Brain metastases in HER2-positive breast cancer: The evolving role of lapatinib

Institut Jules Bordet, Université Libre de Bruxelles, 121 Boulevard de Waterloo, 1000, Brussels, Belgium.
Critical reviews in oncology/hematology (Impact Factor: 4.03). 12/2009; 75(2):110-21. DOI: 10.1016/j.critrevonc.2009.11.003
Source: PubMed
ABSTRACT
Due to improvements in diagnosis and systemic therapy, brain metastases are an increasingly common cause of morbidity and mortality for patients with advanced breast cancer. The incidence of symptomatic brain metastases among women with metastatic breast cancer ranges from 10% to 16%. The HER2 receptor, which is overexpressed in approximately 25% of all breast cancers, is an important risk factor for the development of central nervous system metastases. Surgery and radiation therapy are the primary approaches to the treatment of brain metastases but new chemotherapy and biological agents promise to play an important role in the future management of central nervous system disease. This article reviews the epidemiology, current treatment options and recent advances in the field, with a focus on HER2-positive disease and the emerging role of lapatinib for the treatment and prevention of brain metastases.

Full-text

Available from: Gianluca Tomasello, Sep 11, 2015
Critical Reviews in Oncology/Hematology 75 (2010) 110–121
Brain metastases in HER2-positive breast cancer: The evolving
role of lapatinib
Gianluca Tomasello
a,b,
, Philippe L. Bedard
a,1
, Evandro de Azambuja
a,2
,
Dominique Lossignol
a,3
, Daniel Devriendt
a,4
, Martine J. Piccart-Gebhart
a,5
a
Institut Jules Bordet, Université Libre de Bruxelles, 121 Boulevard de Waterloo, 1000, Brussels, Belgium
b
Struttura Complessa di Oncologia, Azienda Istituti Ospitalieri di Cremona, Cremona, Italy
Accepted 13 November 2009
Contents
1. Introduction ......................................................................................................... 111
2. HER2-positive breast cancer and brain metastases ....................................................................... 111
3. Treatment of brain metastases ......................................................................................... 112
3.1. Radiation therapy .............................................................................................. 113
3.2. Surgery ....................................................................................................... 115
3.3. Chemotherapy ................................................................................................. 115
3.4. Trastuzumab ................................................................................................... 116
3.5. Lapatinib ...................................................................................................... 117
4. Conclusions ......................................................................................................... 118
Reviewers ........................................................................................................... 118
Conflict of interest statement .......................................................................................... 118
References .......................................................................................................... 118
Biography ........................................................................................................... 121
Abstract
Due to improvements in diagnosis and systemic therapy, brain metastases are an increasingly common cause of morbidity and mortality
for patients with advanced breast cancer. The incidence of symptomatic brain metastases among women with metastatic breast cancer ranges
from 10% to 16%. The HER2 receptor, which is overexpressed in approximately 25% of all breast cancers, is an important risk factor for
the development of central nervous system metastases. Surgery and radiation therapy are the primary approaches to the treatment of brain
Corresponding author at: Struttura Complessa di Oncologia, Azienda Istituti Ospitalieri di Cremona, Viale Concordia 1, 26100 Cremona, Italy. Tel.: +39
0372 405248; fax: +39 0372 405702.
E-mail addresses: g.tomasello@ospedale.cremona.it (G. Tomasello), philippe.bedard@bordet.be (P.L. Bedard), evandro.azambuja@bordet.be
(E. de Azambuja), dominique.lossignol@bordet.be (D. Lossignol), daniel.devriendt@bordet.be (D. Devriendt), martine.piccart@bordet.be
(M.J. Piccart-Gebhart).
1
Address: Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles (U.L.B.), 121 Boulevard de Waterloo, 1000, Brussels, Belgium.
Tel.: +32 2 541 72 76; fax: +32 2 538 08 58.
2
Address: Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles (U.L.B.), 121 Boulevard de Waterloo, 1000, Brussels, Belgium.
Tel.: +32 2 541 72 44; fax: +32 2 541 34 77.
3
Tel.: +32 2 541 32 06; fax: +32 2 538 08 58.
4
Address: Department of Radiation Therapy, Institut Jules Bordet, Université Libre de Bruxelles (U.L.B.), 121 Boulevard de Waterloo, 1000, Brussels,
Belgium. Tel.: +32 2 541 38 00; fax: +32 2 538 75 42.
5
Address: Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles (U.L.B.), 121 Boulevard de Waterloo, 1000, Brussels, Belgium.
Tel.: +32 2 541 32 06; fax: +32 2 538 08 58.
1040-8428/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.critrevonc.2009.11.003
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G. Tomasello et al. / Critical Reviews in Oncology/Hematology 75 (2010) 110–121 111
metastases but new chemotherapy and biological agents promise to play an important role in the future management of central nervous system
disease. This article reviews the epidemiology, current treatment options and recent advances in the field, with a focus on HER2-positive
disease and the emerging role of lapatinib for the treatment and prevention of brain metastases.
© 2009 Elsevier Ireland Ltd. All rights reserved.
Keywords: Brain metastases; Breast cancer; HER2-positive; Trastuzumab; Lapatinib
1. Introduction
Brain metastases (BM) are the most common type of brain
tumor in adults and are an important cause of morbidity and
mortality for patients with cancer. In patients with advanced
systemic malignancies, BM occur in 10–30% of adults and
6–10% of children [1–6]. Carcinomas are the most common
primary tumors responsible for BM in adults, including lung,
breast, kidney, colorectal cancers, and melanoma [1,2,7,8].
