HER2-positive breast cancer: new therapeutic frontiers and overcoming resistance

Abstract

The introduction of anti-HER2 therapies to the treatment of patients with HER2-positive breast cancer has led to dramatic improvements in survival in both early and advanced settings. Despite this breakthrough, nearly all patients with metastatic HER2-positive breast cancer eventually progress on anti-HER2 therapy due to de novo or acquired resistance. A better understanding not only of the underlying mechanisms of HER2 therapy resistance but of tumor heterogeneity as well as the host and tumor microenvironment is essential for the development of new strategies to further improve patient outcomes. One strategy has focused on inhibiting the HER2 signaling pathway more effectively with dual-blockade approaches and developing improved anti-HER2 therapies like antibody–drug conjugates, new anti-HER2 antibodies, bispecific antibodies, or novel tyrosine kinase inhibitors that might replace or be used in addition to some of the current anti-HER2 treatments. Combinations of anti-HER2 therapy with other agents like immune checkpoint inhibitors, CDK4/6 inhibitors, and PI3K/AKT/mTOR inhibitors are also being extensively evaluated in clinical trials. These add-on strategies of combining optimized targeted therapies could potentially improve outcomes for patients with HER2-positive breast cancer but may also allow de-escalation of treatment in some patients, potentially sparing some from unnecessary treatments, and their related toxicities and costs.

Full text

https://doi.org/10.1177/1758835919833519
https://doi.org/10.1177/1758835919833519
Therapeutic Advances in Medical Oncology
journals.sagepub.com/home/tam 1
Ther Adv Med Oncol
2019, Vol. 11: 1 –16
DOI: 10.1177/
1758835919833519
© The Author(s), 2019.
Article reuse guidelines:
sagepub.com/journals-
permissions
Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License
(http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission
provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
Introduction
A better understanding of tumor biology and
HER2 signaling has led to the development and
approval of new HER2-targeted agents that,
together with the use of continued anti-HER2
therapy beyond progression, have resulted in
unpreceded survival outcomes in patients with
advanced HER2-positive breast cancer.1
The addition of trastuzumab to standard therapy
dramatically improved prognosis for patients with
HER2-positive breast cancer, and became a land-
mark in the treatment of these patients.2,3 The
second anti-HER2 agent that was incorporated
into routine practice of advanced HER2-positive
disease was lapatinib, an oral tyrosine kinase
inhibitor (TKI) that reversibly inhibits HER1 or
epidermal growth factor receptor (EGFR)
and HER2 kinases. The approval of lapatinib was
based on the improvement in progression-free
survival (PFS) found in a phase III trial when
combined with capecitabine versus capecitabine
alone though no improvement in overall survival
(OS) was observed.4 Pertuzumab is a humanized
monoclonal antibody that binds to HER2 on
extracellular domain II, a different domain than
trastuzumab, preventing homo- and heterodimer
formations and blocking one of the most powerful
heterodimers, HER2/HER3, that activates sev-
eral intracellular signaling cascades including cell
proliferation and survival. The addition of pertu-
zumab to a taxane and trastuzumab combination
HER2-positive breast cancer: new
therapeutic frontiers and overcoming
resistance
Sonia Pernas and Sara M. Tolaney
Abstract: The introduction of anti-HER2 therapies to the treatment of patients with HER2-
positive breast cancer has led to dramatic improvements in survival in both early and
advanced settings. Despite this breakthrough, nearly all patients with metastatic HER2-
positive breast cancer eventually progress on anti-HER2 therapy due to de novo or acquired
resistance. A better understanding not only of the underlying mechanisms of HER2 therapy
resistance but of tumor heterogeneity as well as the host and tumor microenvironment is
essential for the development of new strategies to further improve patient outcomes. One
strategy has focused on inhibiting the HER2 signaling pathway more effectively with dual-
blockade approaches and developing improved anti-HER2 therapies like antibody–drug
conjugates, new anti-HER2 antibodies, bispecific antibodies, or novel tyrosine kinase inhibitors
that might replace or be used in addition to some of the current anti-HER2 treatments.
Combinations of anti-HER2 therapy with other agents like immune checkpoint inhibitors,
CDK4/6 inhibitors, and PI3K/AKT/mTOR inhibitors are also being extensively evaluated in
clinical trials. These add-on strategies of combining optimized targeted therapies could
potentially improve outcomes for patients with HER2-positive breast cancer but may also
allow de-escalation of treatment in some patients, potentially sparing some from unnecessary
treatments, and their related toxicities and costs.
Keywords:
breast cancer, drug–antibody conjugates, HER2-positive, new anti-HER2 therapies,
novel combinations, resistance, tyrosine kinase inhibitors
Received: 25 October 2018; revised manuscript accepted: 23 January 2019.
Correspondence to:
Sara M. Tolaney
Department of Medical
Oncology, Dana-Farber
Cancer Institute, 450
Brookline Avenue, Boston,
MA 02215, USA
Sara_Tolaney@DFCI.
HARVARD.EDU
Sonia Pernas
Department of Medical
Oncology, Dana-Farber
Cancer Institute, Boston,
MA, USA; Department of
Medical Oncology-Breast
Cancer Unit, Institut
Catala d’Oncologia (ICO)-
H.U. Bellvitge-IDIBELL,
Barcelona, Spain
833519TAM0010.1177/1758835919833519Therapeutic Advances in Medical OncologyS Pernas and SM Tolaney
review-article20192019
Review

Therapeutic Advances in Medical Oncology 11
2 journals.sagepub.com/home/tam
compared with taxane and trastuzumab therapy
alone as a first-line treatment in advanced HER2-
positive breast cancer resulted in an improvement
not only in PFS but also in OS by almost 16
months, reaching a median survival of nearly 5
years and establishing this regimen as the pre-
ferred regimen in the first-line setting.1 Finally,
trastuzumab emtansine (T-DM1) is an antibody–
drug conjugate (ADC) comprised of trastuzumab
covalently linked to a maytansine derivate (DM1),
a potent antimitotic agent that binds microtu-
bules.5 After selectively binding to HER2, the
conjugate is internalized within endocytic vesicles
and degraded in the lysosomes, releasing the
active payload within the cell. This results in cell
death by mitotic catastrophe.6 T-DM1 signifi-
cantly improved both PFS and OS compared
with lapatinib plus capecitabine as a second-line
treatment7 and as a later line in patients with
advanced HER2-positive breast cancer previously
treated with trastuzumab.8 Based on those results,
T-DM1 is currently the only ADC approved to
treat breast cancer and the standard second-line
therapy for advanced HER2-positive disease. To
date, there is no standard of care treatment for
patients with advanced HER2-positive tumors
following treatment with trastuzumab, pertu-
zumab and T-DM1. Treatment options at this
point include lapatinib plus capecitabine, combi-
nations of trastuzumab with other chemothera-
pies (such as vinorelbine or gemcitabine), or
dual-blockade combinations without chemother-
apy, such as trastuzumab with lapatinib or endo-
crine therapy with either trastuzumab or lapatinib
in patients with hormone receptor (HR)-positive
disease.
Despite the outstanding improvement in survival
with the introduction of anti-HER2 therapies
alone or as dual HER2-blockade in the standard
treatment of advanced disease, most patients ulti-
mately develop progressive disease and die.
Furthermore, up to 40–50% of patients with
advanced HER2-positive breast cancer will
develop brain metastases during their disease
course. Better options for the prevention and
treatment of brain metastases are clearly needed.9
A growing understanding of the underlying mech-
anisms of primary and acquired resistance to anti-
HER2 therapies and compensatory pathways as
well as tumor heterogeneity and the tumor micro-
environment is essential for the development of
novel therapeutic strategies. A substantial num-
ber of novel anti-HER2 treatments are being
investigated extensively in the preclinical and
clinical settings to further improve patient out-
comes. Here, we review the rationale and latest
evidence of those novel treatments and approaches
to overcome resistance in advanced HER2-
positive breast cancer.
Mechanisms of resistance and response
heterogeneity to anti-HER2 therapy
Many potential resistance mechanisms to anti-
HER2 therapy have been described that ultimately
lead to reactivation of the HER2 pathway or its
downstream signaling, through pathway redun-
dancy or stimulation of alternative survival path-
ways.10 Some of these mechanisms include
incomplete blockade of the HER2 receptor that
activates compensatory mechanisms within the
HER family (such as HER3), activation of alterna-
tive receptor tyrosine kinases (RTKs) or other
membrane receptors outside of the HER family
[such as insulin-like growth factor 1 receptor
(IGF-1R)11 and MET12], and alterations in down-
stream signaling pathways, such as hyperactivation
of the PI3K/AKT/mTOR pathway13,14 by reduced
levels of tumor suppressor genes (like PTEN and
INPP4-B), or by activating mutations in PIK3CA
(phosphatidylinositol-4,5 bisphosphate 3-kinase
catalytic subunit).15 Several other biologic features
have been associated with response heterogeneity
to anti-HER2 therapy, including HER2 mRNA or
protein levels,16 tumor intrinsic subtype,17 altera-
tions in the HER2-receptor (such as p95HER2),18
and host and tumor microenvironment compo-
nents, such as tumor infiltrating lymphocytes
(TILs)19 and FCγR polymorphisms.20 In the
CLEOPATRA trial for instance, high HER2 pro-
tein and high HER2 and HER3 mRNA levels were
associated with a significantly better outcome (p <
0.05). In contrast, PIK3CA mutation was identi-
fied as a strong negative prognostic biomarker,
despite deriving benefit from pertuzumab and tras-
tuzumab treatment.21 In the EMILIA trial, a
greater benefit in OS was also observed in patients
treated with T-DM1 and high HER2 mRNA
expression.22 Notably, PIK3CA mutations were
associated with significantly shorter PFS and OS
in patients treated with capecitabine plus lapatinib,
but not in T-DM1 treated patients (median PFS
10.9 vs. 9.8 months; OS, not reached in mutant or
wild type).22 Regarding TILs, an increased quan-
tity of stromal TILs was significantly associated
with improved OS in patients with advanced
HER2-positive breast cancer treated with doc-
etaxel, trastuzumab, and pertuzumab or placebo in
the CLEOPATRA trial.19

