ArticlePDF AvailableLiterature Review

Therapy of breast cancer brain metastases: challenges, emerging treatments and perspectives

Authors:

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.
https://doi.org/10.1177/1758835918780312
https://doi.org/10.1177/1758835918780312
Therapeutic Advances in Medical Oncology
journals.sagepub.com/home/tam 1
Ther Adv Med Oncol
2018, Vol. 10: 1 –10
DOI: 10.1177/
1758835918780312
© The Author(s), 2018.
Reprints and permissions:
http://www.sagepub.co.uk/
journalsPermissions.nav
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
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.
Keywords:
brain metastases, breast cancer, challenges, innovation, therapy
Received: 25 February 2018; revised manuscript accepted: 25 April 2018.
Correspondence to:
Ahmad Awada
Medical Oncology Clinic,
Institut Jules Bordet, 1 rue
Heger Bordet, Université
Libre de Bruxelles,
Brussels, Belgium
ahmad.awada@bordet.be
Nuria Kotecki
Medical Oncology Clinic,
Institut Jules Bordet,
Université Libre de
Bruxelles, Belgium
Florence Lefranc
Department of
Neurosurgery, Hopital
Erasme, Université Libre
de Bruxelles, Belgium
Daniel Devriendt
Department of
Radiotherapy, Institut
Jules Bordet, Université
Libre de Bruxelles,
Belgium
780312TAM0010.1177/1758835918780312Therapeutic Advances in Medical OncologyN Kotecki, F Lefranc
research-article20182018
Review
Therapeutic Advances in Medical Oncology 10
2 journals.sagepub.com/home/tam
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
PDX models.22
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.
journals.sagepub.com/home/tam 3
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
cancer
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
radiotherapy).46
General considerations to improve treatments
efficacy
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
4 journals.sagepub.com/home/tam
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
extracranial disease.
Emerging systemic therapies in BMs from
breast cancer
Currently there are several systemic treatments
being developed with promising CNS activity,
especially for breast cancer (Table 1).
Chemotherapy
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
overall survival.67
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.
journals.sagepub.com/home/tam 5
Table 1. Emerging systemic therapies in brain metastases from breast cancer.
Mechanism
of action
Study name Study
design
Experimental
drug
Tumor subtypes Number of
patients
CNS endpoint
Targeted
therapy
Pan-HER
inhibitor
NCT0149466256,57 Phase II Neratinib
monotherapy HER2+ BCBM
progression in the
CNS after one or
more line of CNS-
directed therapy
40 ORR: 8%
Neratinib
(+ capecitabine)
39 VORR 49%
RanoBM-ORR 24%
CDK 4/6 inhibitor NCT0230802058 Phase II Abemaciclib HR+, HER2- mBC
who have 1
measurable brain
lesion
23 ORR: 8.2%
Chemotherapy Peptide-paclitaxel
conjugate
NCT0204805959 Phase II Ang-1005 BCBM with or
without LC
72 ORR: 14%
SD 57%
Long-acting
topoisomerase-I
inhibitor-polymer
conjugate
NCT0149210160,61 Phase III EP
versus IC
mBC
BM subgroup:
stable BM
locally pretreated
67
36
(treated with
EP)
12-month survival
rate (44% versus
20% IC)
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
6 journals.sagepub.com/home/tam
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
Conclusions
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.
Acknowledgements
The authors acknowledge the contribution of the
AJE (American Journal Experts) Support Team
and Ornella Martini for English-language editing
of this manuscript.
Funding
This research received no specific grant from any
funding agency in the public, commercial, or not-
for-profit sectors.
Conflict of interest statement
The authors declare that there is no conflict of
interest.
References
1. Nieder C, Spanne O, Mehta MP, Grosu AL and
Geinitz H. Presentation, patterns of care, and
survival in patients with brain metastases: what
has changed in the last 20 years? Cancer 2011;
117: 2505–2512.
2. Tabouret E, Chinot O, Metellus P, etal.
Recent trends in epidemiology of brain
metastases: an overview. Anticancer Res
2012; 32: 4655–4662.
3. Smedby KE, Brandt L, Bäcklund ML, etal.
Brain metastases admissions in Sweden between
1987 and 2006. Br J Cancer 2009; 101: 1919–
1924.
4. Taillibert S and Le Rhun É. Épidémiologie
des lésions métastatiques cérébrales. Cancer/
Radiothérapie 2015; 19: 3–9.
N Kotecki, F Lefranc et al.
journals.sagepub.com/home/tam 7
5. McKee MJ, Keith K, Deal AM, etal. A
multidisciplinary breast cancer brain metastases
clinic: the University of North Carolina
experience. Oncologist 2016; 21: 16–20.
6. Graesslin O, Abdulkarim BS, Coutant C,
etal. Nomogram to predict subsequent brain
metastasis in patients with metastatic breast
cancer. J Clin Oncol 2010; 28: 2032–2037.
7. Lin X and DeAngelis LM. Treatment of brain
metastases. J Clin Oncol 2015; 33: 3475–3484.
8. Soffietti R, Abacioglu U, Baumert B, etal.
Diagnosis and treatment of brain metastases
from solid tumors: guidelines from the European
Association of Neuro-Oncology (EANO). Neuro-
Oncol 2017; 19: 162–174.
9. Peters S, Bexelius C, Munk V, etal. The impact
of brain metastasis on quality of life, resource
utilization and survival in patients with non-
small-cell lung cancer. Cancer Treat Rev 2016; 45:
139–162.
10. Meyers CA, Smith JA, Bezjak A, etal.
Neurocognitive function and progression in
patients with brain metastases treated with whole-
brain radiation and motexafin gadolinium: results
of a randomized phase III trial. J Clin Oncol Off J
Am Soc Clin Oncol 2004; 22: 157–165.
11. Mulvenna P, Nankivell M, Barton R, etal.
Dexamethasone and supportive care with or
without whole brain radiotherapy in treating
patients with non-small cell lung cancer with
brain metastases unsuitable for resection or
stereotactic radiotherapy (QUARTZ): results
from a phase 3, non-inferiority, randomised trial.
Lancet 2016; 388: 2004–2014.
12. O’Sullivan CC, Davarpanah NN, Abraham J,
etal. Current challenges in the management of
breast cancer brain metastases. Semin Oncol 2017;
44: 85–100.
13. Seoane J and De Mattos-Arruda L. Brain
metastasis: new opportunities to tackle
therapeutic resistance. Mol Oncol 2014; 8:
1120–1131.
14. Custódio-Santos T, Videira M and Brito MA.
Brain metastasization of breast cancer. Biochim
Biophys Acta 2017; 1868: 132–147.
15. Witzel I, Oliveira-Ferrer L, Pantel K, etal. Breast
cancer brain metastases: biology and new clinical
perspectives. Breast Cancer Res 2016; 18: 8.
16. Termini J, Neman J and Jandial R. Role of the
neural niche in brain metastatic cancer. Cancer
Res 2014; 74: 4011–4015.
