies ha e shown an inc ease in PFS ollowing hei second-line combina ion
chemo he apies (22), while o he s ha e shown no signi ican inc ease (21). These a ia ions we e a ibu ed