S Pernas and SM Tolaney
journals.sagepub.com/home/tam 3
It has also been demonstrated that the cyclin
D1-CDK4 pathway can mediate resistance to
HER2-targeting therapies in vitro and in vivo and
that targeting resistant tumor cells with CDK 4/6
inhibitors re-sensitizes them to anti-HER2 ther-
apy and delays tumor recurrence in HER2-driven
breast cancers in vivo in patient-derived xenograft
tumors.23 As discussed below, trials are currently
underway to evaluate the efficacy of combined
HER2 and CDK4/6 inhibition in HER2-positive
breast cancer.
Substantial preclinical and clinical studies support
the bidirectional cross-talk between HER2 and
estrogen receptor (ER) signaling when both recep-
tors are expressed in breast cancer cells.24 Tumors
that express both ER and HER2 are less sensitive
to endocrine therapy than ER-positive and HER2-
negative tumors, and ER can act as an escape
pathway to HER2 inhibition.25,26 Concurrent
inhibition of ER together with dual anti-HER2
therapy can improve outcomes, as demonstrated
in several trials in early and advanced HER2-
positive breast cancer.27–29
The HER2Δ16 splice variant is a major onco-
genic driver that promotes trastuzumab resist-
ance. Preclinical data suggest trastuzumab-resistant
HER2Δ16 cells are sensitive to the SRC kinase
inhibitor dasatinib and data from a phase I/II
(GEICAM/2010-04) study suggest there may be
a signal for activity when dasatinib is combined
with trastuzumab and paclitaxel in the first-line
treatment for patients with advanced HER2-
positive breast cancer.30,31 In addition, SRC acti-
vation by itself has been associated with
trastuzumab resistance.32
The mechanisms that contribute to T-DM1
resistance are not fully understood. There are
multiple components to consider when identify-
ing mechanisms of resistance for ADCs, such as
the ones related to the antibody, the linker or
the payload. Preclinical studies have shown that
CDK1/cyclin B1 activity is needed for T-DM1
action. Silencing cyclin B1 induces resistance to
T-DM1 while increasing the levels of cyclin B1
in resistant cells partially restores sensitivity.33
Other potential mechanisms of T-DM1 resist-
ance have been proposed including the reduc-
tion of the intracellular DM1 payload due to
upregulation of multidrug resistance proteins
(e.g. MDR1),34 impaired lysosomal proteolytic
activity35 or lysosomal transporter loss (e.g.
SLC46A3).34
Interestingly, molecular imaging seems promising
not only to further our understanding of tumor
heterogeneity in advanced HER2-positive breast
cancer but also to identify patients who will
unlikely benefit from T-DM1.36 In the prospec-
tive ZEPHIR trial, striking levels of inter- and
intrapatient heterogeneity in HER2 expression
were observed, with one-third of patients having
little or no trastuzumab-zirconium uptake
(HER2-Positron emission tomography (PET)/
computed tomography (CT) scan [PET/CT
scan]) across their metastatic sites. Moreover, the
combined use of HER2-PET/CT scan and early
fluorodeoxyglucose-PET/CT scan discriminated
patients treated with T-DM1 with a median time
to treatment failure (TTF) of 2.8 months from
those with 15 months of TTF.36 Despite the
extensive translational research being conducted,
most of the mechanisms of HER2 resistance and
potential biomarkers of response or resistance
either have not been clinically validated, or the
results are contradictory.37 To date, no biomarker
beyond HER2 exists for patient selection for anti-
HER2 therapy in HER2-positive breast cancer.
Of note, the interpretation of mechanisms of
resistance based solely in preclinical models can
be challenging due to tumor heterogeneity, the
complex nature of drug resistance and compensa-
tory pathways, and the use of different tumor cell
lines. Moreover, multiple mechanisms of resist-
ance may coexist in the same cell.
Novel strategies to overcome resistance to
HER2-targeted therapy
Replacement of current anti-HER2 therapies
for improved anti-HER2 drugs
ADCs. ADCs are a therapeutic class that provide
wider therapeutic window by more efficient and
specific drug delivery. ADCs exploit target selectiv-
ity of monoclonal antibodies (MAbs) to deliver
cytotoxic drugs to antigen-expressing cells to
improve tumor selectivity and reduce damage to
normal cells.38 The success observed with the first-
in-class T-DM1 has led to a rapid and extensive
development of new ADCs. Table 1 lists several
anti-HER2 ADCs in clinical development.7,39–41
Trastuzumab deruxtecan (DS-8201, Daiichi
Sankyo, Inc.) is an ADC comprising trastuzumab,
a cleavable drug linker, and a topoisomerase I pay-
load that has a high drug to antibody ratio (7–8).
In preclinical studies, DS-8201a showed a broader
anti-tumor activity than T-DM1, including

Therapeutic Advances in Medical Oncology 11
4 journals.sagepub.com/home/tam
efficacy against low HER2-expressing tumors. In
an updated subgroup analysis from a phase I study
with multiple expansion cohorts,42 DS-8201a
demonstrated an overall response rate (ORR) of
54.5% (54/99 patients) in patients with HER2-
positive metastatic breast cancer pretreated with
T-DM1 (as well as trastuzumab and pertuzumab
in the majority of cases). Median duration of
response and median PFS had not yet been
reached.39 Interestingly, in patients with HER2
low-expressing metastatic breast cancer [defined
as immunohistochemistry (IHC) 1+ or 2+ and in
situ hybridization (ISH)-negative], the ORR was
50% (17/34 patients). Trastuzumab deruxtecan
was relatively well tolerated; common adverse
events (AEs) included nausea (73.5%; 3.5% grade
⩾3), decreased appetite (59.5%; 4.5% grade ⩾3)
and vomiting (39.5%; 1.5% grade ⩾3). In August
2017, trastuzumab deruxtecan received a United
States Food and Drug Administration (US FDA)
Breakthrough Therapy designation for the treat-
ment of patients with HER2-positive, locally
advanced, or metastatic breast cancer who have
been treated with trastuzumab and pertuzumab
and, have progressed to T-DM1. DS-8201a is
being evaluated in numerous trials, including two
phase III studies: the DESTINY-Breast02
(ClinicalTrials.gov identifier: NCT03523585) is
evaluating DS-8201a versus investigator’s choice
(capecitabine with trastuzumab or lapatinib) for
patients with HER2-positive, unresectable or met-
astatic breast cancer pretreated with prior T-DM1,
and the DESTINY-Breast03 (ClinicalTrials.gov
identifier: NCT03529110) is a randomized, open-
label study of DS-8201a versus T-DM1 for patients
with HER2-positive, metastatic breast cancer pre-
viously treated with trastuzumab and taxane.
SYD985 (Synthon Biopharmaceuticals BV) is a
third generation ADC based on trastuzumab and
a ‘cleavable’ linker – duocarmycin payload, which
is present as an inactive prodrug (valine-citrulline-
seco – DUocarmycin – hydroxyBenzamide –
Azaindole -vc-seco-DUBA). Proteases present in
endosomes result in the linker cleavage in SYD985
and the release of the membrane-permeable active
toxin. It then binds to the minor groove of DNA,
causing irreversible DNA alkylation. This results in
cell death in both dividing and nondividing cells in
the tumor microenvironment but also in neighbor-
ing tumor cells due to the bystander effect. SYD985
has shown impressive preclinical results in breast
cancer (even more potent than T-DM1) and
encouraging clinical activity. Results from a dose-
escalation phase I trial showed encouraging activity
in heavily pretreated patients43,44 and led the US
Table 1. HER2-directed ADCs in clinical development.
Agent Anti-HER2 MAb/payload
(target)
Drug to
antibody
ratio
Linker drug Phase of
development
ORR in
HER2-
positive
ORR in
HER2 low
(IHC1+/2+/ISH-)
Trastuzumab-
DM1 (T-DM1)7
Trastuzumab/
DM1 (anti-tubulin)
3.5 Noncleavable US FDA
Approved
43.6% ———
Trastuzumab
duruxtecan
(DS-8201a)39
Trastuzumab/ exatecan
derivative (topoisomerase I
inhibitor)
8 Cleavable II/III
NCT03248492
NCT03529110
NCT03523585
54.5% 50%
SYD98540 Duocarmycin derivative
(alkylating agent)
2.8 Cleavable III
NCT03262935
33% HR + 27%
HR − 40%
XMT-152241 XMT-1519/ monomethyl
auristatin (anti-tubulin)
12 Cleavable I
NCT02952729
unknown unknown
ARX788 Anti-HER2 MAb/ auristatin
analog 269 (AS269) (anti-
tubulin)
1.9 Non-
cleavable
I
NCT03255070
unknown unknown
DHES0815A Trastuzumab/ alkylator 2 Cleavable I
NCT03451162
unknown unknown
ADC, antibody–drug conjugate; HR+, hormone receptor positive; HR−, hormone receptor negative; IHC, immunohistochemistry; ISH, In Situ
Hybridization; MAb, monoclonal antibody; NCT, ClinicalTrials.gov identifier; ORR, overall response rate; US FDA, United States Food and Drug
Administration.