17. Puhalla S, Elmquist W, Freyer D, etal.
Unsanctifying the sanctuary: challenges and
opportunities with brain metastases. Neuro-Oncol
2015; 17: 639–651.
18. Singh M, Bakhshinyan D, Venugopal C, et al.
Preclinical modeling and therapeutic avenues
for cancer metastasis to the central nervous
system. Front Oncol 2017; 7: 220. doi:10.3389/
fonc.2017.00220.
19. Singh M, Venugopal C, Tokar T, etal. RNAi
screen identifies essential regulators of human
brain metastasis-initiating cells. Acta Neuropathol
(Berl) 2017; 134: 923–940.
20. Kabraji S, Ni J, Lin NU, et al. Drug resistance
in HER2-positive breast cancer brain metastases:
blame the barrier or the brain? Clin Cancer
Res. 2018 Apr 15; 24(8): 1795–1804. doi:
10.1158/1078-0432.CCR-17-3351
21. Kodack DP, Askoxylakis V, Ferraro GB,
etal. The brain microenvironment mediates
resistance in luminal breast cancer to PI3K
inhibition through HER3 activation. Sci
Transl Med 2017; 9: eaal4682. DOI: 10.1126/
scitranslmed.aal4682.
22. Ni J, Ramkissoon SH, Xie S, etal. Combination
inhibition of PI3K and mTORC1 yields durable
remissions in mice bearing orthotopic patient-
derived xenografts of HER2-positive breast
cancer brain metastases. Nat Med 2016; 22:
723–726.
23. Brastianos PK, Carter SL, Santagata S, etal.
Genomic characterization of brain metastases
reveals branched evolution and potential
therapeutic targets. Cancer Discov 2015; 5:
1164–1177.
24. Han CH and Brastianos PK. Genetic
characterization of brain metastases in the era of
targeted therapy. Front Oncol [Internet] 2017; 7:
230. https://www.ncbi.nlm.nih.gov/pmc/articles/
PMC5622141/ (accessed 10 December 2017).
25. Pentsova EI, Shah RH, Tang J, etal. Evaluating
cancer of the central nervous system through
next-generation sequencing of cerebrospinal fluid.
J Clin Oncol 2016; 34: 2404.
26. Boral D, Vishnoi M, Liu HN, etal. Molecular
characterization of breast cancer CTCs associated
with brain metastasis. Nat Commun 2017;
8: 196.
27. Rogawski DS, Vitanza NA, Gauthier AC, etal.
Integrating RNA sequencing into neuro-oncology
practice. Transl Res J Lab Clin Med 2017; 189:
93–104.
28. Shalaby T and Grotzer MA. Tumor-associated
CSF MicroRNAs for the prediction and
evaluation of CNS malignancies. Int J Mol Sci
2015; 16: 29103–29119.
Therapeutic Advances in Medical Oncology 10
8 journals.sagepub.com/home/tam
29. Marchiò C, Mariani S, Bertero L, etal. Liquoral
liquid biopsy in neoplastic meningitis enables
molecular diagnosis and mutation tracking: a
proof of concept. Neuro-Oncol 2017; 19: 451–
453.
30. Siravegna G, Geuna E, Mussolin B, etal.
Genotyping tumour DNA in cerebrospinal fluid
and plasma of a HER2-positive breast cancer
patient with brain metastases. ESMO Open 2017;
2: e000253.
31. Sen Y and Wang Q. 35P_PRAnalysis of EGFR
mutation status in blood and CSF in lung
adenocarcinoma patients with EGFR mutation
and CNS metastasis by ddPCR. Ann Oncol
[Internet]. 2017; 28(Suppl. 10). http://academic.
oup.com/annonc/article/doi/10.1093/annonc/
mdx729/4652866 (accessed 13 December 2017).
32. Gounder MM and Spriggs DR. Inclusion of
patients with brain metastases in phase I trials: an
unmet need. Clin Cancer Res 2011; 17: 3855–
3857.
33. Lin NU, Lee EQ, Aoyama H et al. Response
Assessment in Neuro-Oncology (RANO)
group. Challenges relating to solid tumour
brain metastases in clinical trials, part 1: patient
population, response, and progression. A report
from the RANO group. Lancet Oncol. 2013
September; 14(10): e396–406. doi: 10.1016/
S1470-2045(13)70311-5. Review. PubMed
PMID: 23993384.
34. Lin NU, Prowell T, Tan AR, etal.
Modernizing Clinical Trial Eligibility Criteria:
Recommendations of the American Society of
Clinical Oncology-Friends of Cancer Research
Brain Metastases Working Group. J Clin Oncol
Off J Am Soc Clin Oncol 2017; JCO2017740761.
35. Camidge DR, Lee EQ, Lin NU, etal. Clinical
trial design for systemic agents in patients with
brain metastases from solid tumours: a guideline
by the Response Assessment in Neuro-Oncology
Brain Metastases working group. Lancet Oncol
2018; 19: e20–e32.
36. Steeg PS, Camphausen KA and Smith QR. Brain
metastases as preventive and therapeutic targets.
Nat Rev Cancer 2011; 11: 352–363.
37. Owonikoko TK, Arbiser J, Zelnak A, etal.
Current approaches to the treatment of metastatic
brain tumours. Nat Rev Clin Oncol 2014; 11: 203.
38. Wang J and Bettegowda C. Applications of DNA-
based liquid biopsy for central nervous system
neoplasms. J Mol Diagn JMD 2017; 19: 24–34.
39. Ruiz-Espana S, Jimenez-Moya A, Arana E,
etal. Functional diffusion map: a biomarker of
brain metastases response to treatment based on
magnetic resonance image analysis. Conf Proc
Annu Int Conf IEEE Eng Med Biol Soc 2015;
2015: 4282–4285.
40. Martínez-Aranda A, Hernández V, Guney
E, etal. FN14 and GRP94 expression are
prognostic/predictive biomarkers of brain
metastasis outcome that open up new therapeutic
strategies. Oncotarget 2015; 6: 44254.
41. Mahmood F, Johannesen HH, Geertsen P, etal.
Repeated diffusion MRI reveals earliest time
point for stratification of radiotherapy response
in brain metastases. Phys Med Biol 2017;
62: 2990.
42. Jilaveanu LB, Parisi F, Barr ML, etal. PLEKHA5
as a biomarker and potential mediator of
melanoma brain metastasis. Clin Cancer Res 2015;
21: 2138–2147.
43. Lin NU, Lee EQ, Aoyama H, et al. Response
Assessment in Neuro-Oncology (RANO) group.
Response assessment criteria for brain metastases:
proposal from the RANO group. Lancet Oncol.
2015 June; 16(6): e270–278. doi: 10.1016/
S1470-2045(15)70057-4. Epub 2015 May 27.
Review. PubMed PMID: 26065612.
44. Okada H, Weller M, Huang R, etal.
Immunotherapy Response Assessment in Neuro-
Oncology (iRANO): A Report of the RANO
Working Group. Lancet Oncol 2015; 16: e534–
e542.