The reasons why particular histologies are more apt to spread
to the brain are not well understood.
Autopsy studies reveal that BM is present in far more
patients with disseminated malignancy than produce clinical
symptoms [9,10]. Clinically occult disease is often detected
in patients with advanced breast cancer (BC), as evidenced
by the recent report of silent central nervous system (CNS)
metastases in 15% of advanced BC screened for a clini-
cal trial [11]. Several reasons for this rising incidence of
detectable BM have been hypothesized: (a) aging popu-
lation; (b) improved detection of subclinical disease with
sophisticated imaging; (c) better control of systemic disease
providing a longer time frame for the appearance of BM [12].
Hematogenous spread is the most common mechanism
of metastasis to the brain. This complex multistage process
involves extravasation of individual cancer cells from the
primary site, transportation to the CNS, and local invasion
through the blood–brain barrier (BBB) where micrometas-
tases can lay dormant for various lengths of time before
producing clinically apparent disease [13]. Metastases are
usually located directly at the junction of the gray matter
and white matter where blood vessels decrease in diameter,
trapping disseminated cancer cells [14].
Brain metastases can cause a variety of symptoms,
including headache, focal neurological deficits, cognitive
dysfunction, seizures, nausea, vomiting, and stroke. Histor-
ically, the prognosis of patients with BC who developed
BM was widely regarded as dismal. The median survival
of untreated patients is approximately 1 month; this median
survival can be increased to 2 months if corticosteroids are
administered, to 4–6 months after whole-brain irradiation
(WBRT), and to 8–9 months if surgery or radiosurgery is
utilized [1,3–5].
There is reason to believe that improvements in detection,
systemic control, and brain directed therapy have altered the
natural history of BC patients with BM. This review will
highlight recent advances in the field, with a focus on HER2-
positive disease and the emerging role of lapatinib for the
treatment and prevention of BM.
2. HER2-positive breast cancer and brain metastases
The incidence of symptomatic BM among women with
metastatic BC ranges from 10% to 16% [15]. Metastatic
spread of BC to either the brain parenchyma or the
leptomeninges is generally a late feature of metastatic
progression. Rarely, patients are diagnosed with CNS com-
plications before the detection of their primary tumor. The
median time between the initial diagnosis of BC and the
onset of BM is 2–3 years [16]. Frequently, CNS lesions are
oligometastatic, with the cerebrum as the most common site
of involvement, followed by cerebellum and brainstem. The
incidence of leptomeningeal metastases varies from 2% to
5% [17].
Many risk factors are associated with the development of
BM, such as young age [18–21], hormone receptor-negative
primary tumors [21–25] and heavy burden of disease (large
primary tumors, lymph node involvement, prior lung, liver,
or bone metastases, increased number of metastatic sites, and
elevated lactate dehydrogenase [LDH] levels) [11,20,26,27].
Overexpression of the HER2 protein also appears to be
an important risk factor [11,28]. Amplified in approximately
25% of primary BC, the HER2 oncogene encodes a trans-
membrane tyrosine kinase receptor involved in proliferation,
survival, and angiogenesis [29]. To determine the incidence
of BM in HER2-overexpressing patients, Gabos et al. ana-
lyzed a cohort of newly diagnosed 301 HER2-positive (8%
of whom received adjuvant trastuzumab therapy) and 363
HER2-negative patients [30]. After a median follow-up of
3.9 years, BM metastases occurred in 9% (27 patients)
with HER2-overexpressing BC compared with only 1.9% (7
patients) in the HER2-negative patients (hazard ratio (HR)
4.23, P = 0.0007). HER2-overexpression was an independent
prognostic factor for the development of BM in multivariate
analysis.
A retrospective analysis of 9524 women with early stage
BC enrolled in 10 adjuvant trials led by the International
Breast Cancer Study Group (IBCSG) identified HER2 as a
clear risk factor for the development of CNS relapse [31].
Conducted between 1978 and 1999, these studies involved
patients who did not receive adjuvant anthracyclines, tax-
anes, or trastuzumab. At a median follow-up of 13 years, the
10-year cumulative incidence of CNS disease as the site of
first relapse was 2.7% in patients with HER2-positive primary
tumors compared with 1.0% in patients with HER2-negative
tumors (P < 0.01). The 10-year cumulative incidence of CNS
metastasis as either the first or subsequent disease event for
HER2-positive primary tumors was 6.8% vs. 3.5% for HER2-
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112 G. Tomasello et al. / Critical Reviews in Oncology/Hematology 75 (2010) 110–121
negative primary tumors (P < 0.01). Factors predictive of
CNS as first recurrence included: node-positive disease (2.2%
for >3 positive nodes), estrogen receptor-negative (2.3%),
tumor size >2 cm (1.7%), tumor grade 3 (2.0%), age <35
years (2.2%), HER2-positivity (2.7%), and combined estro-
gen receptor-negativity and lymph nodal involvement (2.6%).
The risk of subsequent CNS recurrence was elevated in
patients diagnosed with lung metastases (16.4%). The precise
biological explanation for the propensity of HER2-positive
BC cells to metastasize to CNS has not been completely elu-
cidated; it has been proposed that it may occur as a result of
both the aggressiveness of this BC subtype and of a particular
affinity for CNS.