S Pernas and SM Tolaney
journals.sagepub.com/home/tam 5
FDA to grant the agent Fast Track designation in
January 2018. Results from the expansion cohorts
recently reported an ORR of 33% and a median
PFS of 9.4 months40 in a cohort of patients with
advanced HER2-positive disease, previously
treated with a median of six lines of therapy for
metastatic disease (n = 50). Interestingly, SYD985
was also effective in patients with HER2-low meta-
static breast cancer, with an ORR of 27% and 40%
in the HR-positive, HER2-low, and in the
HR-negative, HER2-low cohorts, respectively.
Enrollment was based on central HER2 analysis by
IHC and ISH and HER2 low was defined as
IHC 1+/2+ and fluorescence in situ hybridization
(FISH) negative. Most of the adverse drug reac-
tions were mild or moderate, with ocular toxicity
and fatigue being most frequently reported. A
phase III pivotal study (TULIP) is ongoing
(ClinicalTrials.gov identifier: NCT03262935)
which compares SYD985 with the treatment of the
physician’s choice in patients with HER2-positive
metastatic breast cancer in the third line and
beyond.
MEDI4276 (Medimmune) is a bispecific ADC
that targets two different domains of the HER2
receptor, resulting in crosslinking followed by
internalization of the complex, cleavage of the
linker, and release of the payload. MEDI-4276
comprises the single-chain variable fragment
(scFv) of trastuzumab, which binds to domain IV
of HER2, and the anti-HER2 Mab 39S, which
binds to domain II of HER2. The bispecific anti-
body is then conjugated, via a cleavable linker, to
the cytotoxic anti-microtubule agent tubulysin.
Results from the phase I study (ClinicalTrials.
gov identifier: NCT02576548) in patients with
advanced HER2-positive breast or gastric can-
cer45 showed clinical activity, but also considera-
ble toxicity with 28% of patients (12/43) having
drug-related AEs of grade 3–4 severity; most
common were grade 3 elevated aspartate
transaminase (AST; 19%) and grade 3 elevated
alanine transaminase (ALT; 12%). Given the
challenges with toxicity, clinical testing with this
agent has been discontinued for breast and gastric
cancers.
ADCT-502 (ADC Therapeutics) is also a novel
pyrrolobenzodiazepine (PBD)-based ADC that
targets HER2-expressing solid tumors, including
breast cancers.46 However, based on data from
the phase I study (ClinicalTrials.gov identifier:
NCT03125200) that showed that ADCT-502
did not meet the necessary efficacy and safety
profile required for patient benefit, clinical testing
of this drug was recently halted.
In preclinical models, another bivalent bipara-
topic HER2-targeting ADC that targets two non-
overlapping epitopes on HER2 and is conjugated
with microtubule inhibitor demonstrated supe-
rior activity than T-DM1 in breast cancer models
and was able to overcome T-DM1 resistance.
This biparatopic ADC also demonstrated
bystander killing activity.47
In contrast with T-DM1, most of these new
ADCs have a cleavable drug linker (see Table 1)
that mediates the bystander killing effect. This is
the passive diffusion of the free cytotoxin from
target-positive cancer cells into the tumor micro-
environment, killing neighboring cancer cells that
are insensitive to the ADC because of the lack or
limited target expression. This desired feature of
those novel HER2-targeting ADCs, given that
heterogeneity is frequent in HER2-positive breast
cancer, may be however, a double-edged sword
with an increased toxicity.
Novel anti-HER2 antibodies. Margetuximab
(MGAH22, MacroGenics) is an Fc-optimized
chimeric monoclonal antibody that binds to the
same epitope as trastuzumab. Margetuximab has
enhanced Fcγ receptor-binding properties with
an increased affinity for CD16A polymorphisms
and a decreased affinity for FcγRIIB (CD16B),
an inhibitory receptor, which allows it to bind
more tightly to effector cells and increase anti-
body-dependent cell-mediated cytotoxicity
(ADCC); it also preserves the antiproliferative
properties of trastuzumab.48 A first-in-human
phase I study demonstrated promising single-
agent activity of margetuximab in heavily pre-
treated patients with HER2-positive solid tumors.
Among 24 patients with metastatic breast cancer,
the ORR was 17% and 3 out of the 4 responders
remained on treatment for 39–54 months.49 The
most common AEs were grade 1–2 constitutional
symptoms and no cardiotoxicity was observed.
Margetuximab is currently being evaluated in the
randomized phase III SOPHIA trial (ClinicalTri-
als.gov identifier: NCT02492711) that compares
margetuximab plus chemotherapy with trastu-
zumab plus chemotherapy as a third-line therapy
in patients with HER2-positive breast cancer after
prior treatment with trastuzumab, pertuzumab,
and T-DM1. The US FDA has granted Fast Track
designation for the investigation of margetuximab
for the treatment of patients with metastatic or

Therapeutic Advances in Medical Oncology 11
6 journals.sagepub.com/home/tam
locally advanced HER-positive breast cancer pre-
viously treated with anti-HER2-targeted therapy.
Bispecific antibodies. Bispecific antibodies
(BsAbs) combine the functionality of two MAbs
that target two different targets or epitopes, either
in the same or in different receptors. BsAbs can
interfere with two or more RTK signaling path-
ways, by inactivating either the RTKs or their
ligand. Several are currently being studied in
patients with advanced HER2-positive disease.
MCLA-128 (Merus) is a full-length immuno-
globulin (Ig)G1 BsAb with enhanced ADCC
activity targeting both HER2 and HER3.
Preliminary results from a phase I/II study in
solid tumors (ClinicalTrials.gov identifier: NCT
02912949) that include eight patients with heav-
ily pretreated (median of five prior lines in the
metastatic setting) HER2-positive metastatic
breast cancer showed an encouraging clinical
benefit rate of 70%.50 A phase II study
(ClinicalTrials.gov identifier: NCT03321981) is
ongoing to evaluate the activity of MCLA-128
in two metastatic breast cancer populations: in
HER2-positive/amplified patients (cohort 1) in
combination with trastuzumab ± chemotherapy,
and in ER-positive/low-HER2 expression (cohort
2) in which MCLA-128 is administered in combi-
nation with endocrine therapy.
ZW25 (Zymeworks Inc.) is a novel Azymetric
bispecific antibody biparatopic that binds to two
different epitopes on the extracellular domain of
HER2 ECD2 and ECD4. This results in increased
tumor cell binding, blockade of ligand-dependent
and independent growth, and improved receptor
internalization and downregulation relative to tras-
tuzumab. Also, in vivo studies demonstrate anti-
tumor activity in HER2-low to high expressing
models. Results from the phase I study
(ClinicalTrials.gov identifier: NCT02892123)
evaluating the safety and efficacy of single-agent
ZW25 in separate expansion cohorts, including
HER2-high (IHC 3+ or 2+/FISH+) breast, gas-
tric/esophageal, and other cancers, demonstrated a
promising anti-tumor activity and no dose-limiting
toxicities were observed. In patients with heavily
pretreated HER2-expressing breast cancers that
had progressed to a median of five HER2-targeted
regimens for metastatic disease, a partial response
rate of 33% (6/18 patients) was observed with a dis-
ease control rate of 50%. The most common AEs
were diarrhea and infusion reaction, all grade 1 or
2, with no treatment-related discontinuations.51
T-cell bispecific antibodies (TCBs) are engi-
neered molecules that include, within a single
entity, binding sites to the invariant CD3 chain of
the T-cell receptor (TCR) and to tumor-associ-
ated or tumor-specific antigens. Binding to the
tumor antigen results in crosslinking of the TCR
and subsequent lymphocyte activation and tumor
cell killing. However, on-target off-tumor effects
caused by redirected lymphocytes can result in
severe toxicities. Several are currently in clinical
development:
GBR1302 (Glenmark Pharmaceuticals) is a
HER2xCD3 bsAb developed to direct T-cells to
HER2-expressing tumor cells. Preclinically,
GBR1302 has demonstrated potent killing of
HER2-positive human cancer cells, as well as
growth suppression of the trastuzumab-resistant
cell line JIMT-1. In contrast, the GBR1302 con-
centration required to kill primary cardiomyo-
cytes with normal HER2 levels was up to 1000
times greater than the concentration needed to
kill HER2 3+ tumor cell lines. A first-in-human
phase I study of single-agent GBR1302 in pro-
gressive HER2-positive solid tumors is ongoing
(ClinicalTrials.gov identifier: NCT02829372).
Preliminary biomarker and pharmacodynamic
data from this study were recently presented,
demonstrating modulation of peripheral T-cell
populations and cytokines.52
PRS-343 (Pieris Pharmaceuticals, Inc.) is a mon-
oclonal antibody-bispecific protein targeting
HER2 and the immune receptor CD137. CD137
is a key costimulatory immunoreceptor and a
member of the tumor necrosis factor receptor
superfamily. PRS-343 is designed to promote
CD137 clustering by bridging CD137-positive
T-cells with HER2-positive tumor cells, thereby
providing a potent costimulatory signal to tumor
antigen-specific T-cells that has demonstrated
tumor inhibition and TIL expansion in a human-
ized mouse model.53 The two clinical studies
evaluating PRS-343 in HER2-positive solid
tumors are ongoing, either as a single-drug agent
(ClinicalTrials.gov identifier: NCT03330561) or
in combination with atezolizumab (ClinicalTrials.
gov identifier: NCT03650348).
Expression of the tumor-specific antigen
p95HER2, a truncated form of HER2, occurs in
about 40% of HER2-positive tumors. Rius Ruiz
and colleagues have developed a TCB against
p95HER2 (p95HER2-TCB) that has a potent
anti-tumor effect on breast tumors expressing