45. Nayak L, DeAngelis LM, Brandes AA, etal.
The Neurologic Assessment in Neuro-Oncology
(NANO) scale: a tool to assess neurologic
function for integration into the Response
Assessment in Neuro-Oncology (RANO) criteria.
Neuro-Oncol 2017; 19: 625–635.
46. Gil-Gil MJ, Martinez-Garcia M, Sierra A, etal.
Breast cancer brain metastases: a review of
the literature and a current multidisciplinary
management guideline. Clin Transl Oncol 2014;
16: 436–446.
47. Hersh DS, Wadajkar AS, Roberts N, etal.
Evolving drug delivery strategies to overcome the
blood brain barrier. Curr Pharm Des 2016; 22:
1177.
48. Pardridge WM. Drug and gene targeting to the
brain with molecular Trojan horses. Nat Rev
Drug Discov 2002; 1: 131–139.
49. Lajoie JM and Shusta EV. Targeting receptor-
mediated transport for delivery of biologics across
the blood-brain barrier. Annu Rev Pharmacol
Toxicol 2015; 55: 613.
50. Zhu J, Jiang Y, Xu G, etal. Intranasal
administration: a potential solution for cross-BBB
N Kotecki, F Lefranc et al.
journals.sagepub.com/home/tam 9
delivering neurotrophic factors. Histol Histopathol
2012; 27: 537–548.
51. Jiang Y, Zhu J, Xu G, etal. Intranasal delivery
of stem cells to the brain. Expert Opin Drug Deliv
2011; 8: 623–632.
52. Marianecci C, Rinaldi F, Hanieh PN, etal. Drug
delivery in overcoming the blood–brain barrier:
role of nasal mucosal grafting. Drug Des Devel
Ther 2017; 11: 325.
53. van Vulpen M, Kal HB, Taphoorn MJB, etal.
Changes in blood-brain barrier permeability
induced by radiotherapy: implications for timing
of chemotherapy? (Review). Oncol Rep 2002; 9:
683–688.
54. Carpentier A, Canney M, Vignot A, etal. Clinical
trial of blood-brain barrier disruption by pulsed
ultrasound. Sci Transl Med 2016; 8: 343re2.
55. Sharabi AB, Tran PT, Lim M, etal. Stereotactic
radiotherapy combined with immunotherapy:
augmenting radiation’s role in local and systemic
treatment. Oncol Williston Park N 2015; 29: 331.
56. 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 20
March 2016; 34(9): 945–952.
57. Freedman RA, Gelman RS, Melisko ME, et
al. TBCRC 022: phase II trial of neratinib +
capecitabine for patients (Pts) with human
epidermal growth factor receptor 2 (HER2+)
breast cancer brain metastases (BCBM). J Clin
Oncol 2017; 35(Suppl. 15): 1005.
58. Tolaney SM, Lin NU, Thornton D, etal.
Abemaciclib for the treatment of brain metastases
(BM) secondary to hormone receptor positive
(HR+), HER2 negative breast cancer. J Clin
Oncol 2017; 35(Suppl. 15): 1019.
59. Tang S, Kumthekar P, Brenner A, etal.
ANG1005, a novel peptide-paclitaxel conjugate
crosses the BBB and shows activity in patients
with recurrent CNS metastasis from breast
cancer. Ann Oncol 2016; 27: 103–113.
60. Perez EA, Awada A, O’Shaughnessy J, etal.
Etirinotecan pegol (NKTR-102) versus
treatment of physician’s choice in women with
advanced breast cancer previously treated with
an anthracycline, a taxane, and capecitabine
(BEACON): a randomised, open-label,
multicentre, phase 3 trial. Lancet Oncol 2015; 16:
1556–1568.
61. Twelves C, Cortés J, O’Shaughnessy J, etal.
Health-related quality of life in patients with
locally recurrent or metastatic breast cancer
treated with etirinotecan pegol versus treatment
of physician’s choice: results from the randomised
phase III BEACON trial. Eur J Cancer 2017; 76:
205–215.
62. Hoch U, Staschen C-M, Johnson RK, etal.
Nonclinical pharmacokinetics and activity of
etirinotecan pegol (NKTR-102), a long-acting
topoisomerase 1 inhibitor, in multiple cancer
models. Cancer Chemother Pharmacol 2014; 74:
1125–1137.
63. Kehrer DF, Yamamoto W, Verweij J, etal.
Factors involved in prolongation of the terminal
disposition phase of SN-38: clinical and
experimental studies. Clin Cancer Res 2000; 6:
3451–3458.
64. Jameson GS, Hamm JT, Weiss GJ, etal.
A multicenter, phase I, dose-escalation
study to assess the safety, tolerability, and
pharmacokinetics of etirinotecan pegol in patients
with refractory solid tumors. Clin Cancer Res
2013; 19: 268–278.
65. Adkins CE, Nounou MI, Hye T, etal. NKTR-
102 Efficacy versus irinotecan in a mouse model
of brain metastases of breast cancer. BMC Cancer
2015; 15: 685.
66. Cortés J, Rugo HS, Awada A, etal. Prolonged
survival in patients with breast cancer and
a history of brain metastases: results of a
preplanned subgroup analysis from the
randomized phase III BEACON trial. Breast
Cancer Res Treat 2017; 165: 329–341.
67. Tripathy D, Tolaney S, Seidman AD, etal.
Abstract OT1–04–08: Phase 3 study of
etirinotecan pegol versus treatment of physician9s
choice in patients with metastatic breast cancer
who have stable brain metastases previously
treated with an anthracycline, a taxane, and
capecitabine. Cancer Res 2017; 77(Suppl. 4):
OT1–04–08-OT1–04–8.
68. Fitzgerald DP, Emerson DL, Qian Y, etal.
TPI-287, a new taxane family member, reduces
the brain metastatic colonization of breast
cancer cells. Mol Cancer Ther 2012; 11:
1959–1967.
69. Goldlust SA, Nabors LB, Mohile N, etal.
Final results from the dose-escalation stage of
a phase 1/2 trial of TPI 287, a brain penetrable
microtubule inhibitor, plus bevacizumab in
patients with recurrent glioblastoma. J Clin Oncol
2017; 35(Suppl. 15): 2021.
70. TPI 287 in Breast Cancer Metastatic to the Brain
- Full Text View - ClinicalTrials.gov [Internet].
https://clinicaltrials.gov/ct2/show/NCT01332630
(accessed 25 February 2018).
Therapeutic Advances in Medical Oncology 10
10 journals.sagepub.com/home/tam
71. Nahta R and Esteva FJ. HER2 therapy:
molecular mechanisms of trastuzumab resistance.
Breast Cancer Res 2006; 8: 215.
72. Zhao X, Xie J, Chen X, etal. Neratinib
reverses ATP-binding cassette B1-mediated
chemotherapeutic drug resistance in vitro, in vivo,
and ex vivo. Mol Pharmacol 2012; 82: 47–58.