More recently, Duchnowska et al. retrospectively analyzed
264 consecutive HER2-positive metastatic BC patients to
assess the impact of selected clinical and pathological vari-
ables on the risk of brain relapse [32]. At a median follow-up
of 3.1 years (range 0–11.4 years), symptomatic brain relapse
occurred in 39% of patients and the median time from diag-
nosis of metastatic disease to brain relapse was 15 months
(range 0–81 months). Interestingly, the only variable signif-
icantly related to an increased risk of brain relapse was time
from initial diagnosis to distant relapse shorter than 2 years
(HR = 1.55, 95% CI, 1.03–2.33; P = 0.034) in a univariate
analysis.
An important question is whether the advent of anti-
HER2-directed therapy has altered the frequency and pattern
of CNS relapse in HER2-positive breast cancer. Currently,
there are two main therapeutic strategies that target the
HER2 receptor: monoclonal antibodies and small molecule
kinase inhibitors. Trastuzumab (Herceptin
®
; F. Hoffmann-
LaRoche Ltd., Basel, Switzerland; Genentech, Inc., South
San Francisco, CA) is a recombinant, humanised anti-HER2
monoclonal antibody. Trastuzumab exerts its action through
several mechanisms including: (1) induction of receptor
downregulation/degradation [33], (2) prevention of HER2
ectodomain cleavage [34], (3) inhibition of HER2 kinase
signal transduction via antibody-dependent cell-mediated
cytotoxicity (ADCC) [35], and (4) inhibition of angiogen-
esis [36]. Several retrospective analyses of women with
metastatic HER2-positive BC receiving trastuzumab-based
treatment at large cancer centers suggest that approximately
one-third of patients eventually develop CNS metastases
[37–39]. Approximately one half of CNS metastases were
diagnosed in patients who had stable or responding disease
and non-CNS sites.
An interesting study reported that nearly 10% of patients
receiving trastuzumab for metastatic disease in combination
with chemotherapy developed isolated CNS metastases as
first site of tumor progression [40]. Progression in the CNS
tended to be a later event than progression at other sites.
Interestingly, trastuzumab therapy did not delay the onset of
CNS metastases as the initial site of progression.
Moreover, Park et al. retrospectively evaluated the medical
records of 251 patients treated with palliative chemotherapy
(with or without trastuzumab) for HER2-positive metastatic
BC at a single institution [41]. In spite of a significantly
higher incidence of brain relapses in patients treated with
trastuzumab (37.8% vs. 25.0%; P = 0.028), the same group
of patients had longer time to development of BM compared
with the group of patients who did not receive trastuzumab
(median 15 months vs. 10 months; P = 0.035). The time to
death (TTD) from BM was also significantly longer (median
14.9 months vs. 4.0 months; P = 0.0005) in the trastuzumab
group. Interestingly, the factors associated with prolonged
TTD from BM were: extracranial disease control at the time
of BM, 12 months or more of progression-free survival of
extracranial disease and treatment with lapatinib. This last
finding highlights the potential impact of additional anti-
HER2 therapy on CNS disease control beyond trastuzumab.
For early HER2-positive BC, the first results of the com-
bined NSABP B-31 and N9831 analysis revealed that the
incidence of isolated BM as a first event was higher in
the trastuzumab group than in the control group (21 vs. 11
in NSABP B-31 and 12 vs. 4 in N9831), although these
comparisons did not achieve statistical significance [42,43].
Similarly, in the first analysis of the HERA trial, CNS
metastases were more frequent in the trastuzumab group
than in the control group (21 vs. 15, respectively) [44,45].
A recently published meta-analysis of HER2-positive BC
patients receiving adjuvant chemotherapy with or without
trastuzumab found a higher incidence of CNS metasta-
sis as the first recurrence event among patients treated
with trastuzumab (6752 patients; relative risk (RR) 1.60;
P = 0.033) [46].
The increased incidence of BM in patients with
trastuzumab therapy is thought to be due to the inability
of the drug to penetrate the intact blood–brain barrier. This
is likely a reflection of both the inherent aggressiveness of
HER2-positive disease, as well as the prolongation in survival
and control of extracranial disease attributable to trastuzumab
therapy [47].
3. Treatment of brain metastases
The primary approaches to the treatment of BM include
whole-brain radiation therapy (WBRT), surgery, and stereo-
tactic radiosurgery (SRS). In order to guide treatment
decision-making, three different prognostic indices have been
developed. The three indices include: (1) the score index for
radiosurgery (SIR) [48], which is the sum of scores (0–2)
for each of five prognostic factors (age, Karnofsky perfor-
mance status (KPS), status of systemic disease, number of
lesions, and largest lesion volume); (2) the basic score for
brain metastases (BSBM) [49], which is the sum of scores
(0–1) for three prognostic factors (KPS, control of primary
tumor, and extracranial metastases); (3) the Radiation Ther-
apy Oncology Group (RTOG) recursive partitioning analysis
(RPA).
By using RPA, a statistical methodology that creates
a regression tree according to prognostic significance, the
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G. Tomasello et al. / Critical Reviews in Oncology/Hematology 75 (2010) 110–121 113
Table 1
Different prognostic scores currently used in treatment decision-making.
