J Neurooncol (2016) 127:407–414
DOI 10.1007/s11060-016-2075-3
TOPIC REVIEW
Brain metastasis in breast cancer: a comprehensive literature
review
Rezvan Rostami1 • Shivam Mittal2 • Pooya Rostami3
Fattaneh Tavassoli4 • Bahman Jabbari1
Received: 6 July 2015 / Accepted: 10 February 2016 / Published online: 24 February 2016
Ó Springer Science+Business Media New York 2016
Abstract This comprehensive review provides informa-
tion on epidemiology, size, grade, cerebral localization,
clinical symptoms, treatments, and factors associated with
longer survival in 14,599 patients with brain metastasis
from breast cancer; the molecular features of breast cancers
most likely to develop brain metastases and the potential
use of these predictive molecular alterations for patient
management and future therapeutic targets are also
addressed. The review covers the data from 106 articles
representing this subject in the era of modern neuroimaging
(past 35 years). The incidence of brain metastasis from
breast cancer (24 % in this review) is increasing due to
advances in both imaging technologies leading to earlier
& Rezvan Rostami
rezvanazadi@yahoo.com
Shivam Mittal
Shivam.Mittal@uhhospitals.org
Pooya Rostami
prostami@sgu.edu
Fattaneh Tavassoli
fattaneh.tavassoli@yale.edu
Bahman Jabbari
bahman.jabbari@yale.edu
1
Department of Neurology, Yale University School of
Medicine, 15 York Street, LCI Building, New Haven,
CT 06520, USA
2
Department of Neurology, Case Western Reserve University
School of Medicine, Cleveland, OH 44106-5040, USA
3 score. Novel therapies such as application of agents to
School of Medicine, St. George University, St. George’s,
Grenada, West Indies
4 blood brain barrier are being explored with preliminary
Department of Pathology, Yale University School of
Medicine, 20 York Street, Ste East Pavilion Suite 2608,
New Haven, CT 06510, USA
•
detection of the brain metastases and introduction of novel
therapies resulting in longer survival from the primary
breast cancer. The mean age at the time of breast cancer
and brain metastasis diagnoses was 50.3 and 48.8 years
respectively. Axillary node metastasis was noted in 32.8 %
of the patients who developed brain metastasis. The median
time intervals between the diagnosis of breast cancer to
identification of brain metastasis and from identification of
brain metastasis to death were 34 and 15 months, respec-
tively. The most common symptoms experienced in
patients with brain metastasis consisted of headache
(35 %), vomiting (26 %), nausea (23 %), hemiparesis
(22 %), visual changes (13 %) and seizures (12 %). A
majority of the patients had multiple metastases (54.2 %).
Cerebellum and frontal lobes were the most common sites
of metastasis (33 and 16 %, respectively). Of the primary
tumors for which biomarkers were recorded, 37 % were
estrogen receptor (ER)?, 41 % ER-, 36 % progesterone
receptor (PR)?, 34 % PR-, 35 % human epithelial growth
factor receptor 2 (HER2)?, 41 % HER2-, 27 % triple
negative and 18 % triple positive (TP). Treatment in most
patients consisted of a multimodality approach often with
two or more of the following: whole brain radiation therapy
(52 %), chemotherapy (51 %), stereotactic radiosurgery
(20 %), surgical resection (14 %), trastuzumab (39 %) for
HER2 positive tumors, and hormonal therapy (34 %) for
ER and/or PR positive tumors. Factors that had an impact
on prognosis included grade and size of the tumor, multiple
metastases, presence of extra-cranial metastasis, triple
negative or HER2? biomarker status, and high Karnovsky
reduce tumor angiogenesis or alter permeability of the
results suggesting a potential to improve survival after
brain metastasis. Other potential therapies based on genetic
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alterations in the tumor and the microenvironment in the
brain are being investigated; these are briefly discussed.