S Pernas and SM Tolaney
journals.sagepub.com/home/tam 7
p95HER2, both in vitro and in vivo.54 In contrast
with HER2, p95HER2 is not expressed in nor-
mal tissues, therefore, it has no effect on nontu-
mor cells that do not overexpress HER2. Those
findings support further investigation with this
compound.
Novel TKIs. TKIs are orally bioavailable small
molecules developed to further block the HER
receptor family, acting on the intracellular
domain. Those HER-directed TKIs have a lower
molecular weight compared with MAbs, allowing
them a more efficacious penetration through the
blood–brain barrier and therefore, theoretically
may be more effective for the treatment of HER2
brain metastases. Lapatinib was the first TKI
approved in HER2-positive advanced breast can-
cer (and to date, remains the only one) based on
the results described above. Dual blockade with
lapatinib plus trastuzumab without chemother-
apy also demonstrated benefit in OS in heavily
pretreated patients with advanced disease, when
compared with lapatinib alone.55 Initial results
with these molecules, however, have not been the
ones initially expected, even in the treatment of
brain metastases.56,57As a first-line therapy, lapa-
tinib was found to be inferior to trastuzumab
when combined with paclitaxel.58 In the same
way, afatinib was found to be not as effective as
trastuzumab and less tolerated when each was
combined with vinorelbine in a phase III trial
(LUX-Breast1 study).59 No difference was
detected between lapatinib-capecitabine and
trastuzumab-capecitabine for the incidence of
brain metastases in the phase III CEREBEL
(EGF111438) study.56 In the phase II LUX-
Breast3 trial, patients with HER2-positive breast
cancer and progressive brain metastasis previ-
ously treatment with trastuzumab, lapatinib or
both, were randomized to afatinib alone, afatinib
plus vinorelbine or the investigator’s choice of
treatment. Similarly, afatinib-containing regimens
not only did not show better activity than investi-
gator-selected treatments but also seemed to be
less tolerated. No further development of afatinib
for HER2-positive breast cancer is currently
planned. There are, however, several novel TKIs
in clinical development (Table 2).60–66
Neratinib is an irreversible pan-HER TKI that has
been recently approved as an extended adjuvant
therapy in early HER2-positive breast cancer based
on the results of the phase III ExteNET study.67 In
previously untreated patients with HER2-positive
advanced breast cancer, neratinib-paclitaxel was
not superior to trastuzumab-paclitaxel in terms of
PFS in the randomized phase II NEfERT-T trial
that included 479 women.68 Median PFS was
12.9 months in both arms [hazard ratio, 1.02;
95% confidence interval (CI), 0.81–1.27; p =
0.89]. However, the incidence of central nervous
system (CNS) recurrences was significantly lower
(relative risk, 0.48; 95% CI, 0.29–0.79; p = 0.002)
and time to CNS metastases significantly delayed
with neratinib-paclitaxel (hazard ratio, 0.45; 95%
CI, 0.26–0.78; p = 0.004). Diarrhea and gastroin-
testinal toxicity (i.e. nausea, vomiting) were more
common with neratinib-paclitaxel (30.4% versus
3.8% of diarrhea grade 3); however, primary
prophylaxis for diarrhea was not mandatory in this
trial. In patients with HER2-positive breast cancer
brain metastases, the combination of neratinib
and capecitabine demonstrated a reduction of
CNS lesions in 49% of patients in the phase II
trial TBCRC 022.60 This regimen has now been
endorsed by the National Comprehensive Cancer
Network for the treatment of HER2-positive brain
metastases.69 The phase III NALA study (Clinical
Trials.gov identifier: NCT01808573) is directly
comparing the combination of neratinib plus
capecitabine to lapatinib plus capecitabine in
patients with HER2-positive metastatic breast
cancer who have received at least two prior HER2-
directed regimens in the metastatic setting. This
study has already completed recruitment and it
will provide valuable data on the real efficacy of
lapatinib and neratinib after the current standard
treatments of pertuzumab and T-DM1.
Tucatinib (ONT-380) is an oral HER2-
selective small molecule TKI with nanomolar
potency and is approximately1000-fold more
potent for HER2 than EGFR. Because of its
selectivity for HER2, there are fewer EGFR-
related toxicities, such as rash and diarrhea,
which are common with many of the other anti-
HER TKIs. In a phase Ib study, in which
tucatinib was combined with capecitabine or
trastuzumab in heavily pretreated patients with
HER2-positive metastatic breast cancer (includ-
ing patients with brain metastases), the triple
combination demonstrated an ORR of 61% (in
14 patients out of 23 with measurable disease)
and a median duration of response of 10 months
(95% CI: 2.8–19.3). In patients with measurable
brain metastases at baseline, an encouraging
ORR of 42% (5/12) in the brain was observed.62
Median PFS and median duration of response
were 7.8 months, and 10 months, respectively.
In June 2017, tucatinib was granted US FDA

Therapeutic Advances in Medical Oncology 11
8 journals.sagepub.com/home/tam
Orphan Drug status for HER2-positive patients
with brain metastases. An ongoing phase II trial,
HER2CLIMB (ClinicalTrials.gov identifier:
NCT02614794), is randomizing patients with
HER2-positive breast cancer with or without
brain metastases to capecitabine and trastu-
zumab with or without tucatinib. The combina-
tion of tucatinib and T-DM1 was evaluated in
another phase Ib study (ClinicalTrials.gov iden-
tifier: NCT01983501), showing promising
activity in patients with HER2-positive meta-
static breast cancer who had undergone a median
of two prior HER2 therapies. ORR was 48% and
the median PFS of 8.2 months (95% CI, 4.8–
10.3 months). Among the 30 patients with brain
metastases included in this study, the median
PFS was 6.7 months (95% CI, 4.1–10.2 months)
and the brain-specific ORR among patients with
measurable disease was 36% (including 2
patients with complete response).63 Importantly,
the combination of tucatinib with T-DM1
appeared to have an acceptable toxicity, with
most AEs attributable to T-DM1 and consistent
with those observed in other studies that used
T-DM1 as a single agent.
Pyrotinib is a novel irreversible pan-HER TKI
that has demonstrated promising activity and
acceptable tolerability in a phase II trial in patients
with advanced HER2-positive breast cancer
treated with at least two previous lines of ther-
apy.65,70 Patients were randomized to receive
pyrotinib plus capecitabine or lapatinib plus
capecitabine. ORR was 78.5% in the pyrotinib/
capecitabine arm and 57.1% in the capecitabine/
lapatinib arm, with a median PFS of 18 months
and 7 months, respectively (hazard ratio = 0.36; p
< 0.001). In contrast, pyrotinib was associated
with higher rates of AEs, which included hand-foot
syndrome (25 versus 21%), diarrhea (15 versus 5%)
and neutropenia (9 versus 3%). Biomarker analyses
suggest that PIK3CA and TP53 mutations in
Table 2. HER2-directed TKIs in clinical development.
Agent Target Reported results of
efficacy in HER2-positive
advanced disease
CNS ORR
(monotherapy)
CNS ORR in
combination with
capecitabine
Phase of
development
Neratinib60,61 Irreversible
pan-HER
Single-agent
ORR 56% (phase II)
8% 49% (phase II) US FDA approved
only in the adjuvant
setting
III (metastatic)
NALA-NCT01808573
Tucatinib 62–64 Selectively
inhibits HER2
relative to EGFR
In combination with
capecitabine and
trastuzumab:
ORR 61%
PFS of 7.8m
In combination with
T-DM1:
ORR 48%
PFS 8.2 m
(phase Ib)
5–9%
(+trastuzumab)
42%
(+trastuzumab)
II
HER2CLIMB-
NCT02614794
Pyrotinib65 Irreversible
pan-HER
Single-agent ORR 50%,
CBR 61%, PFS 35.4 w
(phase I)
In combination with
capecitabine ORR 78.5%
PFS 18 m (phase II)
NA NA III
NCT003080805
Poziotinib66 Irreversible
pan-HER
Single-agent
DCR 75%
PFS 4 m (phase II)
NA NA II
CBR, clinical benefit rate; CNS, central nervous system; DCR, disease control rate; EGFR, epidermal growth factor receptor; m, months; NA, not
applicable; NCT, ClinicalTrials.gov identifier; ORR, overall response rate; PFS, progression-free survival; TKI, tyrosine kinase inhibitor; US FDA,
United States Food and Drug Administration; w, weeks.