73. Hegedüs C, Truta-Feles K, Antalffy G, etal.
Interaction of the EGFR inhibitors gefitinib,
vandetanib, pelitinib and neratinib with the
ABCG2 multidrug transporter: implications
for the emergence and reversal of cancer
drug resistance. Biochem Pharmacol 2012; 84:
260–267.
74. 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.
75. Raub TJ, Gelbert LM, Wishart GN, etal. Brain
exposure of two selective dual CDK4 and
CDK6 inhibitors and the antitumor activity
of CDK4 and 6 inhibition in combination
with temozolomide in an intracranial
glioblastoma xenograft. Drug Metab Dispos 2015;
dmd.114.062745.
76. McMullin RP, Wittner BS, Yang C, etal. A
BRCA1 deficient-like signature is enriched in
breast cancer brain metastases and predicts DNA
damage-induced poly (ADP-ribose) polymerase
inhibitor sensitivity. Breast Cancer Res BCR 2014;
16: R25.
77. Owens T, Renno T, Taupin V, etal.
Inflammatory cytokines in the brain: does the
CNS shape immune responses? Immunol Today
1994; 15: 566–571.
78. Goldberg SB, Gettinger SN, Mahajan A, etal.
Pembrolizumab for patients with melanoma or
non-small-cell lung cancer and untreated brain
metastases: early analysis of a non-randomised,
open-label, phase 2 trial. Lancet Oncol 2016; 17:
976–983.
79. Margolin K, Ernstoff MS, Hamid O, etal.
Ipilimumab in patients with melanoma and brain
metastases: an open-label, phase 2 trial. Lancet
Oncol 2012; 13: 459–465.
80. Tawbi HA-H, Forsyth PAJ, Algazi AP, etal.
Efficacy and safety of nivolumab (NIVO) plus
ipilimumab (IPI) in patients with melanoma
(MEL) metastatic to the brain: results of the
phase II study CheckMate 204. J Clin Oncol
2017; 35(Suppl. 15): 9507.
81. Long GV, Atkinson V, Menzies AM, etal. A
randomized phase 2 study of nivolumab and
nivolumab combined with ipilimumab in patients
(pts) with melanoma brain metastases: The
Anti-PD1 Brain Collaboration (ABC Study). J
Clin Oncol 2016; 34(Suppl. 15): TPS9591.
82. Escudier BJ, Chabaud S, Borchiellini D, etal.
Efficacy and safety of nivolumab in patients with
metastatic renal cell carcinoma (mRCC) and
brain metastases: preliminary results from the
GETUG-AFU 26 (Nivoren) study. J Clin Oncol
2017; 35(Suppl. 15): 4563.
83. Hu ZI, McArthur HL and Ho AY. The abscopal
effect of radiation therapy: what is it and how can
we use it in breast cancer? Curr Breast Cancer Rep
2017; 9: 45–51.
Visit SAGE journals online
journals.sagepub.com/
home/tam
SAGE journals
... Brain metastases (BM) have gradually become the most common malignancy of the central nervous system, with 20-40% of patients with cancer developing BM (1,2). Primarily, BM arises from tumors in the lungs and the breast; however, they are observed at other sites as well (3). ...
... Annually, the global incidence of BM has progressively increased and is associated with a poor prognosis. The overall survival varies from 3 to 25 months depending on tumor type and subtype, BM has become a clinically important disease that poses a remarkable threat to human health (2,4). An estimated 30-50% of patients with metastatic breast cancer (MBC) develop BM (5,6). ...
Article
Full-text available
Objectives Ultrasound (US) imaging is a relatively novel strategy to monitor the activity of the blood–brain barrier, which can facilitate the diagnosis and treatment of neurovascular-related metastatic tumors. The purpose of this study was to investigate the clinical significance of applying a combination of US imaging outcomes and the associated genes. This was performed to construct line drawings to facilitate the prediction of brain metastases arising from breast cancer. Methods The RNA transcript data from The Cancer Genome Atlas (TCGA) database was obtained for breast cancer, and the differentially expressed genes (DEGs) associated with tumor and brain tumor metastases were identified. Subsequently, key genes associated with survival prognosis were subsequently identified from the DEGs. Results Tripartite motif-containing protein 67 ( TRIM67 ) was identified and the differential; in addition, the survival analyses of the TCGA database revealed that it was associated with brain tumor metastases and overall survival prognosis. Applying independent clinical cohort data, US-related features (microcalcification and lymph node metastasis) were associated with breast cancer tumor metastasis. Furthermore, ultrasonographic findings of microcalcifications showed correlations with TRIM67 expression. The study results revealed that six variables [stage, TRIM67 , tumor size, regional lymph node staging (N), age, and HER2 status] were suitable predictors of tumor metastasis by applying support vector machine–recursive feature elimination. Among these, US-predicted tumor size correlated with tumor size classification, whereas US-predicted lymph node metastasis correlated with tumor N classification. The TRIM67 upregulation was accompanied by upregulation of the integrated breast cancer pathway; however, it leads to the downregulation of the miRNA targets in ECM and membrane receptors and the miRNAs involved in DNA damage response pathways. Conclusions The TRIM67 is a risk factor associated with brain metastases from breast cancer and it is considered a prognostic survival factor. The nomogram constructed from six variables—stage, TRIM67 , tumor size, N, age, HER2 status—is an appropriate predictor to estimate the occurrence of breast cancer metastasis.
... Certain subgroups of patients with HR+ ABC have poorer prognoses compared with other populations, including patients with central nervous system (CNS) metastases [8,9], patients who have received multiple lines of prior chemotherapy [10], patients with visceral metastases (particularly liver metastases) [11,12], or patients with poor performance status (PS) [13]. CNS metastases often occur in patients with breast cancer, with brain metastases being diagnosed in up to 30% of patients with breast cancer overall [8], although patients with estrogen-receptor positive disease tend to have a lower incidence (5%-10%) [14]. ...
... Many patients with some types of distant metastases, poor PS, or prior treatment, have poor prognosis without effective treatment and are often excluded from clinical trials [8][9][10][11][12][13][16][17][18][19], resulting in a paucity of evidence regarding optimal treatment regimens [1]. ...
Article
Full-text available
Background The phase IIIb CompLEEment-1 study evaluated ribociclib plus letrozole in patients with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC). Outcomes were investigated in the following subgroups: central nervous system (CNS) metastases, prior chemotherapy for advanced disease, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2, and visceral metastases with prior chemotherapy for advanced disease or ECOG PS 2. Patients and methods Patients with HR+, HER2– ABC without prior hormonal treatment for advanced disease received oral ribociclib (600 mg once daily, 3 weeks on/1 week off) plus letrozole (2.5 mg once daily, continuous). Primary endpoint was safety/tolerability, assessed via occurrence of adverse events (AEs); key secondary endpoints included time to progression (TTP), overall response rate, and clinical benefit rate. Results 51 patients had CNS metastases, 194 received prior chemotherapy for advanced disease, 112 had ECOG PS 2, 146 had visceral metastases plus prior chemotherapy, and 77 had visceral metastases plus ECOG PS 2. Safety results were consistent with those in the overall CompLEEment-1 population; no new safety concerns were identified. The AE profile was manageable with low rates of discontinuations due to AEs. TTP in patients with CNS metastases was consistent with the overall study population and shorter for other patient subgroups. Each patient subgroup achieved meaningful clinical benefit from treatment, consistent with the overall population. Conclusion These findings confirm the clinical benefit of ribociclib plus endocrine therapy in high-risk patient subgroups of clinical interest commonly underrepresented in clinical trials.
