Therapeutic Advances in Medical Oncology
Ther Adv Med Oncol
2018, Vol. 10: 1 –10
© The Author(s), 2018.
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Brain metastases (BMs) are the most common
central nervous system (CNS) tumors in adults.
The incidence of BMs is increasing due to both
improved diagnostic techniques (e.g. magnetic
resonance imaging: (MRI)) and increased cancer
patient survival through advanced systemic treat-
ment approaches (e.g. anti-HER2 in metastatic
HER2 breast cancer, epidermal growth factor
receptor (EGFR) tyrosine-kinase inhibitors in
EGFR-mutated non-small cell lung cancer
(NSCLC)).1–3 The incidence of BMs depends on
the type of primary cancer, varying from approxi-
mately 5–50%.4 CNS involvement occur more
commonly in lung cancer, breast cancer, mela-
noma, and renal cell carcinoma patients.4 BMs
are associated with a poor prognosis. Overall sur-
vival varies according to the tumor types and
tumor subtypes from 3 to 25 months.4 In breast
cancer, differences in survival of patients with
BMs by tumor subtype (luminal, HER2 and tri-
ple-negative metastatic breast cancer) have been
observed and highlight the need for a tailored
approach in this patient population.5 Several pre-
dicting factors for BMs have been identified to
date and include age, histological grade, negative
status of estrogen receptor, HER2 and number of
non-CNS metastatic sites (1 versus >1).6
Treatment options are limited and usually involve
multimodality approaches that include surgery,
radiotherapy, radiosurgery and rarely systemic
therapy, depending on the number of CNS
lesions, location, and primary tumor type, as well
as patient performance status, considering vali-
dated prognostic indexes.7,8 Moreover, quality of
life (QoL) and neurocognitive function are often
impaired in patients with BMs compared with
patients with extracranial metastases due to both
the CNS disease and its treatments.9,10 In partic-
ular, the role of whole brain radiotherapy (WBRT)
is subject to discussion especially since a recent
phase III trial showed that WBRT provides little
additional clinically significant benefit on either
overall survival and QoL in NSCLC patients with
BMs.11 Treatments and outcomes of patients
with BMs remain disappointing and represent an
unmet medical need in current care of cancer
patients, especially in breast cancer, where BMs
are frequent and result in impaired QoL and
Therapy of breast cancer brain
metastases: challenges, emerging
treatments and perspectives
Nuria Kotecki, Florence Lefranc, Daniel Devriendt and Ahmad Awada
Abstract: Brain metastases are the most common central nervous system tumors in adults,
and incidence of brain metastases is increasing due to both improved diagnostic techniques
(e.g. magnetic resonance imaging) and increased cancer patient survival through advanced
systemic treatments. Outcomes of patients remain disappointing and treatment options are
limited, usually involving multimodality approaches. Brain metastases represent an unmet
medical need in solid tumor care, especially in breast cancer, where brain metastases are
frequent and result in impaired quality of life and death. Challenges in the management of
brain metastases have been highlighted in this review. Innovative research and treatment
strategies, including prevention approaches and emerging systemic treatment options for
brain metastases of breast cancer, are further discussed.
brain metastases, breast cancer, challenges, innovation, therapy
Received: 25 February 2018; revised manuscript accepted: 25 April 2018.
Medical Oncology Clinic,
Institut Jules Bordet, 1 rue
Heger Bordet, Université
Libre de Bruxelles,
Medical Oncology Clinic,
Institut Jules Bordet,
Université Libre de
Erasme, Université Libre
de Bruxelles, Belgium
Jules Bordet, Université
Libre de Bruxelles,
780312TAM0010.1177/1758835918780312Therapeutic Advances in Medical OncologyN Kotecki, F Lefranc
Therapeutic Advances in Medical Oncology 10
death.12 Challenges in the management of BMs
will be highlighted in this review. Emerging
research and treatment strategies in BMs from
breast cancer will be discussed.