S Pernas and SM Tolaney
journals.sagepub.com/home/tam 9
circulating tumor DNA rather than in archival
tumor samples may predict response to pyro-
tinib.65,70 An ongoing phase III trial (ClinicalTrials.
gov identifier: NCT03080805) is comparing
pyrotinib plus capecitabine versus lapatinib plus
capecitabine in patients with HER2-positive
breast cancer previously treated with trastuzumab
and taxane.
Poziotinib is also an oral pan-HER kinase show-
ing potent activity through irreversible inhibition
of these kinases. Results from a single-arm, phase
II trial (ClinicalTrials.gov identifier: NCT0241
8689) evaluating the efficacy and safety of pozio-
tinib as monotherapy in heavily pretreated
patients with HER2-positive metastatic breast
cancer showed a disease control rate of 75.5%
(77/102), including 20 patients with confirmed
partial response and a median PFS of 4 months
(95% CI, 2.9–4.4 months). The most common
AEs were diarrhea and stomatitis (being grade ⩾3
15% and 26%, respectively).66
Combinations of anti-HER2 agents with other
drugs
Immunotherapy. Preclinical and clinical data
suggest that HER2-positive breast cancer is
immunogenic.71 In contrast with luminal tumors,
HER2-positive tumors have a higher mutational
burden, and harbor higher numbers of TILs and
programmed cell death protein 1 ligand (PD-L1)
positivity.72 In addition, mechanisms of action of
anti-HER2 MAbs include not only ADCC but
also the generation of adaptive immunity.73
Together, these data support the rationale of
combining anti-HER2 therapies with immune
checkpoint blockade (anti-PD-1 or anti-PD-L1
agents). Results from the JAVELIN phase I
study,74 however, were disappointing and no
responses were seen with single-agent avelumab
in the subgroup of patients with advanced pre-
treated HER2-positive breast cancer. The first
study to evaluate the addition of pembrolizumab
to trastuzumab in patients with trastuzumab-
resistant HER2-positive breast cancer was the
PANACEA (IBCSG 45-13/BIG 4-13/KEY-
NOTE-014) study. This phase Ib/II study dem-
onstrated that the combination was associated
with an ORR of 15.2% and a median of PFS and
OS of 2.7 months and 16 months, respectively, in
PD-L1 positive patients.75 However, these data
also highlight the limitations of this combination,
as no responses were seen in the PD-L1 negative
cohort and most of the PD-L1 positive patients
who initially responded eventually developed
resistant disease. Several randomized studies are
ongoing to further evaluate the role of immune
checkpoints inhibitors in HER2-positive meta-
static breast cancer. Results from the phase II
KATE2 trial (ClinicalTrials.gov identifier:
NCT02924883) assessing the efficacy and safety
of T-DM1 in combination with atezolizumab or
placebo in pretreated patients with HER2-posi-
tive advanced breast cancer were recently pre-
sented.76 In this trial, the addition of atezolizumab
to T-DM1 did not demonstrate a significant PFS
benefit in the ITT population (8.2 versus 6.8
months; hazard ratio 0.82; 95% CI 0.55–1.23).
However, an exploratory endpoint demonstrated
promising PFS in the PD-L1 positive (PD-L1
IHC expression >1%) and stromal TIL sub-
groups.76 The phase III NRG-BR004 trial
(ClinicalTrials.gov identifier: NCT03199885) is
investigating the combination of paclitaxel, trastu-
zumab, pertuzumab with or without atezolizumab
as a first-line treatment. In addition, trastuzumab
deruxtecan (DS-8201a) is also being evaluated in
combination with nivolumab in a phase Ib study
(ClinicalTrials.gov identifier: NCT03523572) in
patients with advanced breast (with high and low
HER2 expression) and urothelial cancers.
Immunotherapy with HER2-targeting vaccines
are also being currently investigated in clinical tri-
als. The HER2 vaccine NeuVaxTM (Nelipepimut-S
or E75 peptide combined with granulocyte mac-
rophage-colony stimulating factor)77 is being
evaluated in two phase II clinical trials in combi-
nation with trastuzumab in breast cancer patients
with HER2–3+ (ClinicalTrials.gov identifier:
NCT02297698) and in HER2–1+/2+
(ClinicalTrials.gov identifier: NCT02297698),
respectively. ETBX-021 is another HER2-
targeting vaccine comprising an Ad5 vector and a
modified HER2 gene insert that is being evalu-
ated in a phase I clinical trial with locally advanced
or metastatic HER2-low-expressing (IHC
1+/2+) breast cancer.
CDK4/6 inhibitors
There is a strong rationale to evaluate CDK4/6
inhibitors in HER2-positive breast cancer.
Activity of CDK4/6 is regulated by several mech-
anisms that include mitogenic signaling pathways
(such as HER2) by increasing CCND1 expression
or increasing cyclin D1 protein stability.23,78 In
addition, mouse models have shown that cyclin
D1/CDK4 plays an important role in the

Therapeutic Advances in Medical Oncology 11
10 journals.sagepub.com/home/tam
formation and growth of breast tumors driven by
ERBB2.23,79,80 Preclinical studies demonstrate a
clear synergy between anti-HER2 therapy and
CDK4/6 inhibitors,81,82 and that CDK4/6 inhibi-
tion can specifically overcome acquired resistance
to anti-HER2 therapy.23 Moreover, CDK4/6
inhibition delayed recurrence of HER2-driven
breast cancers in mouse models.23 Early clinical
data also support the use of CDK4/6 inhibitors in
HER2-driven breast cancers, especially in the
subset of patients with ER-positive, HER2-
positive disease.83,84 Currently, there are many
clinical trials evaluating the role of CDK4/6
inhibitors in advanced HER2-positive breast can-
cer, including two global, randomized trials: the
MonarcHER study (ClinicalTrials.gov identifier:
NCT02675231), which evaluates the role of abe-
maciclib with trastuzumab in pretreated meta-
static disease, and the PATINA study
(ClinicalTrials.gov identifier: NCT02947685),
which explores the benefits of adding palbociclib
to trastuzumab, pertuzumab and an aromatase
inhibitor after an induction of standard first-line
therapy. Initial reports from the phase II SOLTI-
1303 PATRICIA trial (ClinicalTrials.gov identi-
fier: NCT02448420), which evaluates the
combination of palbociclib, trastuzumab ± letro-
zole in heavily pretreated (up to 2–4 prior lines in
the metastatic setting) patients with HER2-
positive breast cancer, suggest that the combina-
tion is active particularly in the luminal subtype
by PAM50, with a better PFS compared with
nonluminal (12.4 versus 4.1 months, hazard ratio
0.30, 95% CI;0.11–0.86 p = 0.025).85,86 Thus,
identification of the nonluminal subtypes by
PAM50 might help to identify those patients who
might not derive a great benefit from this treat-
ment strategy, regardless of HR status. Other
nonrandomized phase Ib/II studies in advanced
HER2-positive breast cancer are ongoing, includ-
ing those combining palbociclib and T-DM1
(ClinicalTrials.gov identifier: NCT01976169);
palbociclib, trastuzumab, pertuzumab and anas-
trozole (ClinicalTrials.gov identifier: NCT033
04080); ribociclib with trastuzumab or T-DM1
(ClinicalTrials.gov identifier: NCT02657343);
and palbociclib with tucatinib and letrozole
(ClinicalTrials.gov identifier: NCT03054363).
The JPBO trial (ClinicalTrials.gov identifier:
NCT02308020) is testing abemaciclib as a single
agent in patients with brain metastasis secondary
to HR-positive breast cancer, non-small cell lung
cancer, or melanoma, including a cohort of
patients with HR+, HER2-positive breast cancer.
However, within the cohort of HR-positive,
HER2-positive patients, there were no objective
responses seen at the time of the interim analysis,
and the cohort was not able to move to the second
stage.87
PI3K/Akt/mTOR inhibitors
As mentioned previously, dysregulations in the
PI3K/AKT/mTOR pathway seem to play an
important role in trastuzumab resistance. PI3K
inhibition results in an enhanced HER2 signaling
in HER2-overexpressing breast cancer, especially
in an increased expression of HER2 and HER3.88
Targeting both pathways could prevent the devel-
opment of resistance. However, results of two
phase III trials evaluating the role of everolimus,
an mTOR inhibitor, in combination with either
trastuzumab plus paclitaxel as first-line treatment
(BOLERO-1)89 or in combination with trastu-
zumab plus vinorelbine in trastuzumab-resistant
(BOLERO-3)90 advanced HER2-positive breast
cancer were quite disappointing with a significant
increase in toxicity. Although in the PFS sub-
group analysis of both studies, the benefit of add-
ing everolimus to the standard therapy seemed
greater in patients who had HR-negative dis-
ease.89,90 Moreover, the combined biomarker
analyses of the BOLERO-1 and BOLERO-3 tri-
als demonstrate an improved PFS in patients har-
boring PIK3CA mutations or PTEN loss when
treated with everolimus.91 Current efforts have
focused on evaluating α-specific PI3K inhibitors,
the isoform encoded by the PIK3CA gene, such
as alpelisib (BYL719) in combination with anti-
HER2 therapies. Alpelisib was combined with
LJM716 (a HER3 inhibitor) and trastuzumab in
patients with HER2-positive advanced breast
cancer with a PIK3CA mutation and prior pertu-
zumab and T-DM1 (ClinicalTrials.gov identifier:
NCT02167854). Preliminary results of this com-
bination showed a high toxicity profile including
diarrhea, hyperglycemia, hypokalemia, mucositis
and transaminitis, and limited activity (best
response was stable disease (SD) in five of six
evaluable patients).92 A phase I study of alpelisib
and T-DM1 in heavily pretreated HER2-positive
patients showed significant activity, with an ORR
of 43% and median PFS of 8.1 months (95% CI
3.9–10.8). Furthermore, activity was observed in
T-DM1-resistant patients with an ORR and clini-
cal benefit rate of 30% and 60%, respectively,
and median PFS of 6.3 months (95% CI 1.6–
10.5). The dose-limiting toxicity (DLT) was a
maculopapular rash. Most frequently reported
toxicities included fatigue, rash, gastrointestinal