... The efficacy of systemic therapy may be limited by an inability to access the brain, drug efflux pumps that may exclude cytotoxic and ADCs, and acquired resistance to prior treatment regimens. 26,27 Accumulating evidence, however, suggests a potential role for ADCs in HER2+ and TNBC MBC patients with brain metastases (BM). 28 A subgroup analysis from the phase 3 ASCENT trial 29 showed SG led to improvement in response rate and PFS compared to chemotherapy for a patient with metastatic TNBC who had stable BM (5.6 months compared to 1.7 months). ...
Article
Full-text available
Recent advances in bioengineering and manufacturing have catapulted Antibody–drug conjugates (ADCs) to broader clinical applications. ADCs take advantage of the exquisite specificity of monoclonal antibodies (mAb) to deliver a highly potent cytotoxic agent to a specifically targeted cell expressing a selected antigen. HER2-positive breast cancer has served as a testing ground for ADC development in solid tumors that over-express HER2/neu by linking trastuzumab to a payload agent. With the current advances, ADCs leverage the selective targeting of monoclonal antibodies to deliver highly potent agents which otherwise have a narrow therapeutic index. Ado-trastuzumab emtansine (T-DM1) was the first ADC approved for patients with HER2-postive metastatic breast cancer (MBC) and fam-trastuzumab deruxtecan-nxki (T-DXd) was recently approved as well. Sacituzumab govitecan-hziy (SG) was approved in 2020 for patients with triple negative breast cancer (TNBC). Studies focusing on utilizing ADCs in earlier stages of breast cancer in the neoadjuvant or adjuvant setting, and central nervous system (CNS) disease are in progress. New ADCs and bispecific antibodies (bAbs) are also in development.
... BM occurs in 30-55% of patients with HER2+ metastatic BC, and up to half die from intracranial progression, whereas the median survival rate is only six months in triple-negative BC (TNBC) with BM (Lin et al., 2008;Dawood et al., 2009). Unfortunately, effective treatment is not available because the central nervous system is traditionally considered an immune-privileged site due to the blood-brain barrier (BBB) (Witzel et al., 2016;Kotecki et al., 2018). As a result, the identification of genetic and epigenetic alterations is essential for developing the BMtargeted therapies (Pedrosa et al., 2018). ...
Article
Full-text available
Breast cancer (BC) is the second leading cause of brain metastases (BM), with high morbidity and mortality. The aim of our study was to explore the effect of the cartilage intermediate layer protein (CILP) on breast cancer brain metastases (BCBM). Using a weighted gene coexpression network analysis (WGCNA) in GSE100534 and GSE125989 datasets, we found that the yellow module was closely related to the occurrence of BCBM, and CILP was a hub gene in the yellow module. Low CILP expression was associated with a poor prognosis, and it was an independent prognostic factor for stage III–IV BC determined using Cox regression analysis. A nomogram model including CILP expression was established to predict the 5-, 7-, and 10-year overall survival (OS) probabilities of stage III–IV BC patients. We found that CILP mRNA expression was downregulated in BCBM through GSE100534, GSE125989, and GSE43837 datasets. In addition, we found that CILP mRNA expression was negatively correlated with vascular endothelial growth factor A (VEGFA), which is involved in regulating the development of BM. UALCAN analysis showed that CILP expression was downregulated in HER2-positive (HER2+) and triple-negative breast cancer (TNBC), which are more prone to BM. The vitro experiments demonstrated that CILP significantly inhibited BC cell proliferation and metastasis. Western blot (WB) results further showed that the mesenchymal protein marker vimentin was significantly downregulated following CILP overexpression, suggesting that CILP could participate in migration through epithelial–mesenchymal transition (EMT). A comparison of CILP expression using immunohistochemistry in BC and BCBM showed that CILP was significantly downregulated in BCBM. In addition, gene set variation analysis (GSVA) revealed that CILP was associated with the T-cell receptor signaling pathway in BCBM and BC, indicating that CILP may be involved in BCBM through immune effects. BCBM showed lower immune infiltration than BC. Moreover, CILP expression was positively correlated with HLA-II, T helper cells (CD4 ⁺ T cells), and Type II IFN Response in BCBM . Collectively, our study indicates that CILP is associated with immune infiltration and may be a putative gene involved in BCBM. CILP offers new insights into the pathogenesis of BCBM, which will facilitate the development of novel targets for BCBM patients.
... However, long-term survival is complicated by increased prevalence of breast cancer brain metastasis (BCBrM), which is associated with poor prognosis and decreased quality of life (2). Specifically, breast cancer is the second most common primary origin of BrM, with 15-30% of patients estimated to develop BrM during the course of advanced disease (3,4). ...
Article
Full-text available
Background There is a concern that HER2-directed systemic therapies, when administered concurrently with stereotactic radiosurgery (SRS), may increase the risk of radiation necrosis (RN). This study explores the impact of timing and type of systemic therapies on the development of RN in patients treated with SRS for HER2+ breast cancer brain metastasis (BCBrM). Methods This was a single-institution, retrospective study including patients >18 years of age with HER2+ BCBrM who received SRS between 2013 and 2018 and with at least 12-month post-SRS follow-up. Presence of RN was determined via imaging at one-year post-SRS, with confirmation by biopsy in some patients. Demographics, radiotherapy parameters, and timing (“during” defined as four weeks pre- to four weeks post-SRS) and type of systemic therapy (e.g., chemotherapy, HER2-directed) were evaluated. Results Among 46 patients with HER2+ BCBrM who received SRS, 28 (60.9%) developed RN and 18 (39.1%) did not based on imaging criteria. Of the 11 patients who underwent biopsy, 10/10 (100%) who were diagnosed with RN on imaging were confirmed to be RN positive on biopsy and 1/1 (100%) who was not diagnosed with RN was confirmed to be RN negative on biopsy. Age (mean 53.3 vs 50.4 years, respectively), radiotherapy parameters (including total dose, fractionation, CTV and size target volume, all p >0.05), and receipt of any type of systemic therapy during SRS (60.7% vs 55.6%, p =0.97) did not differ between patients who did or did not develop RN. However, there was a trend for patients who developed RN to have received more than one agent of HER2-directed therapy independent of SRS timing compared to those who did not develop RN (75.0% vs 44.4%, p =0.08). Moreover, a significantly higher proportion of those who developed RN received more than one agent of HER2-directed therapy during SRS treatment compared to those who did not develop RN (35.7% vs 5.6%, p =0.047). Conclusions Patients with HER2 BCBrM who receive multiple HER2-directed therapies during SRS for BCBrM may be at higher risk of RN. Collectively, these data suggest that, in the eight-week window around SRS administration, if HER2-directed therapy is medically necessary, it is preferable that patients receive a single agent.