Challenges in the management of BMs
Understanding BM biology
BM pathogenesis. The pathogenesis of BMs has
not been thoroughly characterized to date. Tumor
cells spread from the primary tumor or from the
metastatic lesion and colonize the brain paren-
chyma, involving several biological processes:
local invasion, intravasation into the bloodstream,
extravasation into the brain parenchyma through
the blood–brain barrier (BBB) and interaction
with the CNS microenvironment.13 The impor-
tance of genetic and epigenetic changes, in brain
metastasization of breast cancer, has also been
recently promoted.14 The BBB is a selective bar-
rier formed by endothelial cells interconnected by
tight junctions, pericytes, astrocytes, neuronal
end-foots and other cells from the microglia form-
ing the neurovascular unit and that separates the
bloodstream circulation from the brain and the
cerebrospinal fluid (CSF). Transport across the
BBB is highly regulated and includes paracellular
transport, passive and active transport and cell-
mediated transcytosis. Consequently, pathogene-
sis of BMs results in a multitude of biological
pathway activations in both tumor and the brain
microenvironment.15 The existence of brain
metastases initiating cells (BMICs) is being
increasingly discussed. BMICs have the ability to
escape the primary tumor and invade the neural
niche to initiate tumor growth. These cells might
also exploit a period of dormancy to transform
the local brain milieu into a favorable environ-
ment and reactivate years later.16 In addition,
although the BBB is frequently compromised by
BMs, the residual BBB permeability also limits
drug delivery (e.g. efflux pumps).17
Further biological findings may help to identify
promising therapeutic targets and the develop-
ment of new compounds. This research could be
undertaken with the help of more accurate pre-
clinical models to recapitulate BM pathogenesis.
By combining both in vitro models (e.g. Transwell,
cell exclusion, scratch wound, microfluidics) and
in vivo models (e.g. genetically engineered mouse
models, patient-derived xenograft (PDX) mod-
els), it might be possible to identify crosstalk
between signaling pathways, search for specific
BM homing signatures, use in vivo imaging tech-
niques and identify targets associated with the
BMs, the BBB or the microenvironment.18 As an
example, Singh and colleagues used an in vitro
model to identify a subset of stem-like cells from
primary human patient BMs, known as BMICs,
and managed to establish a BMIC PDX trans-
plantation model that enabled them to identify
essential regulators of BMICs potentially targeta-
ble.19 Also, several preclinical data suggest that
the PI3K-AKT-mTOR pathway activation is a
frequent brain-specific mechanism of drug resist-
ance to HER2-targeted therapies suggesting that
preclinical knowledge will help to identify new
drug targets that could be tested in clinical tri-
als.20–22 For example, HER3 blockade has been
shown to overcame the resistance of HER2-
amplified or PIK3CA-mutant breast cancer BMs
to PI3K inhibitors in vivo21 and combined inhibi-
tion of PI3K and mTOR resulted in durable
tumor regressions in breast cancer BMs from
Heterogeneity between the primary tumor and the
BMs. BMs share alterations that are not neces-
sarily detected in primary tumors, regional
lymph nodes, or extracranial metastases as dem-
onstrated by whole-exome sequencing of 86
matched BMs, primary tumors, extracranial
metastases and normal tissue.23 Consequently,
primary tumor or extracranial metastatic site
genotyping could potentially overlook actionable
oncogenic driver mutations present on the BMs.
Moreover, BMs can harbor mutations confer-
ring specific drug resistance or activation of an
alternative signaling pathway interfering with
drug activity.23 Brain biopsies are considered
invasive. Liquid biopsy is being investigated as
potential screening tool by using for example
ctDNA or circulating tumor cells (CTCs) in
the CSF or ctDNA, miRNA and exosomes in
the circulation.24–30 Pentsova and colleagues
sequenced cancer-associated genes in cell-free
DNA from CSF in 53 patients with suspected or
known CNS cancer involvement and detected
somatic alterations in 63% (n = 20/32) of
patients with CNS metastases of solid tumors
and, interestingly, in none of the patients with-
out BMs.25 Similar results have also been shown
recently in BMs from NSCLC.31 Furthermore,
Boral and colleagues showed a difference in
CTC transcriptomic signatures in patients with
breast cancer BMs that is different from primary
tumors that may be used either as a screening,
monitoring and therapeutic tools.26
N Kotecki, F Lefranc et al.
Challenges and opportunities in clinical
research of BMs
Patients with progressive BMs are often excluded
from clinical trials, usually because they are known
to have a poor prognosis and because most of sys-
temic treatments fail to penetrate the BBB, but
also due to the high risk of CNS hemorrhage or
toxicity.32 Patients with BMs are often heavily pre-
treated, randomized trials in patients with BMs are
difficult to perform and anticancer response is dif-
ficult to observe. In existing clinical trials, defini-
tions of clinical endpoints are also variable.