S Pernas and SM Tolaney
journals.sagepub.com/home/tam 11
side effects, thrombocytopenia, anemia, elevated
liver enzymes, and hyperglycemia.93 Taselisib
(GDC-0032), a β-sparing PI3K inhibitor, is
being evaluated in an ongoing phase Ib dose-
escalation trial in combination with different anti-
HER2 therapies in patients with advanced
HER2-positive breast cancer (ClinicalTrials.gov
identifier: NCT02390427). Copanlisib is a pan-
class I PI3K inhibitor with particular activity
against PI3Kα that is being evaluated in combi-
nation with trastuzumab. Results from a phase Ib
(ClinicalTrials.gov identifier: NCT02705859;
PantHER trial) in pretreated metastatic HER2-
positive breast cancer (with a median of four prior
lines) showed no DLTs but grade 3 hypertension
was reported in 33% (n = 4) of patients. The best
response was stable disease in 9/12 patients and 6
patients continued treatment ⩾16 weeks. The
PIK3CA mutation was present in 6/12 (50%) of
tumors.94 MEN1611 is a potent, selective, orally
available class I PI3k inhibitor showing high activ-
ity against p110α mutant isoforms, and minimal
inhibition of the δ isoform that is going to be eval-
uated in a phase Ib study in combination with
trastuzumab with or without fulvestrant (B-PRE
CISE-01 study). The study will enroll patients
with PIK3CA-mutated, HER2-positive, advan-
ced breast cancer pretreated with anti-HER2
based therapy.
Conclusion
Although the use of anti-HER2-targeted therapy
has dramatically changed the outlook for patients
with advanced HER2-positive breast cancer,
almost all patients ultimately experience disease
progression. Most of them advance to the point
where no approved HER2-targeting treatment
controls their disease. This might change in the
near future as many promising anti-HER2 thera-
pies are being developed in this setting. The newer
HER2 ADCs such as DS-8201a and SYD985
may replace T-DM1 in the second-line treatment
space or may be utilized in the third-line and
beyond setting after progression on T-DM1.
Moreover, these newer ADCs, as opposed to
T-DM1, are active not only in patients with
HER2-positive breast cancer but also in patients
with HER2 low-expressing tumors (IHC1+ or
2+/FISH) in whom to date, there are no current
anti-HER2 therapies specifically indicated. This
desired feature of its bystander effect may be par-
ticularly useful in heterogeneous cancer cell popu-
lations among HER2-positive disease. On the
other hand, the new TKIs, such as neratinib or
tucatinib, are being explored with capecitabine
and may demonstrate activity in the third-line
setting, though may be associated with increased
toxicity relative to trastuzumab. And finally, mar-
getuximab plus chemotherapy is being compared
with trastuzumab plus chemotherapy also in the
third-line setting in a registrational study.
These strategies of combining optimized HER2-
targeted therapies could potentially improve out-
comes for HER2-positive breast cancer patients
but may also allow de-escalation of treatment in
selected patients, potentially sparing some from
unnecessary treatments and their related toxicities.
Hence, potential biomarkers of response or resist-
ance such as intrinsic subtypes, might be helpful to
better select patients for these strategies. Moreover,
specific strategies for HR-positive, HER2-positive
breast cancer are needed, such as the current stud-
ies exploring the use of CDK 4/6 inhibitors in the
first and later line setting with anti-HER2 therapy
and specific trials allowing patients with progres-
sive brain metastases (who are generally excluded
from clinical trials) should be enhanced. The
underlying mechanisms of resistance to anti-HER2
therapies and compensatory pathways are indeed
complex and a wide range of mechanisms of resist-
ance may coexist in the same cell. Therefore, com-
bining clinical strategies and strengthening
international collaborations in the translational
setting might be needed to validate predictive bio-
markers beyond HER2, which will help us to bet-
ter select patients and improve their outcomes.
Acknowledgements
We thank Kaitlyn T. Bifolck, BA, for her editorial
support. Fundación AECC (Asociación Española
Contra el Cáncer) and the Spanish Society of
Medical Oncology (SEOM) grants (to S. Pernas)
Funding
This manuscript did not receive specific funding.
Conflict of interest statement
S. Pernas has received honoraria for talks and
travel grants from Roche, outside of the submit-
ted work and has served on advisory boards for
Polyphor. S. Tolaney receives institutional
research funding from Eli Lilly, Pfizer, Novartis,
Exelixis, Eisai, Merck, Bristol Meyers Squibb,
AstraZeneca, Nektar, Nanostring, Cyclacel, and
Immunomedics. S. Tolaney has served on advi-
sory boards or as a consultant for Eli Lilly, Pfizer,
Novartis, Eisai, Merck, AstraZeneca, Nektar,
Nanostring, Immunomedics, and Puma.

Therapeutic Advances in Medical Oncology 11
12 journals.sagepub.com/home/tam
ORCID iD
Sonia Pernas https://orcid.org/0000-0002-14
85-5080
References
1. Swain SM, Baselga J, Kim SB, etal. Pertuzumab,
trastuzumab, and docetaxel in HER2-positive
metastatic breast cancer. N Engl J Med 2015;
372: 724–734.
2. Slamon DJ, Clark GM, Wong SG, etal. Human
breast cancer: correlation of relapse and survival
with amplification of the HER-2/neu oncogene.
Science 1987; 235: 177–182.
3. Slamon DJ, Leyland-Jones B, Shak S, etal. Use
of chemotherapy plus a monoclonal antibody
against HER2 for metastatic breast cancer that
overexpresses HER2. N Engl J Med 2001; 344:
783–792.
4. Geyer CE, Forster J, Lindquist D, etal. Lapatinib
plus capecitabine for HER2-positive advanced
breast cancer. N Engl J Med 2006; 355: 2733–
2743.
5. Lewis Phillips GD, Li G, Dugger DL, etal.
Targeting HER2-positive breast cancer with
trastuzumab-DM1, an antibody-cytotoxic drug
conjugate. Cancer Res 2008; 68: 9280–9290.
6. Barok M, Tanner M, Koninki K, etal.
Trastuzumab-DM1 causes tumour growth
inhibition by mitotic catastrophe in trastuzumab-
resistant breast cancer cells in vivo. Breast Cancer
Res 2011; 13: R46.
7. Verma S, Miles D, Gianni L, etal. Trastuzumab
emtansine for HER2-positive advanced breast
cancer. N Engl J Med 2012; 367: 1783–1791.
8. Krop IE, Kim SB, Martin AG, etal.
Trastuzumab emtansine versus treatment of
physician’s choice in patients with previously
treated HER2-positive metastatic breast cancer
(TH3RESA): final overall survival results from a
randomised open-label phase 3 trial. Lancet Oncol
2017; 18: 743–754.
9. Lin NU. Better treatments needed for breast
cancer brain metastases. Lancet Oncol 2015; 16:
1583–1584.
10. Rimawi MF, Schiff R and Osborne CK.
Targeting HER2 for the treatment of breast
cancer. Annu Rev Med 2015; 66: 111–128.
11. Nahta R, Yuan LX, Zhang B, etal. Insulin-like
growth factor-I receptor/human epidermal growth
factor receptor 2 heterodimerization contributes
to trastuzumab resistance of breast cancer cells.
Cancer Res 2005; 65: 11118–11128.
12. Minuti G, Cappuzzo F, Duchnowska R, etal.
Increased MET and HGF gene copy numbers are
associated with trastuzumab failure in HER2-
positive metastatic breast cancer. Br J Cancer
2012; 107: 793–799.
13. Nagata Y, Lan KH, Zhou X, etal. PTEN
activation contributes to tumor inhibition
by trastuzumab, and loss of PTEN predicts
trastuzumab resistance in patients. Cancer Cell
2004; 6: 117–127.
14. Berns K, Horlings HM, Hennessy BT, etal. A
functional genetic approach identifies the PI3K
pathway as a major determinant of trastuzumab
resistance in breast cancer. Cancer Cell 2007; 12:
395–402.
15. Chandarlapaty S, Sakr RA, Giri D, etal.
Frequent mutational activation of the PI3K-AKT
pathway in trastuzumab-resistant breast cancer.
Clin Cancer Res 2012; 18: 6784–6791.
16. Nuciforo P, Thyparambil S, Aura C, etal. High
HER2 protein levels correlate with increased
survival in breast cancer patients treated with anti-
HER2 therapy. Mol Oncol 2016; 10: 138–147.
17. Carey LA, Berry DA, Cirrincione CT, etal.
Molecular heterogeneity and response to
neoadjuvant human epidermal growth factor
receptor 2 targeting in CALGB 40601, a
randomized phase III trial of paclitaxel plus
trastuzumab with or without lapatinib. J Clin
Oncol 2016; 34: 542–549.
18. Scaltriti M, Rojo F, Ocana A, etal. Expression of
p95HER2, a truncated form of the HER2 receptor,
and response to anti-HER2 therapies in breast
cancer. J Natl Cancer Inst 2007; 99: 628–638.
19. Luen SJ, Salgado R, Fox S, etal. Tumour-
infiltrating lymphocytes in advanced HER2-
positive breast cancer treated with pertuzumab or
placebo in addition to trastuzumab and docetaxel:
a retrospective analysis of the CLEOPATRA
study. Lancet Oncol 2017; 18: 52–62.
20. Musolino A, Naldi N, Bortesi B, etal.
Immunoglobulin G fragment C receptor
polymorphisms and clinical efficacy of
trastuzumab-based therapy in patients with
HER-2/neu-positive metastatic breast cancer. J
Clin Oncol 2008; 26: 1789–1796.
21. Baselga J, Cortes J, Im SA, etal. Biomarker
analyses in CLEOPATRA: a phase III, placebo-
controlled study of pertuzumab in human
epidermal growth factor receptor 2-positive, first-
line metastatic breast cancer. J Clin Oncol 2014;
32: 3753–3761.
22. Baselga J, Lewis Phillips GD, Verma S, etal.
Relationship between tumor biomarkers