Keywords Breast cancer
Brain metastasis

Biomarkers
Hormonal therapy
Chemotherapy

Extracranial metastasis
Surgical resection
Introduction
A major challenge in management of breast cancer is its
propensity for distant metastasis to liver, bone, lung and
brain. Breast cancer is the second most common cause of
metastatic brain disease [1]. The risk of developing brain
metastasis has been reported to range from 10 to 16 %
among living, advanced breast cancer patients [2] and as
high as 30 % in autopsy series [3]. Brain is the first site of
metastasis from breast cancer in 12 % of patients [4]. It has
been suggested that brain metastases from breast cancer
(BMBC) occur more frequently among younger women,
those with larger tumors or higher nuclear grade, in certain
subtypes such as estrogen-receptor (ER)-negative, triple
negative, HER2 overexpressing tumors, and those with
nodal metastases [1]. In recent years, overall prognosis of
patients with BMBC has improved and it is now more
favorable than that of patients with brain metastasis from
lung cancer [5]. Considering the rapid evolution of this
field, literature reviews with focus on factors relevant to
survival and the progress in treatment of brain metastasis
can be helpful in management of the growing population of
patients with BMBC.
The literature was searched through Yale search engine
(from 1980—era of modern neuroimaging (MRI) to
include, but not limited to, Medline (PubMed), Erasmus
and Ovid. The search words consisted of breast tumors and
brain metastasis, breast carcinoma and brain metastasis,
breast cancer brain metastasis (BCBM), metastatic breast
cancer, metastatic breast cancer and survival, as well as
breast cancer and magnetic resonance imaging. The search
gathered information on epidemiology, age at onset of the
primary cancer and at the time of brain metastasis,
pathology, tumors’ biomarker status, location of brain
metastases, other metastatic sites, treatment and survival
after brain metastasis.
Results
We have searched the literature between January 1979 to
June 2015 for articles on brain metastasis related to breast
cancer, breast neoplasm or breast tumor [1, 4–46]. A total
of 271 studies were identified. All single case reports (80)
were excluded. Of the remaining 191 reports another 85,
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J Neurooncol (2016) 127:407–414
which lacked important demographic information (age,
sex) or provided vague and inconsistent information were
also excluded. The remaining 106 articles became the
subject of this review. The total number of patients with
breast cancer (BC) in these studies was 60,794; of these,
14,599 patients had brain metastases (24 %). The mean age
of the patients at the time of diagnosis of BC was
50.3 years, while the mean patient age at the time of
diagnosis of BMBC was 48.8 years. The interval between
the diagnoses of BC to identification of BM varied from 1
to 97 months (mean 32, median 34 months). The interval
from identification of BM to death ranged from 1 to
55 months (mean 17 and median 15 months). Information
about ethnicity was available for 8483 breast cancer
patients with or without brain metastasis; 68 % were
Caucasian, 17 % African American and 11 % were His-
panic. Of the 9057 patients for whom the menopausal
status was recorded, 2685 (30 %) were premenopausal at
the time of breast cancer diagnosis, while 4186 (46 %)
were postmenopausal; the menopausal status was not
recorded in all reports. The types of BC reported for 88 %
of patients (whole population) included ductal (79 %),
lobular (6 %), and medullary (3 %). The status of axillary
lymph nodes, at the time of BC diagnosis, was reported in
35 studies; a total of 12,520 (68 %) of the 18,274 cases
recorded were node positive at the time of initial BC
diagnosis. The number of positive nodes varied from B10
in 54 % to [0 nodes in 15 % of cases. A total of 5754 of
18,274 (32 %) cases had negative axillary lymph nodes.
The status of lymph nodes in patients with BM was
reported in 20 studies; 649 of 1981 (32.8 %) cases were
node positive suggesting that axillary node metastasis is
not a prerequisite for subsequent development of BM.
The number and location of BM were noted in a majority
of patients evaluated by magnetic resonance imaging (MRI).