Prognostic index Variables Score or class Median survival (months)
SIR [48] Age, KPS, systemic disease status,
largest lesion volume, number of
lesions
1 3 2.9
4 7 7.0
8 10 31.4
BSBM [49] KPS, control of primary tumor,
extracranial metastases
0 1.9
1 3.3
2 13.1
3 Undefined (55% at 32 months)
RPA [50] Number of BM, KPS, age, prior
surgery, histology, primary lesion,
primary site, time interval, sentinel
lesion side, sentinel location,
neurologic function, headache, total
radiation dose, tumor response
Class I (KPS 70, age <65 years
with controlled primary and no
extracranial metastases)
7.1
Class III (KPS <70)
Class II (all others) 2.3
4.2
GPA [52] Age, KPS, number of CNS
metastases, extracranial metastases
0 1 2.6
1.5 2.5 3.8
3 6.9
3.5 4 11.0
Abbreviations: KPS = Karnofsky performance status; PD = progression of disease; PR = partial response; SD = stable disease; CR = complete response; NED = no
evidence of disease.
RTOG analyzed a database of more than 1200 patients
from three consecutive RTOG trials conducted between 1979
and 1993, which tested several different dose fractionation
schemes and radiation sensitizers.
The RPA tree identified three distinct prognostic sub-
groups: the best survival (median: 7.1 months) was observed
in patients <65 years of age with a KPS of at least 70, and
a controlled primary tumor with the brain the only site of
metastases (class 1); the worst survival (median: 2.3 months)
was seen in patients with a KPS less than 70 (class 3); all other
patients had a median survival of 4.2 months (class 2) [50].
These results were subsequently validated in another RTOG
trial that included 445 patients with BM and histologic proof
of malignancy at the primary site (different primary tumors
were included). The median survival was 6.2 months for class
1 patients and 3.8 months for those in class 2 (only patients
in RPA classes I and II were eligible for this trial) [51].
Very recently, the graded prognostic assessment (GPA)
has been developed to overcome the limitations associated
with these three prior indices [52]. The GPA is the sum of
scores (0, 0.5, and 1.0) for four factors: age, KPS, extracra-
nial metastases (none and present), and number of metastases
(one, two to three, and more than three). All four indices were
compared using the RTOG database of 1960 patients with BM
from five randomized trials. In this retrospective analysis,
the RPA and GPA were able to distinguish between patient
groups (P < 0.001 for all classes), unlike the other indices
(SIR and BSBM). However, GPA requires prospective vali-
dation and may replace the RPA in the future. Table 1 provides
a summary of the different prognostic scores currently in use.
Finally, in the attempt to create a simple and specific
prognostic score for patients with BM from breast cancer,
Le Scodan and colleagues analyzed several different poten-
tial prognostic factors in 117 patients treated with WBRT
alone [53]. In a multivariate analysis, RTOG RPA Class III,
lymphopenia (0.7 × 10
9
L
1
) and hormone receptor (HR)
negative status were independent prognostic factors for poor
survival. This three-factor prognostic tool for patients with
BM from breast cancer requires validation in an independent
data set.
3.1. Radiation therapy
WBRT is the conventional treatment for most patients with
BM. It remains the preferred treatment for patients with a poor
performance status and for those with extensive intracranial
disease. There is no general consensus on dose or schedule.
Currently, typical radiation treatment schedules for BM con-
sist of short courses (7–15 days) of whole-brain irradiation
with relatively high doses per fraction (1.5–4 Gy/d) and total
doses in the range of 30–50 Gy. The RTOG has examined
several schedules of WBRT (ranging from 4000 rad/4 weeks
to 2000 rad/1 week) and did not find any difference in overall
survival (OS) [54]. The acute side effects of WBRT include
alopecia, mild to moderate dermatitis, otitis externa, serous
otitis media, and, rarely, a somnolence syndrome. Late side
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114 G. Tomasello et al. / Critical Reviews in Oncology/Hematology 75 (2010) 110–121
effects may include neurocognitive impairment, cerebellar
dysfunction, cataracts, and rarely blindness.
A variety of strategies have been tested to improve the local
control, such as radiation dose escalation, brachytherapy,
radiosensitizers’ use, and SRS. Results generated by more
dose-intensive regimens were disappointing [55]. Further-
more, increased focal irradiation of the tumor site in the brain
has not proven to be beneficial. Giving a booster dose at the
tumor site along with WBRT is no better than WBRT alone for
preventing neurologic recurrence or increasing survival time
[56]. In addition to its use for gliomas, brachytherapy has also
been used for the treatment of CNS metastases. Small studies
with Iodine-125 in patients with newly diagnosed or recur-
rent BM report promising median survival of 10–18 months,
however, these results require confirmation in larger random-
ized controlled trials [57–59]. Another promising approach
involves the use of radiosensitizers. Two randomized con-
trolled trials evaluating adjunctive efaproxiral, an allosteric
modifier of hemoglobin, to WBRT showed a significant ben-
efit in overall survival, response rate and quality of life, when
compared to WBRT alone. Interestingly, this improvement
was observed in a population of BC patients [60,61].