S Pernas and SM Tolaney
journals.sagepub.com/home/tam 13
and efficacy in EMILIA, a phase III study
of trastuzumab emtansine in HER2-positive
metastatic breast cancer. Clin Cancer Res 2016;
22: 3755–3763.
23. Goel S, Wang Q, Watt AC, etal. Overcoming
therapeutic resistance in HER2-positive breast
cancers with CDK4/6 inhibitors. Cancer Cell
2016; 29: 255–269.
24. Giuliano M, Hu H, Wang YC, etal. Upregulation
of ER signaling as an adaptive mechanism of cell
survival in HER2-positive breast tumors treated
with anti-HER2 therapy. Clin Cancer Res 2015;
21: 3995–4003.
25. Kaufman B, Mackey JR, Clemens MR, etal.
Trastuzumab plus anastrozole versus anastrozole
alone for the treatment of postmenopausal
women with human epidermal growth factor
receptor 2-positive, hormone receptor-positive
metastatic breast cancer: results from the
randomized phase III TAnDEM study. J Clin
Oncol 2009; 27: 5529–5537.
26. Johnston S, Pippen J Jr., Pivot X, etal. Lapatinib
combined with letrozole versus letrozole and
placebo as first-line therapy for postmenopausal
hormone receptor-positive metastatic breast
cancer. J Clin Oncol 2009; 27: 5538–5546.
27. Rimawi MF, Mayer IA, Forero A, etal.
Multicenter phase II study of neoadjuvant
lapatinib and trastuzumab with hormonal
therapy and without chemotherapy in patients
with human epidermal growth factor receptor
2-overexpressing breast cancer: TBCRC 006. J
Clin Oncol 2013; 31: 1726–1731.
28. Llombart-Cussac A, Cortes J, Pare L, etal.
HER2-enriched subtype as a predictor of
pathological complete response following
trastuzumab and lapatinib without chemotherapy
in early-stage HER2-positive breast cancer
(PAMELA): an open-label, single-group,
multicentre, phase 2 trial. Lancet Oncol 2017; 18:
545–554.
29. Rimawi M, Ferrero JM, de la Haba-Rodriguez
J, etal. First-line trastuzumab plus an aromatase
inhibitor, with or without pertuzumab, in human
epidermal growth factor receptor 2-positive
and hormone receptor-positive metastatic or
locally advanced breast cancer (PERTAIN):
a randomized, open-label phase II trial. J Clin
Oncol 2018; 36: 2826–2835.
30. Ocana A, Gil-Martin M, Martin M, etal. A phase
I study of the SRC kinase inhibitor dasatinib with
trastuzumab and paclitaxel as first line therapy
for patients with HER2-overexpressing advanced
breast cancer. GEICAM/2010-04 study.
Oncotarget 2017; 8: 73144–73153.
31. Ocana Fernandez A, Ruiz Borrego M, Gil Martin
M, etal. A phase II trial of dasatinib (D) in
combination with trastuzumab (T) and paclitaxel
(P) in the first line treatment of HER2 positive
metastatic breast cancer (MBC) patients (pts):
GEICAM/2010-04 [abstract]. Ann Oncol 2017;
28(Suppl. 5): abstract 239PD.
32. Zhang S, Huang WC, Li P, etal. Combating
trastuzumab resistance by targeting SRC, a
common node downstream of multiple resistance
pathways. Nat Med 2011; 17: 461–469.
33. Sabbaghi M, Gil-Gomez G, Guardia C, etal.
Defective cyclin B1 induction in trastuzumab-
emtansine (T-DM1) acquired resistance in
HER2-positive breast cancer. Clin Cancer Res
2017; 23: 7006–7019.
34. Li G, Guo J, Shen BQ, etal. Mechanisms of
acquired resistance to trastuzumab emtansine in
breast cancer cells. Mol Cancer Ther 2018; 17:
1441–1453.
35. Rios-Luci C, Garcia-Alonso S, Diaz-Rodriguez
E, etal. Resistance to the antibody-drug
conjugate T-DM1 is based in a reduction in
lysosomal proteolytic activity. Cancer Res 2017;
77: 4639–4651.
36. Gebhart G, Lamberts LE, Wimana Z, etal.
Molecular imaging as a tool to investigate
heterogeneity of advanced HER2-positive breast
cancer and to predict patient outcome under
trastuzumab emtansine (T-DM1): the ZEPHIR
trial. Ann Oncol 2016; 27: 619–624.
37. Gingras I, Gebhart G, de Azambuja E, etal.
HER2-positive breast cancer is lost in translation:
time for patient-centered research. Nat Rev Clin
Oncol 2017; 14: 669–681.
38. Trail PA, Dubowchik GM and Lowinger TB.
Antibody drug conjugates for treatment of breast
cancer: Novel targets and diverse approaches
in ADC design. Pharmacol Ther 2018; 181:
126–142.
39. Iwata H, Tamura K, Doi T, etal. Trastuzumab
deruxtecan (DS-8201a) in subjects with HER2-
expressing solid tumors: long-term results of
a large phase 1 study with multiple expansion
cohorts [abstract]. J Clin Oncol 2018; 36(Suppl.):
abstract 2501.
40. Saura C, Thistlethwaite F, Banerji U, etal. A
phase I expansion cohorts study of SYD985 in
heavily pretreated patients with HER2-positive or
HER2-low metastatic breast cancer [abstract]. J
Clin Oncol 2018; 36(Suppl.): abstract 1014.
41. Yurkovetskiy A, Gumerov D, Ter-Ovanesyan E,
etal. Non-clinical pharmacokinetics of XMT-
1522, a HER2 targeting auristatin-based antibody

Therapeutic Advances in Medical Oncology 11
14 journals.sagepub.com/home/tam
drug conjugate [abstract]. Proc Am Assoc Cancer
Res 2017; 58: abstract 48.
42. Doi T, Shitara K, Naito Y, etal. Safety,
pharmacokinetics, and antitumour activity of
trastuzumab deruxtecan (DS-8201), a HER2-
targeting antibody-drug conjugate, in patients
with advanced breast and gastric or gastro-
oesophageal tumours: a phase 1 dose-escalation
study. Lancet Oncol 2017; 18: 1512–1522.
43. van Herpen CM, Banerji U, Mommers EC,
etal. Phase I dose-escalation trial with the DNA-
alkylating anti-HER2 antibody-drug conjugate
SYD985 [abstract]. Eur J Cancer 2015;
51(Suppl. 3): S65.
44. Aftimos PG, van Herpen CM, Mommers EC,
etal. SYD985, a novel anti-HER2 ADC, shows
promising activity in patients with HER2-positive
and HER2-negative metastatic breast cancer
[abstract]. San Antonio, TX: San Antonio Breast
Cancer Symposium, 2016.
45. Pegram M, Hamilton E, Tan AR, etal. Phase
1 study of bispecific HER2 antibody-drug
conjugate MEDI4276 in patients with advanced
HER2-positive breast or gastric cancer [abstract].
Ann Oncol 2018; 29: mdy048.05.
46. Zammarchi F, Chivers S, Williams DG, etal.
ADCT-502, a novel pyrrolobenzodiazepine
(PBD)-based antibody–drug conjugate (ADC)
targeting low HER2-expressing solid cancers
[abstract]. Eur J Cancer 2016; 69: S28.
47. Li JY, Perry SR, Muniz-Medina V, etal. A
biparatopic HER2-targeting antibody-drug
conjugate induces tumor regression in
primary models refractory to or ineligible for
HER2-targeted therapy. Cancer Cell 2016; 29:
117–129.
48. Nordstrom JL, Gorlatov S, Zhang W, etal.
Anti-tumor activity and toxicokinetics analysis of
MGAH22, an anti-HER2 monoclonal antibody
with enhanced Fcγ receptor binding properties.
Breast Cancer Res 2011; 13: R123.
49. Bang YJ, Giaccone G, Im SA, etal. First-
in-human phase 1 study of margetuximab
(MGAH22), an Fc-modified chimeric
monoclonal antibody, in patients with HER2-
positive advanced solid tumors. Ann Oncol 2017;
28: 855–861.
50. Alsina M, Boni V, Schellens JH, etal. First-in-
human phase 1/2 study of MCLA-128, a full
length IgG1 bispecific antibody targeting HER2
and HER3: final phase 1 data and preliminary
activity in HER2+ metastatic breast cancer
(MBC) [abstract]. J Clin Oncol 2017; 35
(Suppl.): abstract 2522.
51. Meric-Bernstam F, Beeram M, Ignacio
Mayordomo J, etal. Single agent activity of
ZW25, a HER2-targeted bispecific antibody,
in heavily pretreated HER2-expressing cancers
[abstract]. J Clin Oncol 2018; 36 (Suppl.):
abstract 2500.
52. Wermke M, Alt J, Kauh JS, etal. Preliminary
biomarker and pharmacodynamic data from a
phase I study of single-agent bispecific antibody
T-cell engager GBR 1302 in subjects with HER2-
positive cancers [abstract]. J Clin Oncol 2018; 36:
69.
53. Hinner MJ, Bel Aiba R, Wiedenmann A, etal.
Costimulatory T cell engagement via a novel
bispecific anti-CD137/anti-HER2 protein
[abstract]. J Immunother Cancer 2015; 3: P187.
54. Rius Ruiz I, Vicario R, Morancho B, etal.
p95HER2-T cell bispecific antibody for breast
cancer treatment. Sci Transl Med 2018; 10.
55. Blackwell KL, Burstein HJ, Storniolo AM,
etal. Overall survival benefit with lapatinib
in combination with trastuzumab for patients
with human epidermal growth factor receptor
2-positive metastatic breast cancer: final results
from the EGF104900 Study. J Clin Oncol 2012;
30: 2585–2592.
56. Pivot X, Manikhas A, Zurawski B, etal.
CEREBEL (EGF111438): a phase III,
randomized, open-label study of lapatinib
plus capecitabine versus trastuzumab plus
capecitabine in patients with human epidermal
growth factor receptor 2-positive metastatic
breast cancer. J Clin Oncol 2015; 33: 1564–1573.
57. Cortes J, Dieras V, Ro J, etal. Afatinib alone or
afatinib plus vinorelbine versus investigator’s
choice of treatment for HER2-positive breast
cancer with progressive brain metastases after
trastuzumab, lapatinib, or both (LUX-Breast 3):
a randomised, open-label, multicentre, phase 2
trial. Lancet Oncol 2015; 16: 1700–1710.
58. Gelmon KA, Boyle FM, Kaufman B, etal.
Lapatinib or trastuzumab plus taxane therapy
for human epidermal growth factor receptor
2-positive advanced breast cancer: final results
of NCIC CTG MA.31. J Clin Oncol 2015; 33:
1574–1583.
59. Harbeck N, Huang CS, Hurvitz S, etal. Afatinib
plus vinorelbine versus trastuzumab plus
vinorelbine in patients with HER2-overexpressing
metastatic breast cancer who had progressed
on one previous trastuzumab treatment (LUX-
Breast 1): an open-label, randomised, phase 3
trial. Lancet Oncol 2016; 17: 357–366.
60. Freedman RA, Gelman RS, Melisko M, etal.
TBCRC 022: phase II trial of neratinib +