... 11 Furthermore, retrospective cohort studies have demonstrated the survival benefit in metastatic breast cancer patients via the surgical removal of primary tumors and systemic treatments. 12,13 Although previous studies have analyzed the relationship between newly diagnosed BM patients and subtypes, no further analysis of prognostic factors of breast cancer has been performed. 3,7,14,15 Therefore, the present study conducted an analysis based on the Surveillance, Epidemiology, and End Results (SEER) database to evaluate the association between the mortality of BC patients with BM and the molecular phenotypes of breast cancer. ...
Article
Full-text available
Background Brain metastasis is an important cause of breast cancer-related death. Aim We evaluated the relationships between breast cancer subtype and prognosis among patients with brain metastasis at the initial diagnosis. Methods The Surveillance, Epidemiology, and End Results database was searched to identify patients with brain metastasis from breast cancer between 2010 and 2015. Multivariable Cox proportional hazard models were used to identify factors that were associated with survival among patients with initial brain metastases. The Kaplan–Meier method was used to compare survival outcomes according to breast cancer subtype. Results Among 752 breast cancer patients with brain metastasis at diagnosis, 140 patients (18.6%) underwent primary surgery and 612 patients (81.4%) did not undergo surgery, while 460 patients (61.2%) received chemotherapy and 292 patients (38.8%) did not receive chemotherapy. Multivariable analysis revealed that, relative to HR+/HER2– breast cancer, HR–/HER2– breast cancer was associated with significantly poorer overall survival (hazard ratio: 2.52, 95% confidence interval: 1.99–3.21), independent of age, sex, race, marital status, insurance status, grade, liver involvement, lung involvement, primary surgery, radiotherapy, and chemotherapy. The median overall survival intervals were 12 months for HR+/HER2−, 19 months for HR+/HER2+, 11 months for HR−/HER2+, and 6 months for HR–/HER2– ( P < .0001). Relative to HR+/HER2– breast cancer, HR–/HER2– breast cancer was associated with a significantly higher risk of mortality among patients, and the association was stronger among patients who received chemotherapy ( p for interaction = .005). Conclusions Breast cancer subtype significantly predicted overall survival among patients with brain metastasis at diagnosis.
... Melanoma, breast and lung cancer show the highest BrM incidence [1][2][3] . Despite advances in the management of extracranial primary tumors, treatment options for disseminated disease remain limited and largely depend on multimodal approaches involving surgical resection, radio-and/or chemotherapy 4,5 . The success of immunotherapies in several noncerebral cancers has led to considerable optimism for more-effective treatment options for brain tumors, including glioblastoma and BrM 1,3,6,7 . ...
Article
Full-text available
Tumor microenvironment-targeted therapies are emerging as promising treatment options for different cancer types. Tumor-associated macrophages and microglia (TAMs) represent an abundant nonmalignant cell type in brain metastases and have been proposed to modulate metastatic colonization and outgrowth. Here we demonstrate that targeting TAMs at distinct stages of the metastatic cascade using an inhibitor of colony-stimulating factor 1 receptor (CSF1R), BLZ945, in murine breast-to-brain metastasis models leads to antitumor responses in prevention and intervention preclinical trials. However, in established brain metastases, compensatory CSF2Rb–STAT5-mediated pro-inflammatory TAM activation blunted the ultimate efficacy of CSF1R inhibition by inducing neuroinflammation gene signatures in association with wound repair responses that fostered tumor recurrence. Consequently, blockade of CSF1R combined with inhibition of STAT5 signaling via AC4-130 led to sustained tumor control, a normalization of microglial activation states and amelioration of neuronal damage.
... Its incidence has been increasing in recent years due to the improvement in the quality of neuroimaging diagnostic techniques (e.g. magnetic resonance imaging -MRI-) and improved effectiveness of treatment regimens [4][5][6][7] . Breast cancer (BC) represents the second most common cause of BMs in adult patients (15-25%) 1,8 . ...
Article
Full-text available
Background: Whole-brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS) are two treatment modalities commonly utilized to treat brain metastases (BMs). Aim: The purpose of this study is to analyse retrospectively the local control and survival of patients with BMs of breast cancer (BC) treated via radiosurgery using Volumetric Modulated Arc Therapy (VMAT-RS). Methods: 18 patients with 41 BMs of BC and treated by VMAT-RS were studied. They were classified according to the molecular subtype of BC and the modified breast graded prognostic assessment -GPA- index. Patients presented 1-4 BMs, which were treated with 5 non-coplanar VMAT arcs. The spatial distribution of BMs, the influence of receptor status on the location of the lesions and survival assessed via the Kaplan-Meier model were analyzed. Results: The median survival time (MST) was 19.7 months. Statistically significant differences were determined in the MST according to the Karnofsky performance status (p= 0.02) and the HER2 status (p= 0.004), being more prolonged in the HER2+ patients. Finally, our results showed that the cerebellum is the predominant site of breast cancer BMs, and also suggested that HER2+BMs had a predilection for some structures of the posterior circulation, such as the cerebellum, brainstem and occipital lobes (p= 0.048). Conclusions: The VMAT-RS is a technique with an overall survival comparable to other radiosurgery techniques. The baseline situation at the time of treatment, the modified breast-GPA and the molecular subtypes, are factors that significantly influence patient survival.
... However, the options to treat TNBC brain metastasis are limited due to the lack of targetable surface markers on these tumor cells. Radiation treatment, surgical resection, or chemotherapy remains the standard of care (3,4), but the median survival after diagnosis of CNS disease is less than 5 months (3,5,6). CNS metastases can be further subcategorized to parenchymal metastases (PMs) or leptomeningeal carcinomatosis (LC) depending on the site of tumor infiltration (7). ...
Article
Full-text available
Engineered tumor-homing neural stem cells (NSCs) have shown promise in treating cancer. Recently, we transdifferentiated skin fibroblasts into human-induced NSCs (hiNSC) as personalized NSC drug carriers. Here, using a SOX2 and spheroidal culture-based reprogramming strategy, we generated a new hiNSC variant, hiNeuroS, that was genetically distinct from fibroblasts and first-generation hiNSCs and had significantly enhanced tumor-homing and antitumor properties. In vitro, hiNeuroSs demonstrated superior migration to human triple-negative breast cancer (TNBC) cells and in vivo rapidly homed to TNBC tumor foci following intracerebroventricular (ICV) infusion. In TNBC parenchymal metastasis models, ICV infusion of hiNeuroSs secreting the proapoptotic agent TRAIL (hiNeuroS-TRAIL) significantly reduced tumor burden and extended median survival. In models of TNBC leptomeningeal carcinomatosis, ICV dosing of hiNeuroS-TRAIL therapy significantly delayed the onset of tumor formation and extended survival when administered as a prophylactic treatment, as well as reduced tumor volume while prolonging survival when delivered as established tumor therapy.