SRS has recently emerged as an important treatment
modality for newly diagnosed patients, alone or in combi-
nation with WBRT and as salvage therapy for progressive
intracranial disease after WBRT. The supporting rationale
for SRS is to deliver a single, large dose of radiation to a
discrete target volume using multiple convergent beams. It is
appealing as an alternative to surgery for patients with lesions
less than 3 cm in diameter. The advantages of SRS are: (a)
less invasive technique; (b) less risk of complications with
this procedure; (c) the location of BM often limits surgery,
which is not the case for SRS; (d) multiple lesions can be
treated during the same visit. For multiple BM, its role is less
defined. Although randomized trials have not shown a sur-
vival benefit, SRS may improve symptoms and local control
[62].
There are very few randomized studies that have evaluated
the role of SRS. With respect to single metastasis, a multi-
institutional retrospective study [63] of patients treated with
SRS and WBRT showed that the overall local control rate
(defined as lack of progression in the SRS volume) was 86%.
Intracranial recurrence outside of the SRS volume was seen
in 27 patients (22%). The only characteristics significantly
correlated with survival at the multivariate analysis were: a
good baseline KPS and the absence of other sites of metastatic
disease. These results are comparable to recent randomized
trials of surgical resection followed by WBRT [61,62].
In order to evaluate the efficacy of SRS compared with
surgery plus WBRT, 64 patients with a single small (3 cm)
brain metastasis were randomly assigned to microsurgery
plus WBRT or Gamma Knife surgery alone [64]. The two
groups did not differ in terms of survival (P = 0.8), neuro-
logical death (P = 0.3), and freedom from local recurrence
(P = 0.06). SRS was shown to be a less invasive technique,
significantly associated with a shorter hospital stay and less
toxicity. Further prospective randomized studies of SRS com-
pared to surgical resection followed by WBRT are warranted.
Four randomized trials recently tested the role of SRS in
the treatment of multiple metastases. In a Japanese study,
132 patients with 1–4 BM (<3 cm in diameter) were ran-
domly assigned to receive SRS plus WBRT upfront or SRS
alone [65]. No significant difference in median survival was
found between the two treatment arms (P = 0.42); however,
SRS plus WBRT was associated with better tumor control in
the brain (12-month brain tumor recurrence rate 46.8% vs.
76.4%; P < 0.001) resulting in less need for salvage treatment.
Kondziolka et al. randomized patients with two to four BM
to initial brain tumor management with WBRT alone (30 Gy
in 12 fractions) or WBRT plus radiosurgery (Table 2) [66].
The study was prematurely discontinued after 60% accrual
(27 patients overall) based upon an interim efficacy analysis
demonstrated an improvement in the rate of local control,
median time to local failure, and median time to any brain
failure in the combined modality group. There was a trend to
improved overall survival in the WBRT plus radiosurgery
group, 7.5 months vs. 11 months (P = 0.22), that did not
achieve statistical significance. Preliminary results from a
trial of 109 patients with 1–3 BM who were randomized
to radiosurgery, radiosurgery plus WBRT, or WBRT alone
Table 2
Randomized trials of local treatments for brain metastases.
Treatment Sample size Median survival Reference
SRS
SRS vs. SRS + WBRT 132 8 months vs. 7.5 months (P = 0.42) [65]
WBRT + SRS vs. WBRT 27 11 months vs. 7.5 months (P = 0.22) [66]
WBRT + SRS vs. WBRT 333 6.5 months vs. 4.9 months (P = 0.04)
a
[68]
Surgery
Surgery + WBRT vs. WBRT 48 40 weeks vs. 15 weeks (P < 0.01) [69]
Surgery + WBRT vs. WBRT 66 10 months vs. 6 months (P = 0.04) [70]
Surgery + WBRT vs. WBRT 84 5.6 months vs. 6.3 months (P = 0.24) [71]
Surgery + WBRT vs. surgery 95 48 weeks vs. 43 weeks (P = 0.39)
b
[72]
Abbreviations: SRS = stereotactic radiosurgery; WBRT = whole-brain radiation therapy.
a
Survival advantage at univariate analysis for patients with a single brain metastasis.
b
Recurrence of tumor in the brain (primary end point) was significantly less (P < 0.001) in the radiation group (9/49 [18%]) than in the observation group
(32/46 [70%]).
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G. Tomasello et al. / Critical Reviews in Oncology/Hematology 75 (2010) 110–121 115
were published in abstract form [67]. The authors found no
statistically significant difference in survival or local con-
trol rates among the three treatment arms. Of note, almost
half of the patients had surgery for at least one symptomatic
brain metastasis prior to study entry and prior surgery was not
a stratification factor for treatment assignment. The RTOG
undertook the largest randomized trial in this particular set-
ting. Three-hundred thirty-three patients with 1–3 newly
diagnosed BM were randomized to either WBRT followed
by radiosurgery boost or WBRT alone [68]. Univariate anal-
ysis showed that there was a survival benefit in the WBRT
and stereotactic radiosurgery group for patients with a sin-
gle brain metastasis (median survival time 6.5 months vs.
4.9 months, P = 0.0393). Patients in the stereotactic surgery
group were also more likely to have a stable or improved
KPS score at 6 months follow-up than were patients allo-
cated WBRT alone (43% vs. 27%, respectively; P = 0.03). In
multivariate analysis, an improvement in survival was seen
in patients with RPA class 1 (P < 0.0001) or a squamous or
non-small cell type of tumor (P = 0.0121). The authors’ con-
clusion was that WBRT and stereotactic radiosurgery should
be standard treatment for patients with a single unresectable
brain metastasis and should be considered for patients with
two or three BM. There may also be a role for SRS as a sal-
vage treatment following recurrence after WBRT, however,
further study is required before this indication can be widely
adopted.