S Pernas and SM Tolaney
journals.sagepub.com/home/tam 15
capecitabine for patients (Pts) with human
epidermal growth factor receptor 2 (HER2+)
breast cancer brain metastases (BCBM)
[abstract]. J Clin Oncol 2017; 35: 1005.
61. Freedman RA, Gelman RS, Wefel JS, etal.
Translational breast cancer research consortium
(TBCRC) 022: a phase II trial of neratinib for
patients with human epidermal growth factor
receptor 2-positive breast cancer and brain
metastases. J Clin Oncol 2016; 34: 945–952.
62. Hamilton E, Borges V, Conlin A, etal. Efficacy
results of a phase 1b study of ONT-380, an oral
HER2-specic inhibitor, in combination with
capecitabine (C) and trastuzumab (T) in HER2+
metastatic breast cancer (MBC), including patients
(pts) with brain metastases (mets) [abstract].
San Antonio, TX: San Antonio Breast Cancer
Symposium, 2016.
63. Borges VF, Ferrario C, Aucoin N, etal.
Tucatinib combined with ado-trastuzumab
emtansine in advanced ERBB2/HER2-positive
metastatic breast cancer: a phase 1b clinical trial.
JAMA Oncol 2018; 4: 1214–1220.
64. Metzger O, Barry W, Krop I, etal. Phase I dose-
escalation trial of ONT-380 in combination with
trastuzumab in patients (pts) with HER2+ breast
cancer brain metastases [abstract]. San Antonio,
TX: San Antonio Breast Cancer Symposium,
2016.
65. Ma F, Li Q, Chen S, etal. Phase I study
and biomarker analysis of pyrotinib, a novel
irreversible pan-ErbB receptor tyrosine kinase
inhibitor, in patients with human epidermal
growth factor receptor 2-positive metastatic
breast cancer. J Clin Oncol 2017; 35: 3105–3112.
66. Park YH, Lee KH, Sohn JH, etal. A phase II trial
of the pan-HER inhibitor poziotinib, in patients
with HER2-positive metastatic breast cancer who
had received at least two prior HER2-directed
regimens: results of the NOV120101-203 trial.
Int J Cancer 2018; 143: 3240–3247.
67. Martin M, Holmes FA, Ejlertsen B, etal.
Neratinib after trastuzumab-based adjuvant
therapy in HER2-positive breast cancer
(ExteNET): 5-year analysis of a randomised,
double-blind, placebo-controlled, phase 3 trial.
Lancet Oncol 2017; 18: 1688–1700.
68. Awada A, Colomer R, Inoue K, etal. Neratinib
plus paclitaxel vs trastuzumab plus paclitaxel in
previously untreated metastatic ERBB2-positive
breast cancer: the NEfERT-T randomized
clinical trial. JAMA Oncol 2016; 2: 1557–1564.
69. National Comprehensive Cancer Network.
NCCN Guidelines for Patients: Breast Cancer
Metastatic. Plymouth Meeting, PA: National
Comprehensive Cancer Network, 2018.
70. Xu B, Ma F, Ouyang Q, etal. Abstract PD3-08:
A randomized phase II trial of pyrotinib plus
capecitabine versus lapatinib plus capecitabine
in patients with HER2-positive metastatic
breast cancer previously treated with taxanes,
anthracyclines and/or trastuzumab. Cancer Res
2018; 78: Abstract nr PD3-08.
71. Bianchini G and Gianni L. The immune
system and response to HER2-targeted
treatment in breast cancer. Lancet Oncol 2014;
15: e58–e68.
72. Kim A, Lee SJ, Kim YK, etal. Programmed
death-ligand 1 (PD-L1) expression in tumour cell
and tumour infiltrating lymphocytes of HER2-
positive breast cancer and its prognostic value. Sci
Rep 2017; 7: 11671.
73. Stagg J, Loi S, Divisekera U, etal. Anti-ErbB-2
mAb therapy requires type I and II interferons
and synergizes with anti-PD-1 or anti-CD137
mAb therapy. Proc Natl Acad Sci U S A 2011;
108: 7142–7147.
74. Dirix LY, Takacs I, Jerusalem G, etal. Avelumab,
an anti-PD-L1 antibody, in patients with locally
advanced or metastatic breast cancer: a phase 1b
JAVELIN Solid Tumor study. Breast Cancer Res
Treat 2018; 167: 671–686.
75. Loi S, Giobbie-Hurder A, Gombos A, etal.
Phase Ib/II study evaluating safety and efficacy of
pembrolizumab and trastuzumab in patients with
trastuzumab-resistant HER2-positive metastatic
breast cancer: results from the PANACEA (IBCSG
45-13/BIG 4-13/KEYNOTE-014) study [abstract].
San Antonio, TX: San Antonio Breast Cancer
Symposium, 2017.
76. Emens LA, Esteva F, Beresford M, etal. Results
from KATE2, a randomized phase 2 study of
atezolizumab (atezo)+trastuzumab emtansine
(T-DM1) vs placebo (pbo)+T-DM1 in previously
treated HER2+ advanced breast cancer (BC)
[abstract]. San Antonio, TX: San Antonio Breast
Cancer Symposium, 2018.
77. Mittendorf EA, Clifton GT, Holmes JP, etal.
Final report of the phase I/II clinical trial of
the E75 (nelipepimut-S) vaccine with booster
inoculations to prevent disease recurrence in
high-risk breast cancer patients. Ann Oncol 2014;
25: 1735–1742.
78. Diehl JA, Cheng M, Roussel MF, etal. Glycogen
synthase kinase-3beta regulates cyclin D1
proteolysis and subcellular localization. Genes &
Dev 1998; 12: 3499–3511.

Therapeutic Advances in Medical Oncology 11
16 journals.sagepub.com/home/tam
79. Yu Q, Geng Y and Sicinski P. Specific protection
against breast cancers by cyclin D1 ablation.
Nature 2001; 411: 1017–1021.
80. Choi YJ, Li X, Hydbring P, etal. The
requirement for cyclin D function in tumor
maintenance. Cancer Cell 2012; 22: 438–451.
81. Finn RS, Dering J, Conklin D, etal. PD
0332991, a selective cyclin D kinase 4/6 inhibitor,
preferentially inhibits proliferation of luminal
estrogen receptor-positive human breast cancer
cell lines in vitro. Breast Cancer Res 2009; 11:
R77.
82. Witkiewicz AK, Cox D and Knudsen ES.
CDK4/6 inhibition provides a potent adjunct
to Her2-targeted therapies in preclinical breast
cancer models. Genes Cancer 2014; 5: 261-72.
83. DeMichele A, Clark AS, Tan KS, etal. CDK
4/6 inhibitor palbociclib (PD0332991) in Rb+
advanced breast cancer: phase II activity, safety,
and predictive biomarker assessment. Clin Cancer
Res 2015; 21: 995–1001.
84. Patnaik A, Rosen LS, Tolaney SM, etal. Efficacy
and safety of abemaciclib, an inhibitor of CDK4
and CDK6, for patients with breast cancer, non-
small cell lung cancer, and other solid tumors.
Cancer Discov 2016; 6: 740–753.
85. Ciruelos E, Villagrasa P, Pare L, etal. PAM50
intrinsic subtype predicts survival outcome in HER2-
positive/hormone receptor-positive metastatic breast
cancer treated with palbociclib and trastuzumab:
a correlative analysis of the PATRICIA (SOLTI
13-03) trial [abstract]. San Antonio, TX: San
Antonio Breast Cancer Symposium, 2017.
86. Ciruelos E, Villagrasa P, Paré L, etal. SOLTI-
1303 PATRICIA phase II trial (STAGE 1) —
Palbociclib and trastuzumab in postmenopausal
patients with HER2-positive metastatic breast cancer
[abstract]. San Antonio, TX: San Antonio Breast
Cancer Symposium, 2018.
87. Bachelot T, Kabos P, Yardley D, etal.
Abemaciclib for the treatment of brain metastases
secondary to hormone receptor positive breast cancer
[abstract]. San Antonio, TX: San Antonio Breast
Cancer Symposium, 2017.
88. Serra V, Scaltriti M, Prudkin L, etal. PI3K
inhibition results in enhanced HER signaling
and acquired ERK dependency in HER2-
overexpressing breast cancer. Oncogene 2011; 30:
2547–2557.
89. Hurvitz SA, Andre F, Jiang Z, etal. Combination
of everolimus with trastuzumab plus paclitaxel
as first-line treatment for patients with HER2-
positive advanced breast cancer (BOLERO-1): a
phase 3, randomised, double-blind, multicentre
trial. Lancet Oncol 2015; 16: 816–829.
90. Andre F, O’Regan R, Ozguroglu M, etal.
Everolimus for women with trastuzumab-
resistant, HER2-positive, advanced breast cancer
(BOLERO-3): a randomised, double-blind,
placebo-controlled phase 3 trial. Lancet Oncol
2014; 15: 580–591.
91. Andre F, Hurvitz S, Fasolo A, etal. Molecular
alterations and everolimus efficacy in
human epidermal growth factor receptor
2-overexpressing metastatic breast cancers:
combined exploratory biomarker analysis from
BOLERO-1 and BOLERO-3. J Clin Oncol 2016;
34: 2115–2124.
92. Shah PD, Chandarlapaty S, Dickler MN,
etal. Phase I study of LJM716, BYL719, and
trastuzumab in patients (pts) with HER2-
amplified (HER2+) metastatic breast cancer
(MBC) [abstract]. J Clin Oncol 2015; 33: 590.
93. Jain S, Shah AN, Santa-Maria CA, etal. Phase
I study of alpelisib (BYL-719) and trastuzumab
emtansine (T-DM1) in HER2-positive metastatic
breast cancer (MBC) after trastuzumab and
taxane therapy. Breast Cancer Res Treat 2018;
171: 371–381.
94. Keegan NM, Walshe JM, Toomey S, etal. A
phase Ib trial of copanlisib and tratuzumab in
pretreated recurrent or metastatic HER2-positive
breast cancer “PantHER” [abstract]. J Clin Oncol
2018; 36: 1036.
Visit SAGE journals online
journals.sagepub.com/
home/tam
SAGE journals