Article
Full-text available
The brain is the most common site of first metastasis for patients with HER2-positive breast cancer treated with HER2-targeting drugs. However, the development of effective therapies for breast cancer brain metastases (BCBMs) is limited by an incomplete understanding of the mechanisms governing drug sensitivity in the central nervous system. Pharmacodynamic data from patients and in vivo models suggest that inadequate drug penetration across the 'blood-tumor' barrier is not the whole story. Using HER2-positive breast cancer brain metastases as a case study, we highlight recent data from orthotopic brain metastasis models that implicates brain-specific drug resistance mechanisms in BCBMs and suggests a translational research paradigm to guide drug development for treatment of BCBMs.
Article
1019 Background: Abemaciclib is an oral selective CDK4 and CDK6 inhibitor administered on a continuous dosing schedule, which has demonstrated clinical activity and an acceptable safety profile in patients (pts) with heavily pre-treated HR+ metastatic breast cancer (MBC). Abemaciclib has been shown preclinically to cross the blood-brain barrier, providing rationale for testing this agent in pts with BM. Furthermore, as previously presented, levels of abemaciclib similar to plasma were detected in resected BM in a subset of pts with HR+, HER2- MBC in this study. Methods: Study I3Y-MC-JPBO is an open-label, Phase 2, Simon 2-Stage trial evaluating the safety and efficacy of abemaciclib 200 mg BID in pts with new or progressive BM secondary to HR+ MBC, NSCLC, or melanoma. Eligible pts in Part B (the focus of this presentation) include pts with HR+, HER2- MBC who have ≥1 measurable brain lesion. The primary objective was objective intracranial (IC) response rate as defined by Response Assessment in Neuro-Oncology BM response criteria. Secondary objectives (IC related) include best overall response, duration of response, disease control rate, and clinical benefit rate. Exploratory objectives include assessment of drug concentrations in resected tumors. Safety, tolerability, and PK of abemaciclib were also assessed. Stage 1 includes 23 pts; if < 2 of the 23 pts respond to abemaciclib, futility is met. However, if ≥2 respond, 33 additional pts are to be enrolled to Stage 2. Results: This Stage 1 efficacy analysis included 23 pts; 32 pts were included in the safety analysis. Although 5 pts were considered nonevaluable, 2 pts (8.7%) had confirmed partial response (PR) (meeting the predefined threshold for advancement to Stage 2); enrollment is ongoing. At the time of the analysis, the 2 pts with PR had completed 14 and 15 cycles each (21d cycles) of therapy. The majority of adverse events were gastrointestinal in nature, consistent with previous studies of abemaciclib. Conclusions: This study has provided preliminary evidence that abemaciclib penetrated BM in pts with HR+, HER2- MBC and had antitumor activity in this population. Final results will be presented following Stage 2 analyses. Clinical trial information: NCT02308020.
Article
9507 Background: Brain metastases (BMts) are a major cause of morbidity/death in MEL. We report the first efficacy data in MEL patients (pts) with BMts who received NIVO+IPI in study CheckMate 204. Methods: In this multicenter US trial (NCT02320058), MEL pts with ≥1 measurable BMt 0.5-3.0 cm and no neurologic symptoms or steroid Rx received NIVO 1 mg/kg + IPI 3 mg/kg Q3W x 4, then NIVO 3 mg/kg Q2W until progression or toxicity. Pts with severe adverse events (AEs) during NIVO+IPI could receive NIVO when toxicity resolved; stereotactic radiotherapy (SRT) was allowed for brain oligo-progression if an assessable BMt remained. The primary endpoint was intracranial (IC) clinical benefit rate (complete response [CR] + partial response [PR] + stable disease [SD] > 6 months). The planned 90-pt accrual is complete; we report efficacy and updated safety for 75 pts with disease assessment before the Nov 2016 database lock. Results: Median age was 59 yrs (range 22–79). Median number of induction doses was 3; 26 pts (35%) received 4 NIVO+IPI doses and 38 pts (51%) began NIVO maintenance. Response data are reported at a median follow-up of 6.3 months (Table). The IC objective response rate (ORR) was 56% (95% CI: 44–68); 19% of pts had a complete response. IC and extracranial responses were largely concordant. Rx-related grade 3/4 AEs occurred in 48% of pts, 8% neurologic, including headache and syncope. Only 3 pts (4%) stopped Rx for Rx-related neurologic AEs. One pt died of immune-related myocarditis. Conclusions: In CheckMate 204, prospectively designed to investigate NIVO+IPI in MEL pts with BMts, NIVO+IPI had high IC antitumor activity with objective responses in 56% of pts, CR in 19%, and no unexpected neurologic safety signals. The favorable safety and high anti-melanoma activity of NIVO+IPI may represent a new Rx paradigm for pts with asymptomatic MEL BMts and could change practice to avoid or delay whole brain RT or SRT. Clinical trial information: NCT02320058. [Table: see text]
Article
4563 Background: Nivolumab (N) has been shown active in patients (pts) with mRCC after failure of 1 or 2 TKIs. Efficacy and safety of N in pts with brain metastases (BM) from RCC is still unknown. The aim of this study is to report preliminary data of the Nivoren study in pts with BM. Methods: GETUG-AFU 26 (Nivoren) is a prospective phase 2 study assessing safety and efficacy of N in a broader mRCC patient population than those recruited in the pivotal phase 3, including pts with BM (previously treated or not, but not requiring steroids), with previous mTOR inhibitor, with PS 2 as well as in previously highly pretreated pts. N was given every 2 weeks at 3mg/kg, until disease progression or unacceptable toxicity. Treatment was allowed beyond progression in case of clinical benefit. All pts had brain CT scan or MRI at baseline. Results: Up to December 2016 , 588 pts have been enrolled including 55 pts with BM (35 (67%) ,6 (12%) and 11 (21%) with 1, 2 or > 2 BM, respectively. Of those 55 pts, 10 pts (23%) were PS 2 and 25 (58%) PS 1, and 16 patients (29%) had received more that 2 lines of therapy. No previous treatment for BM was performed in 67% (n = 37), while 9% had previous brain surgery (n = 5 ;) or brain radiation (n = 17 (31%). 2/55 pts never received N. Median duration of therapy in BM pts was 2.4 months (varying from 0 to 9) with a 3-months PFS of 60% (IC95% = 45 – 73). Median OS is not reached at the time of this analysis. Among 44 pts with assessment of response on BM, 10 (23%) had objective response while 21 (48%) had local progressive disease. Neurologic deterioration requiring steroids was observed in 15 pts (32%) . Updated data will be presented at the meeting. Conclusions: This is the first large study to report preliminary safety and efficacy of N in RCC pts with BM. Safety of N in this pt population appears to be acceptable, although some pts do require steroids because of brain progressive disease. Objective response in the brain was observed in 23% of pts. Further follow up is required to determine the real benefit of N in this group of mRCC pts. Clinical trial information: NCT03013335.