3.2. Surgery
Surgical resection is an important treatment option in
selected groups of patients with solitary brain metastasis,
controlled systemic disease, and good performance status.
The benefits of surgical resection include the provision of a
definitive histological diagnosis, rapid relief of neurological
symptoms caused by mass effect, and improved local control.
Performance status and the extent of extracranial disease are
the most important factors in determining the feasibility of
surgery. Patients with extensive or uncontrolled systemic dis-
ease generally have a poor prognosis and only rarely benefit
from surgical resection. Few data are currently available with
respect to the superiority of the combination of surgery plus
WBRT compared to WBRT alone or surgery alone.
Three randomized clinical trials have compared surgery
plus WBRT to WBRT alone. In the first trial, 48 patients with
a single brain metastasis were randomly assigned to either
surgical resection of the tumor followed by radiation therapy
or needle biopsy and radiotherapy [69]. Surgical treatment
was associated with improved local control (52% vs. 20%;
P < 0.02). The OS was significantly longer in the surgical
group (median, 40 weeks vs. 15 weeks in the radiation group;
P < 0.01), with an improvement in patient-assessed quality
of life. Factors significantly correlated with increased sur-
vival in addition to surgical treatment were the absence of
extracranial disease, longer time to the development of BM
and younger age. The second trial enrolled 66 patients with a
single brain metastasis who were prospectively randomized
to resection plus WBRT (accelerated scheme consisting of
two fractions of 2 Gy per day for a total dose of 40 Gy in 2
weeks) or WBRT alone [70]. The combined treatment pro-
longed OS (median 10 months vs. 6 months; P = 0.04). As
seen in prior studies, patients with a single brain metastasis
and controlled or absent extracranial disease benefited most
from the combined modality treatment. In the final study,
84 patients were randomized to receive either WBRT alone
or surgery plus WBRT [71]. Unlike prior trials, this study
failed to demonstrate that the addition of surgery to radiation
therapy improved outcome for patients with a single brain
metastasis.
Only one multicenter randomized trial has addressed the
role of additional WBRT following surgical removal of a
solitary brain metastasis compared to surgery alone [72]. The
rationale of this approach is to eliminate microscopic residual
cancer cells at the site of resection as well as elsewhere within
the brain. Ninety-five patients with solitary BM treated with
complete surgical resections were entered into this study. The
recurrence of tumor anywhere in the brain was less frequent
in the radiotherapy group than in the observation group (18%
vs. 70%; P < 0.001). Patients in the radiotherapy group were
also less likely to die of neurologic causes than patients in
the observation group (14% vs. 44%; P = 0.003). There was
no significant difference in survival. Although the number
of patients enrolled in these trials is small and there are no
studies that have specifically enrolled women with HER2-
positive metastatic disease to the brain, surgical resection is
an important therapeutic option for patients with solitary CNS
lesions, good performance status, and controlled or absent
extracranial disease.
3.3. Chemotherapy
Chemotherapy has been shown to be largely ineffective
for the treatment of BM. The normal anatomic barriers, such
as the BBB and blood tumor barrier, are not permeable to
the majority of chemotherapeutic agents. P-glycoprotein is
highly expressed by the brain capillary endothelium and
effluxes many active chemotherapeutic agents, including
anthracyclines, taxanes, and vinca alkaloids [73]. In addition,
the BBB limits the passage of large molecules (200 Da) and
hydrophilic drugs into the normal brain. In the presence of
metastases, the BBB can be far more permissive, as indicated
by the significant amount of contrast enhancement on com-
puted tomography (CT)-scan or magnetic resonance imaging
(MRI). While hydrophilic chemotherapy agents generally do
not penetrate primary brain tumors, several studies suggest
that such drugs can reach BM [74,75].
As a result, many single agents and numerous combina-
tion regimens have been tested in BC BM (Table 3). As a
general principle, the responsiveness of BM to chemotherapy
mirrors the sensitivity of the primary tumor; BM responses
are normally correlated with a good performance status;
higher response rates are observed when newly diagnosed
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116 G. Tomasello et al. / Critical Reviews in Oncology/Hematology 75 (2010) 110–121
Table 3
Efficacy of chemotherapy for breast cancer brain metastases.
Drug(s) Sample size Response
rate (%)
Reference
CFP/CFP-MV/MVP/CA 100 50 [76]
CDDP + VP-16 22 55 [77]
CMF/CAF 22 59 [78]
HD IV M 32 28 [79]
CAP 7 43 [85]
TMZ + CAP 24 18 [80]
TMZ + CDDP 32 31 [81]
PTX 152 35 [82]
ED 92 68 [83]
TOP 16 38 [84]
Abbreviations: C = cyclophosphamide; F = 5-fluorouracil; P = prednisone;
M = methotrexate; V = vincristine; A = doxorubicin; CDDP = cisplatin; VP-
16 = etoposide; HD = high dose; IV = intravenous; TMZ = temozolomide;
CAP = capecitabine; PTX = paclitaxel; E = epirubicin; D = docetaxel;
TOP = topotecan.
chemotherapy-naïve patients are treated; and the response
rates of intracranial and systemic disease decrease with sec-
ond and further lines of therapy. Despite a lack of randomized
evidence in the setting of BM, the reported response rates vary
from 18% to 68% [76–85]. Of note, none of these studies
was limited to the population of patients with HER2-positive
BM. Without level 1 evidence to support decision-making,
the choice of chemotherapy for HER2-positive BM should
be guided by response to prior regimens and the underlying
activity of the regimen against BC, rather than its alleged
ability to cross BBB.