Moreover, most of the studies do not take into
consideration the number of BMs, the extracranial
disease status, prior therapies received or
sensitivity to these therapeutic approaches.33
However, due to the improvement in systemic
therapies and better systemic control, a number of
patients remain in good clinical condition for an
extended period of time. Therefore, prospective
clinical trials in a selected patient population could
be feasible. Recommendations for clinical trial eli-
gibility criteria have been recently published by the
American Society of Clinical Oncology (ASCO)
BMs working group as described hereunder. First,
they proposed to include patients with treated and
stable BMs for at least 4 weeks or patients with
active BMs in early phase trials when there is a
strong scientific rationale for probability of bene-
fit.34 Similarly the RANO-BM (Response
Assessment in Neuro-Oncology Brain Metastases)
group suggested to consider the likelihood of CNS
activity of the agent to establish inclusion/exclu-
sion criteria in clinical trials.35 The ASCO BMs
working group also proposed to consider a parallel
cohort in later phase trials and include brain imag-
ing monitoring in tumors with high risk of develop-
ing BMs, that statistical approaches should also be
adapted allowing these patients into the intent to
treat population and to differentiate intracranial
and extracranial progression in these patients.34
Likewise, use of alternative study designs and
methodology could also be proposed (e.g. window
of opportunity trials), N-of-1 trials using the
patient as their own control, as well as specific sur-
rogate endpoints [time to next event in the CNS,
intracranial progression-free-survival, intracranial
objective response rate (ORR)].12 Neurological,
neurocognitive, and QoL reporting should be part
of the trial design. Considering the current failure
rates of existing treatments and the impaired QoL,
an interesting approach would be to focus on pri-
mary prevention, and secondary prevention, avoid-
ing or delaying the next CNS event and associated
symptoms after a first CNS metastatic event.36,37
In this context, potential predictive biomarkers for
BMs should be investigated. Circulating biomark-
ers, including in the CSF, as well as functional
imaging are under evaluation and might in the
future be of help for treatment guidance.25–30,38–42
Uniformity in the assessment of CNS metastases
using novel imaging techniques and common crite-
ria for evaluation, should be put forward (e.g.
RANO-BM criteria).43 Recently, The RANO
group proposed also the iRANO guidelines inte-
grating the concept of pseudoprogession of disease
that will evolve successively with further experience
from immunotherapy trials in neuro-oncology44
and the NANO (Neurological Assessment in
Neuro-Oncology) scale, which is a tool to assess
neurological function for integration into the
RANO criteria to provide an overall assessment of
outcome for neuro-oncology patients.45
Emerging treatments in BMs from breast
To date, general indications to use systemic treat-
ments for BMs is limited to highly chemotherapy-
sensitive primary tumors, BMs from primary
tumors with identified molecular alterations ame-
nable to targeted therapy crossing the BBB,
asymptomatic BMs found on screening MRI with
planned systemic treatment, or in cases in which
other therapeutic options have been exhausted
and there is a drug available.7 This is due to the
lack of efficacy of systemic treatment including in
breast cancer patients with BMs. Consequently,
until recently, treatment of BMs from breast can-
cer was focused on local therapy (surgery or
General considerations to improve treatments
The ability to manipulate the BBB offers hope to
increase the efficacy of systemic treatments.
Several strategies enable to manipulate the BBB
and some of them are currently investigated for
the treatment of BMs and primary brain tumors:
(1) enhancement of drug permeability through
the BBB using osmotic/chemical disruption of
the BBB (e.g. mannitol, intra-arterial vasoactive
agents), colloidal-based drug delivery or by tar-
geting BBB transport systems47–49; (2) interstitial
delivery by using, for example, intranasal admin-
istration, intrathecal or intracranial catheters47,50–52;
(3) the use of polymers and microchips for
local drug delivery47; or finally, (4) temporary
Therapeutic Advances in Medical Oncology 10
disruption of the BBB (e.g. radiotherapy tech-
niques, pulsed ultrasound).47,53,54
Indeed, adding active systemic therapy to local
(radiation, surgery) therapy could be one effective
way to improve the outcome of patients with
BMs. The concept aims to use and to enhance
both local and systemic effects of the treatment.