Article
2021 Background: Microtubule inhibitors, including taxanes, are active in preclinical models of glioblastoma (GBM), however, clinical benefit is hampered by poor blood-brain barrier (BBB) accumulation. TPI 287, a third-generation taxane designed to evade P-glycoprotein mediated efflux, readily penetrates the BBB and overcomes this limitation. CB-017 is a multi-center phase 1/2 trial designed to determine the optimal dose of TPI 287 and potential efficacy in patients treated with this drug plus bevacizumab (BEV) for treatment of recurrent GBM. Final results of the dose escalation Phase 1 stage of this trial are reported. Methods: GBM patients at first or second relapse after standard therapy and without prior exposure to anti-angiogenic agents were eligible for enrollment. BEV was administered at 10 mg/kg every 2 weeks and TPI 287 every 3 weeks via IV infusion. MRIs were obtained every six weeks with response assessed via RANO criteria. TPI 287 dose escalation was based on a traditional 3+3 design. Results: Twenty-four patients were enrolled in 7 TPI 287 dose-escalation cohorts (140-220 mg/m2) from 6 U.S. centers. Twenty and 23 patients were evaluable for response and survival, respectively. Median follow-up was 28 months. Results are shown in the table below. Of the 9 patients from which biomarker data was available, tumors from 8 patients (89%) harbored an unmethylated MGMT promoter, an established negative prognostic indicator for survival. No DLTs were reported and myelosuppression (n=3) was the only drug-related grade 3/4 adverse event. Conclusions: TPI 287 in combination with BEV is safe and well tolerated at doses up to 220 mg/m2. Final survival results from the Phase 1 portion of this study compare favorably with historical controls and support further investigation of TPI 287 plus BEV for treatment of recurrent GBM. Clinical trial information: NCT01933815. [Table: see text]
Article
1005 Background: Evidence-based treatments (tx) for metastatic, HER2+ BCBM are limited. We previously found a central nervous system (CNS) objective response rate (ORR) of 8% (95% CI 2-22%) for the irreversible, EGFR/HER2-targeted kinase inhibitor, neratinib. To enhance CNS activity, we evaluated the combination of neratinib + capecitabine in a subsequent cohort, and report results here. Methods: Pts with measurable BCBM (≥ 1 cm in longest dimension) and no prior lapatinib or capecitabine were eligible. All but 3 had CNS progression after local CNS tx. During 21 day cycles, pts received capecitabine 750 mg/m2 twice daily x 14 days followed by 7 days off + neratinib 240 mg orally once daily. Loperamide prophylaxis (16 mg total daily) was recommended during cycle 1. Brain MRI and non-CNS imaging were repeated every 2 cycles until 18 wks, then every 3 cycles. The primary endpoint was composite CNS ORR, requiring all of the following: ≥50% reduction in volumetric sum of target CNS lesions (central review, VORR), no progression of non-target or non-CNS lesions, no new lesions, no escalating steroids, and no progressive neurologic signs/symptoms. We used a two-stage design with hypotheses ORR 15% and 35% (error rates 5% and 20%), responses in ≥5/19 pts to enter 2 nd stage; responses in ≥9/35 [26%] pts to be promising. Results: 39 pts enrolled between 4/2014-11/2016 (2 withdrew before tx, 37 analyzed); median age 51, median prior metastatic lines 2 (range 0-6), 65% had prior WBRT. As of 11/15/16, 23 (62%) patients are alive and 7 remain on protocol tx; median number of cycles initiated = 5 (range 1-26). 18 women (49%) had a VORR (95% CI 32-66%, neurologic exams not yet available on all pts). Overall 12-month survival is 63% (95% CI 43%-77%); 4/7 pts still on protocol therapy have not yet reached 6 cycles. No pts had grade 4 toxicity; 18 (49%) had grade 3 toxicity, with diarrhea most common (32%), and 6 pts discontinued tx for toxicity. Conclusions: The combination of neratinib and capecitabine is active for BCBM with VORR in nearly half of pts, supporting further development of the regimen for BCBM. Updated results will be presented at the meeting. Clinical trial information: NCT01494662.
Article
Patients with active CNS disease are often excluded from clinical trials, and data regarding the CNS efficacy of systemic agents are usually obtained late in the drug development process or not at all. In this guideline from the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group, we provide detailed recommendations on when patients with brain metastases from solid tumours should be included or excluded in clinical trials of systemic agents. We also discuss the limitations of retrospective studies in determining the CNS efficacy of systemic drugs. Inclusion of patients with brain metastases early on in the clinical development of a drug or a regimen is needed to generate appropriate CNS efficacy or non-efficacy signals. We consider how to optimally incorporate or exclude such patients in systemic therapy trials depending on the likelihood of CNS activity of the agent by considering three scenarios: drugs that are considered very unlikely to have CNS antitumour activity or efficacy; drugs that are considered very likely to have CNS activity or efficacy; and drugs with minimal baseline information on CNS activity or efficacy. We also address trial design issues unique to patients with brain metastases, including the selection of appropriate CNS endpoints in systemic therapy trials.
Article
BACKGROUND Microtubule inhibitors are active in preclinical models of glioblastoma (GBM), however, clinical benefit is hampered by poor CNS accumulation. TPI 287, a taxane designed to evade P-glycoprotein mediated efflux, readily penetrates the blood brain barrier and overcomes this limitation. CB-017 is a multi-center phase 1/2 trial designed to determine the optimal dose of TPI 287 and potential efficacy in combination with bevacizumab (BEV) for treatment of recurrent GBM. Final results of the dose escalation Phase 1 stage of this trial are reported. METHODS GBM patients at first or second relapse after standard therapy and without prior exposure to anti-angiogenic agents were eligible for enrollment. BEV was administered at 10 mg/kg every 2 weeks and TPI 287 every 3 weeks IV. RANO response was assessed every 6 weeks. RESULTS Twenty-four patients were enrolled in seven TPI 287 dose-escalation cohorts (140–220 mg/m2) from 6 U.S. centers. Twenty and 23 patients were evaluable for response and survival, respectively. 12/20 (60%) achieved an objective response (3 CR, 9 PR) and 10/23 patients had stable disease. Two of the patients achieving CR had converted from PR after subsequent treatment cycles. Median and 6-month PFS was 5.5 months and 40%, respectively. Median and 12-month overall survival was 13.4 months and 64%, respectively. Fifteen- and 18-month overall survival was 45% and 27%, respectively. Of the 9 patients from which tumor data was available, eight (89%) harbored an unmethylated MGMT promoter at diagnosis. No DLTs were reported and myelosuppression (n=3) was the only drug-related grade 3/4 adverse event. CONCLUSION TPI 287 in combination with BEV is safe and well tolerated at doses up to 220 mg/m2. Final survival results from the Phase 1 portion of this study compare favorably with historical controls and support further investigation of TPI 287 plus BEV for treatment of recurrent GBM.