3.4. Trastuzumab
Approximately one-third of women receiving trastuzumab
for metastatic HER2-positive BC develop CNS metastases
during the course of their illness [37–39]. Interestingly, the
survival time after the diagnosis of BM is longer for patients
with HER2-positive disease than HER2-negative disease
(22.4 months vs. 9.4 months; P = 0.0002), likely reflecting
improved extacranial disease control with trastuzumab ther-
apy [86,87].
It is widely believed that trastuzumab is not able to cross
the intact BBB due to its large molecular weight (185 kDa), as
trastuzumab levels in cerebrospinal fluid (CSF) are 300-fold
lower than those in plasma [88,89]. However, very recent data
suggest that trastuzumab CSF penetration may be improved
with an impaired BBB [90]. The observed ratio of serum
to CSF trastuzumab level was 430:1, which improved to
76:1 after WBRT that disrupts the BBB. With concomitant
meningeal carcinomatosis, this ratio after radiotherapy was
further increased to 49:1. Case reports suggest that intrathe-
cal trastuzumab therapy may be beneficial [91–94], however,
this route of administration requires further study before it
can be administered routinely.
These observations may justify the continuation of
trastuzumab therapy in patients with BM treated by radio-
therapy as a means of improved intracranial disease control.
Unfortunately, the data regarding continued trastuzumab
beyond CNS progression are scant and conflicting. Lai et
al. conducted a retrospective cohort study comparing 264
patients who did not receive trastuzumab therapy with 79
patients who received trastuzumab therapy. There was no
significant difference in median OS after CNS metastases
were detected (26.3 months for patients who did not receive
trastuzumab and 24.9 months for patients who developed
BM while receiving trastuzumab). No association between
trastuzumab therapy and an increased risk of CNS metas-
tases was found [39]. In contrast, Kirsch et al. retrospectively
analyzed the hospital records of 108 women with primary
BC that developed BM between June 1998 and May 2003
[87]. Patients with HER2-overexpressing BC had a sig-
nificantly longer survival after developing BM compared
with patients with tumors that did not overexpress HER2
(22.4 months vs. 9.4 months from date of BM, respectively;
P = 0.0002). Patients with HER2-positive BC who did not
receive trastuzumab had survival similar to that of patients
with HER2-negative tumors. More importantly, survival was
not correlated with better control of BM. Rather, prolonged
survival appeared to be due to better control of extracranial
systemic disease with trastuzumab, as demonstrated by the
observation that half of patients showed disease progression
in the brain within 8 months after the diagnosis of their BM,
regardless of their HER2 status. In light of these important
results, the authors suggest that HER2-positive CNS disease
should be treated aggressively and trastuzumab should not be
interrupted if extracranial disease is under control.
Additional data supporting the use of trastuzumab beyond
CNS progression were provided by a small Italian study in
which the medical records of 22 patients who developed
BM while on treatment with trastuzumab were reviewed
[95]. Two patients were excluded from the analysis because
of rapid tumor progression and received only supportive
care; among the 20 patients who received further sys-
temic treatment upon brain progression, 10 received further
trastuzumab-based therapy and 10 received second-line
chemotherapy without trastuzumab. Continued trastuzumab
use was associated with an improved median OS (11
months for patients crossing over to second-line chemother-
apy, whereas it was not reached for patients continuing
trastuzumab beyond brain progression; P = .008). Intrigu-
ingly, this survival advantage was not correlated with better
control of CNS disease, as there was no difference in the
time to brain progression between the two groups. Like-
wise, Bartsch et al. compared the outcome of patients who
continued on trastuzumab after diagnosis of BM with a histor-
ical control group of 55 patients with HER2-positive disease
and BM who were treated before 2002 [96]. Continued
trastuzumab treatment beyond progression and KPS >70%
were independent predictors of OS. Another small study
recently confirmed the efficacy of continuing trastuzumab
therapy after the diagnosis of BM [97]. Park and colleagues
evaluated 78 HER2-positive BC patients and found that
overall survival after BM development was significantly
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G. Tomasello et al. / Critical Reviews in Oncology/Hematology 75 (2010) 110–121 117
prolonged compared with patients who never received or
completed trastuzumab before they were diagnosed with BM.
Although these data suggest that trastuzumab beyond
intracranial progression is beneficial, there are no prospec-
tive randomized trials to support this approach. Given the
failure of a prior randomized trial of continued trastuzumab
in combination with capecitabine vs. capecitabine alone fol-
lowing systemic progression to reach its accrual target [98],
it is unlikely that there will ever be an adequately powered
study to address this important question. Perhaps the more
relevant question is whether an alternative HER2-directed
therapy should be initiated following CNS progression on
trastuzumab therapy. Hopefully, future clinical studies will
shed light on this issue.