The immune stimulatory effects of radiation ther-
apy in combination with immunotherapy [e.g.
checkpoint inhibitors, CAR (chimeric antigen
receptor)-T cells]55 is an example of this innova-
tive approach. Another major advantage of this
approach will be to control both intracranial and
Emerging systemic therapies in BMs from
Currently there are several systemic treatments
being developed with promising CNS activity,
especially for breast cancer (Table 1).
Potential role of etirinotecan pegol. Etirinote-
can pegol is a next-generation long-acting
topoisomerase-I inhibitor-polymer conjugate,
enabling penetration through the tumor endothe-
lia, thereby enhancing irinotecan and its active
metabolite (SN38) exposure in BMs.62 In addi-
tion, compared with irinotecan, etirinotecan
pegol has a longer half-life than SN38, the active
compound.63,64 Etirinotecan showed sustained
tumor exposure in multiple cancer cell lines
and preclinical models, which may increase the
therapeutic window.62 Preclinical data showed
higher concentrations of irinotecan and SN38 in
brain tumor tissue versus plasma on day 7 after
etirinotecan pegol administration in mice with
intracranial implanted triple-negative breast
cancer tumors.65 Moreover, etirinotecan pegol
leads to regression of established BMs and pro-
longs survival of animals with triple-negative
breast cancer BMs.65
In a phase III study, BEACON trial, patients with
metastatic breast cancer who had failed multiple
prior therapies were randomized to etirinotecan
pegol or treatment of the physician’s choice.
Etirinotecan pegol was associated with a nonsta-
tistically significant 2.1 months improvement in
overall survival. However, in patients with a his-
tory of treated, stable BMs (planned subgroup
analyses), etirinotecan pegol reduced the risk of
death by nearly half for the treated subset of
women (hazard ratio (HR) 0.51) and demon-
strated a doubling of 12-month survival rate (44%
versus 20%)60,66 with less toxicity and better QoL
compared with treatment of the physician’s
choice.60,61 In patients with radiologically detect-
able but stable brain lesions, treatment with
etirinotecan pegol allowed a 7.4-month survival
advantage compared with treatment of physi-
cian’s choice66 (Table 1).
Based on these findings, an open-label, rand-
omized multicenter phase III trial in patients with
stable BMs from advanced breast cancer is cur-
rently recruiting [ClinicalTrials.gov identifier:
NCT02915744].67 A total of 350 patients with
metastatic breast cancer who have stable BMs
and have been previously treated with an anthra-
cycline, a taxane, and capecitabine will be rand-
omized 1:1 to etirinotecan pegol or treatment of
the physician’s choice, limited to one of the fol-
lowing agents: eribulin, ixabepilone, vinorelbine,
gemcitabine, paclitaxel, docetaxel, or nab-pacli-
taxel. The primary objective of the study will be
Other chemotherapy compounds of interest.
ANG1005 is a peptide-drug conjugate contain-
ing paclitaxel and covalently linked to Angio-
pep-2, using the LRP-1 transport system to cross
the BBB.59 This compound has shown interest-
ing results in a phase II study in patients with
metastatic breast cancer with recurrent BMs and
achieved intracranial responses in 14% of the
patients and 57% of the patients had stable dis-
ease59 (Table 1). Extracranial responses were also
observed. A randomized study is planned.59
TPI 287 is a third-generation taxane designed to
overcome efflux pumps systems. Preclinical data
suggest an activity on BMs from breast cancer
cells.68 TPI 287 was used in combination with
bevacizumab in a phase I/II trial for the treatment
of recurrent glioblastoma and showed a promis-
ing 60% overall response rate (n = 23),69 further
verifying its ability to cross the BBB. Studies in
BMs for breast cancer are underway (e.g.
ClinicalTrials.gov identifier: NCT01332630).70
Targeted therapies. In the setting of HER2-
advanced breast cancer, neratinib is an oral, irre-
versible, tyrosine-kinase inhibitor of HER1,
HER2, and HER4 with demonstrated efficacy in
metastatic breast cancer patients also in trastu-
zumab (anti-HER2) resistant disease.71 Neratinib
efficacy in preclinical models suggests good CNS
N Kotecki, F Lefranc et al.