Multiple in 54.2 % of the patients, the metastatic lesions
were supratentorial in 52.2 % and infratentorial in 24.1;
14 % had metastatic disease at both locations. The exact
location of brain metastasis was defined only in a few com-
munications (17 manuscripts, 547 patients): 26 % frontal
lobe, 33 % cerebellum and 5 % the brain stem. Extracranial
metastases at the time of BM and/or prior to the BM were
noted in 1469 of 2374 (63.2 %) patients. Lung, bone and
liver were the most common sites of metastasis with a fre-
quency of 652 of 9622 (40 %), 659 0f 9855 (32 %), and 495
of 9738 (27 %) respectively. The status of biomarkers for the
primary BC was reported in 50 studies; of these, 47.4 % were
estrogen receptor (ER)?, 52.5 % ER-, 51.4 % proges-
terone receptor (PR)?, 48.5 % PR-, 46 % human epithelial
growth factor receptor 2 (HER2)?, 53.9 % HER2-, 27 %
triple negative (TN) and 18 % triple positive (TP).
Among symptoms recorded, those most commonly
associated with BM included headache noted in 392 of
J Neurooncol (2016) 127:407–414
2495 (35 %), vomiting in 155 of 1039 (26 %), nausea in
140 of 967 (23 %), hemiparesis in 118 of 588 (22 %),
visual changes in 53 of 480 (13 %), seizures in 97 of 2251
(12 %) and altered mental status noted in 23 of 362 (7 %)
cases (Fig. 1). Therapies included whole brain radiation
therapy (WBRT) (52 %), chemotherapy (51 %), stereo-
tactic radiosurgery (SRS) (20 %), surgical resection
(14 %), trastuzumab (39 %) for HER2? tumors, and hor-
monal therapy (34 %) for ER? and/or PR? tumors. Mul-
tiple metastases, presence of extra-cranial metastases, [
5 cm size of the metastatic tumor, Karnofsky Performance
Status (KPS) score of B70, and presence of a triple nega-
tive biomarker status statistically correlated with shorter
survival after BM (P \ 0.05) (Table 1). Shorter survival
was also noted among patients with higher tumor grades,
lymph node metastasis, and HER2? cases that had not
received trastuzumab therapy (Table 1); for these factors,
correlation did not reach statistical significance, however.
In patients with BM, age, ethnic background and
the interval between the diagnosis of BC to detection of
BM did not correlate with survival time after brain
metastasis.
Discussion
This review covers data in the modern era of neuroimaging
over the past 35 years and, to our knowledge, is the most
comprehensive review of the subject of brain metastasis
from breast cancer to date. There has been an increase in
frequency of brain metastasis from breast cancer over time.
An incidence of 10 % brain metastasis has been reported
for stage IV breast cancer during early days of neu-
roimaging and before biomarker based therapy [44], rising
to 16 % in later reviews of this subject [2], to 24 and 34 %
in studies conducted between 2005 and 2010 [13, 32, 33];
Fig. 1 Frequency (%) of common signs and symptoms of brain
metastasis due to breast cancer
409
the later figures concurring with 24 % cited in our review.
This rise is a result of both advances in neuroimaging
leading to increased detection of metastatic disease and
longer patient survival due to novel therapies for breast
cancer in general [30, 31].
As to the location of BM from BC, cerebellum appears
to be the most favored location (33 %). In a post-mortem
study of 237 patients with BM from different sites, Graf
et al. [47] reported cerebellum and basal ganglia as the
preferred sites of metastasis for BC. Pakneshan et al. [48]
also found a cerebellar predilection (30 %) for ovarian
cancer metastasis to the brain. The high blood supply of
cerebellum may be the reason for this predilection. Nausea,
vomiting and headaches—common symptoms of posterior
fossa involvement—were also leading symptoms of
patients with BMBC (Fig. 1).