Table 1. Emerging systemic therapies in brain metastases from breast cancer.
Study name Study
Tumor subtypes Number of
NCT0149466256,57 Phase II Neratinib
monotherapy HER2+ BCBM
progression in the
CNS after one or
more line of CNS-
40 ORR: 8%
39 VORR 49%
CDK 4/6 inhibitor NCT0230802058 Phase II Abemaciclib HR+, HER2- mBC
who have ⩾1
23 ORR: 8.2%
NCT0204805959 Phase II Ang-1005 BCBM with or
72 ORR: 14%
NCT0149210160,61 Phase III EP
rate (44% versus
BCBM, breast cancer brain metastases; BM, brain metastases; CNS, central nervous system; EP, etirinotecan pegol; IC, investigator’s choice; LC, leptomeningeal carcinomatosis; mBC,
metastatic breast cancer; ORR, objective response rate; SD, stable disease; VORR, volumetric objective response rate.
Therapeutic Advances in Medical Oncology 10
penetration.72,73 In a randomized phase II trial,
the neratinib-paclitaxel combination showed
interestingly that the incidence of CNS recur-
rence was lower and that time to CNS metastases
was longer compared with trastuzumab plus
paclitaxel in previously untreated metastatic
HER2-positive breast cancer.74 More recently, the
results of the TBCRC 022 trial showed encourag-
ing data regarding neratinib in combination with
capecitabine for the treatment of BMs from
HER2-positive advanced breast cancer with no
prior lapatinib or capecitabine treatment, with
nearly half of the patients presenting a volumetric
CNS ORR on progressive BMs.56
Abemaciclib is a selective cyclin-dependent
kinase (CDK) 4/6 inhibitor that seems to cross
the BBB and reaches concentrations that are
10-fold higher than palbociclib, another CDK
4/6 inhibitor. It is effective against BM in glio-
blastoma xenograft models.75 Preliminary results
of the I3Y-MC-JPBO study evaluating abemaci-
clib in patients with new or progressive BMs sec-
ondary to hormone receptor positive (HR+)
metastatic breast cancer, NSCLC, or melanoma,
provided evidence that abemaciclib had antitu-
mor activity in HR+ breast cancer patients with
BMs58 (Table 1).
Also, findings from preclinical models suggest
that PARP inhibitors might be of benefit for
breast cancer BM treatment and certainly war-
rant further investigations.12,76
Immunotherapy. Patients with BMs have pre-
dominantly been excluded from immunotherapy
clinical trials. Immune responses in the brain are
highly regulated and BMs might also contain
tumor infiltrating lymphocytes, challenging the
use of immunotherapies for the treatment of CNS
secondary tumors.77 In melanoma and NSCLC,
both anti-PD1 and anti-CTLA4 (immune check-
point inhibitors) showed interesting CNS
responses as monotherapy. The activity was even
better in combination with up to 50% CNS
responses in melanoma patients.78–81 Escudier
and colleagues reported preliminary results of the
NIVOREN study, a prospective phase II study
assessing safety and efficacy of nivolumab (anti-
PD1), in patients with BMs from renal cell carci-
noma. Among 44 patients eligible for assessment
of CNS response, 23% had an intracranial ORR.82
To date, immunotherapy has failed to improve the
outcome of breast cancer patients. However,
radiotherapy may increase the local efficacy of
immunotherapy, as well as inducing an abscopal
effect.68 Innovative studies are needed to investi-
gate the effects of radiation combined with immu-
notherapy and combinations with other systemic
therapies on brain tumor control.83
Improving understanding of the biology of BMs is
essential to identify optimal therapeutic targets in
BMs from breast cancer and help overcoming the
BBB challenges. Rethinking clinical research meth-
odology, focusing on BMs prevention approaches
and innovative treatment strategies will help
improve outcome of patients and their QoL. These
approaches should be implemented in a multidisci-
plinary manner in order to bring together the exper-
tise needed to tackle the challenges in this area of
unmet medical need in oncology.
The authors acknowledge the contribution of the
AJE (American Journal Experts) Support Team
and Ornella Martini for English-language editing
of this manuscript.
This research received no specific grant from any
funding agency in the public, commercial, or not-
Conflict of interest statement
The authors declare that there is no conflict of
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