Factors that statistically correlated with longer survival
(P \ 0.05) consisted of a single brain metastasis, smaller
tumor size (B5 cm) of the brain metastases, absence of
extracranial metastasis, KPS score of [70 and absence of
triple negative biomarker status (Table 1). Patients without
lymph node metastasis, HER2? (Fig. 2) status—particu-
larly cases treated with trastuzumab- also had a longer
survival (Table 1). Age, race, ethnic background and the
interval between diagnosis of BC and detection of BM did
not impact survival. In previous reviews, the younger age
at time of BC diagnosis was noted as one of the factors
predictive of better prognosis, while the impact of race and
ethnicity status on prognosis was not established [6, 15,
29].
Treatment of BMBC includes surgery (usually for soli-
tary lesions \4 cm), whole brain radiation or stereotactic
radiosurgery, chemotherapy, and biological therapies. With
the exception of chemotherapy that has shown only a
modest effect on survival due to the poor capacity of
chemotherapeutic agents to cross blood brain barrier
(BBB), advances in other therapeutic approaches have
resulted in longer survival of patients. Stereotactic radio-
surgery with gamma knife is now often used as the initial
approach instead of whole brain radiation when there are
1–4 metastatic foci [49]. In a study of 160 patients, 104
lived beyond one year (12–107 months), of whom only
21 % later required WBRT. Concomitant surgical resection
improved the survival. The increased use of radiosurgical
techniques has shown a potential impact on survival. As an
example, a recent report has demonstrated the median
survival was 33 months for 50 patients who had radio-
surgery for treatment of brain metastasis secondary to
breast cancer [6].
Biological therapy is another novel approach aimed at
intrinsic subtypes of breast cancer identified through global
gene expression analysis. The subtypes consist of luminal
(luminal A = ER?. PR?, HER2-/ki67 low; luminal
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Table 1 Factors correlating

Factor Pt no. Survival (months) P value CI
with shorter survival in patients
with metastatic breast cancer to Brain tumor size
the brain
B5 cm 132 18 0.053 0.21 to 26.90
[5 cm 96 5
Primary tumor grade
I/II 184 10 0.202 -3.99 to 10.66
III/IV 518 6
Number of brain lesions
Single 1742 18 0.001 6.42 to 20.08
Multiple 2220 8
LN status
Negative 384 18 0.148 -2.47 to -1.14
Positive 649 10
Extracranial metastasis
Absent 467 26 0.034 -20.87 to -1.13
Present 3537 14
Biomarkers status
Triple-* 1457 11 0.170 -15.29 to 3.29
Triple? 387 15
HER2? 1727 15 0.957 -5.00 to -8.68
HER2- 1246 12
KPS score
KPS B70 460 8 0.002 -27.54 to -8.68
KPS [70 1093 24
Trastuzumab therapy
Received 1104 17.5 0.221 -18.72 to 4.90
Not received 854 11
Patient numbers in the Table is the number of patients in whom survival was mentioned. It does not
represent the total number of the patients in the study
LN lymph node, Triple- estrogen receptor (ER)-, progesterone receptor (PR)-, and Human epithelial
growth factor receptor 2 (HER2)-, KPS Karnofsky performance status
* At 12 months, however, fewer patients with triple negative markers survived (Fisher exact p value was
0.055)

B = ER?, PR?, HER2±; Ki67 high), HER2? (ER-and
PR-), basal (ER-, PR- and HER2-/triple negative) and
Claudin-low (also often triple negative, but enriched with
stem cell –like features and low expression of the cell–cell
adhesion cluster) subtypes [50]. HER2? and basal sub-
types of breast cancers demonstrate higher rate of existing
brain metastasis (17 and 15 %, respectively) compared to 9
and 11 % for luminal A and B, respectively. Among HER2
positive tumors, treatment with trastuzumab has been
shown to be effective against extracranial metastases pro-
longing the overall survival, but increasing the risk of
existing brain metastasis due to prolonged survival [51,
52]. In advanced HER2? cancers, presence of systemic
metastasis and lack of treatment with trastuzumab clearly
correlated with early brain metastasis [53]. In case of
pertuzumab, the interval between the diagnosis of breast
cancer to brain metastasis was shown to increase from 11.9
to 15 months [54]. Retrospective studies suggest that in the
setting of BM, survival is modestly improved with con-
tinued trastuzumab therapy [55]. In our review, the mean
survival of HER2? patients with BMBC was longer when
treated with trastuzumab (17.5 versus 11 months, Table 1).
Another biologic therapy- administration of small mole-
cule kinase inhibitors lapatinib and capecitabine (both
interact with HER2 receptors)—has shown promising results
in treatment of BM from HER2? BC [56]. In the LAND-
SCAPE trial, combination of these two drugs before WBRT
produced over 80 % reduction in tumor volume in 67 % of
the patients [16]. In another study, the combination of lap-
atinib and capecitabine treatment, applied after WBRT, led
to C50 % reduction in tumor volume in 20 % of the cohort,
considerably higher than the 6 % noted for lapatinib alone
[35]. The low response to lapatinib was attributed to its
limited capacity to cross the blood brain barrier.

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Fig. 2 a Metastatic breast carcinoma in the brain (H&E stain); b metastatic breast carcinoma (HER2 immunostain). There is diffuse and intense
membranous positivity of the metastatic tumor cells for HER2
In view of the poor outcome following a diagnosis of
BCBM, understanding what drives breast cancer cells to
metastasize and colonize the brain could be the first step in
potentially preventing development of metastases and
destroying the colonies of metastatic cells if they succeed
to flourish in the new microenvironment. One recent
approach is administration of drugs that inhibit the function
of the endothelial growth factor, hence reducing angio-
genesis within the metastatic tumor. In this regard, beva-
cizumab produced partial response in 2 of 5 patients, 2
remained stables and 1 developed progressive disease [57].
Assessment of a larger number of patients is necessary to
confirm this observation.
Breast cancer cells (BCCs) cross blood brain barrier and
colonize in brain tissue through mechanisms that require
further elucidation. For example, secretion of substance P
by the neoplastic cells damages the endothelial tight
junction and helps BCC colonize in the brain via activation
of Tumor Necrosis Factor alpha (TNF-a) and angiopoietin-
2 (Ang-2) [58]. Drugs that reduce substance P secretion,
may block crossing of BCCs through the BBB and may be
a preventive measure in management of breast cancer
patients at greatest risk for development of BM. Another
factor pertaining to modification of BBB is the recent
discovery of genes specific to the integrity of BBB [59].
The three genes cyclooxygenase 2 (Cox 2), the epidermal
growth factor receptor (EGFR) ligand HBDGF, and alpha
2,6 sialyl transferase (ST6GALNAC5) have been identified
411
recently as mediators of cancer cells passage through the
BBB. Pharmaceutical agents that modify the function of
these genes may also influence colonization of BCC in
brain tissue. Also focusing on the BBB, Yonemori et al.
[60] noted a positive correlation between the expression of
GLUT1 (glucose transporter 1) and/or BCRP (breast cancer
resistance protein) and brain metastases of HER2? BC,
while a negative correlation was noted between GLUT1
and/or BCRP and brain metastases of basal-type or triple
negative breast cancers. These investigators concluded that
brain metastases from triple negative or basal-type breast
cancers often disrupt the BBB, while brain metastases from
HER2? breast cancers infiltrate brain tissue crossing the
endothelial cells without disrupting the BBB.
Comparison of epigenetically altered (methylated or
silenced) genes between BM and the primary breast car-
cinoma has provided additional information in this field.
After identifying 82 candidate genes through a bioin-
formatics screen of genome-wide breast tumor methylation
data available at the Cancer Genome Atlas (TCGA) and
literature review, Pangeni et al. [61] investigated the
methylation status of these candidate genes and identified
21 genes frequently methylated in BCBM. Among these,
three genes, GALNT9 (an initiator of O-glycosylation),
CCDC8 (a regulator of microtubule dynamics) and BNC1
(a transcription factor with a broad range of targets) were
methylated at a frequency of 55, 73 and 71 % respectively.
While GALNT9 and BNC1 were methylated and silenced
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only in the BM and not in the primary BC, CCDC8 was
commonly methylated in both. This finding suggested that
methylation of CCDC8 occurs at an early stage of meta-
static tumor evolution, while methylation of GANLT9 and
BNC1 occurs at a later stage in this evolutionary process.
Reduced expression and silencing of these three genes
increases the migratory potential of cancer cells and, hence,
their invasive potential. Furthermore, reduced expression
of GALNT9 and CCDC8 was significantly associated with
poor relapse-free survival. The genes involved in the early
initiation of tumor metastases are detectable in the primary
tumor, while those involved in progression and survival of
tumor cells in circulation and survival at metastatic sites
are present in both primary and metastasizing tumor cells.
The same genes may assume different functions at the
primary vs metastatic tumor sites.
These three genes appear to play a role in the progres-
sion of primary breast carcinoma to brain metastases. If
such epigenetic alterations could be determined in circu-
lating tumor DNA or circulating tumor cells in patients’
blood or in dormant BM, they could serve as an extremely
valuable prognostic markers and could potentially provide
novel therapeutic targets.
The predisposition of different intrinsic subtypes of
breast cancer to metastasize preferentially to certain sites
has been suspected and addressed in several studies. It
seems logical to hypothesize that cells more likely to col-
onize the central nervous system (CNS) express genes
capable of BBB penetration and increased cellular
extravasation. In 2009, Bos et al. [59] identified 17 genes
whose expression correlated with brain relapse (Breast
Metastasis Signature or BrMS).
To better understand the biologic basis for breast cancer
metastases, Harrell et al. [62] analyzed 1319 human gene
expression microarrays from primary tumors, metastases
and cancer cell lines. Interestingly, they found that tumors
and their associated metastases shared more similarities
than differences; [90 % of 298 gene expression signatures
were similarly expressed in the matched pairs. Further-
more, the breast cancer intrinsic subtype was maintained
throughout disease progression. The most undifferentiated
breast cancer cells generally expressed a stem cell signa-
ture and preferentially metastasized to the brain and lung.
Among the various subtypes, the Claudin-low tumors are
the least and luminal tumors the best differentiated. After
correlating the HR status, sites of metastases and the
intrinsic subtypes, Harrell et al. [62] found that brain
relapse occurred more often among the non-luminal sam-
ples, while lung relapse occurred within the claudin-low
and basal-like subtypes. Bone metastases was the most
common, regardless of subtype. Since the gene expression
patterns of tumors can be predictive of metastatic behavior,
it could help identify the high risk patients for closer
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follow-up with more frequent imaging studies of the brain
and, potentially, with liquid biopsy screening for circulat-
ing tumor cells in the blood and spinal fluid.
Finally, the impact of microenvironment of the host
tissue for the metastatic tumor cells is another important
area for further future investigation. In the brain, glial and
microglial reaction to the colonized tumor cells may be
associated with elaboration of factors that help the colo-
nization process. It has also been suggested that metastatic
tumor cells could potentially alter the glia in a novel way
resulting in a cross talk between the tumor cells and the
microenvironment [63]. Blocking flow of such factors from
both directions could be another route to prevent successful
colonization.
In conclusion, this large review describes demographi-
cal and clinical factors that correlate with better survival of
patients with breast cancer and brain metastasis. The
improvement of patient survival in recent years correlates
with earlier detection, refinement of the surgical techniques
such introduction of radiosurgery and treatment based on
presence of certain biomarkers. The latter is an evolving
field and its true impact on the survival of patients with
brain metastasis remains to be established.
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