3.5. Lapatinib
Lapatinib ditosylate (GW572016/Tykerb
®
; Glaxo-
SmithKline, Research Triangle Park, NC) is a small
molecule, reversible inhibitor of the intracellular tyrosine
kinase domain of two members of the HER family, HER1
(EGFR) and HER2 [99]. Lapatinib reversibly binds to the
cytoplasmic ATP-binding site of the kinase and blocks
receptor phosphorylation and activation, thereby preventing
subsequent downstream signaling events, through simul-
taneous activation of extracellular signal-related kinase
(ERK)-1/2 and phosphatidylinositol 3
kinase (PI3K)/Akt
[100–104]. Its very low molecular weight (<1 kDa) and
theoretical ability to cross the BBB makes it an ideal
candidate for testing its potential against BM.
Recent preclinical evidence supports the activity of
lapatinib against CNS disease. Gril et al. transfected an
EGFR-overexpressing 231-BR BC cell line with an expres-
sion vector that results in the overexpression of HER2 cDNA
[105]. The administration of lapatinib following intracardiac
injection of this cell line in nude mice resulted in a 54% reduc-
tion in BM when compared with control vehicle, suggesting
that lapatinib may prevent CNS seeding of HER2-positive
BC cells.
This preclinical activity of lapatinib against HER2-
positive disease is mirrored by clinical studies involving
patients with advanced disease. The pivotal phase III trial
randomized 399 women with HER2-positive BC previously
treated with an anthracycline, a taxane, and trastuzumab to
the combination of lapatinib and capecitabine or capecitabine
alone [106]. Combination therapy resulted in a significant
prolongation in time to progression (TTP) (median 27.1
weeks vs. 18.6 weeks, respectively; P < 0.001; HR = 0.57,
CI = 0.43–0.77) with a trend towards improved OS (HR:
0.78, 95% CI: 0.55–1.12, P = 0.177) [107]. An unplanned
exploratory analysis suggested that combination therapy was
associated with fewer CNS relapses as the site of first pro-
gression than capecitabine alone (2% vs. 6%, respectively,
P = 0.045).
For established CNS metastases, a phase II study of lap-
atinib monotherapy enrolled 39 HER2-positive BC patients
with BM following trastuzumab treatment, the vast major-
ity of whom had also received prior brain radiotherapy
[108]. Although only one partial CNS response (2.6%) was
observed by RECIST criteria, an additional seven patients
(18%) did not progress at 16 weeks after enrollment. In
an exploratory analysis of volumetric changes in CNS tar-
get lesions involving 34 assessable patients, three patients
achieved at least a 30% volumetric reduction and an addi-
tional seven patients achieved volumetric reductions of
10–30%. Patients with at least 10% volumetric reduction
showed a significant longer TTP (median TTP from 8-week
MRI, 1.8 months vs. 3.5 months; P = 0.04) than patients
who did not demonstrate volumetric reduction. Although this
study did not reach its primary efficacy endpoint (at least
four responders), the volumetric changes observed confirm
the activity of lapatinib against CNS HER2-positive disease
and raise several interesting questions for future research,
such as the appropriateness of RECIST efficacy criteria in
BM evaluation and the combination of lapatinib with cranial
radiotherapy, based upon preclinical data indicating that lap-
atinib may act as a radiosensitizer [109]. More importantly,
future studies should also take into consideration as the tim-
ing of systemic treatment initiation, since there may be a
delayed response to radiation therapy [110].
These results were confirmed in a larger extended phase
II study of lapatinib monotherapy in 241 women with BM
from HER2-positive BC, all of whom had received prior
trastuzumab and had documented progression of their CNS
disease following prior irradiation (WBRT, SRS or both). In
a preliminary report, partial responses by CNS Composite
Response Criteria (50% CNS volumetric tumor reduction
in the absence of: new lesions, need for increased dose of
steroids, progressive neurological signs/symptoms, or pro-
gressive extra-CNS disease) were documented in 15 patients
(6%) and another 102 patients (42%) experienced stabi-
lization of disease for at least eight weeks [111]. In terms
of volumetric response, a 50% volumetric reduction of
the CNS lesions was observed in 19 patients (7%), while
a 20% reduction was reported in 19% of patients. The
median CNS progression-free survival time was 15.1 weeks
(95% CI, 12.4–15.7 weeks). Patients who experienced CNS
progression and/or extra-CNS progression on single-agent
lapatinib were eligible to receive lapatinib in combination
with capecitabine during an extension phase of the study.
Definitive results were reported for 50 evaluable patients,
with a 50% volumetric reduction of CNS disease observed
in 20% of patients and 20 patients (40%) demonstrated 20%
volumetric reduction of their CNS disease and a median PFS
of 3.65 months (95% CI, 2.43–4.37) [112]. Interestingly, the
median PFS for patients with 20% reduction in tumor vol-
ume was 4.6 months (95% CI, 3.68–8.15) compared with
1.89 months (95% CI, 1.48 - 3.65) for all other patients (HR
0.34; 95% CI, 0.17–0.68).
Taken together, these data suggest that lapatinib is active
in women with HER2-positive BC with CNS disease who
have failed trastuzumab. Objective response rates, however,
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118 G. Tomasello et al. / Critical Reviews in Oncology/Hematology 75 (2010) 110–121
Table 4
Ongoing studies of lapatinib in established brain metastases from HER2-positive breast cancer.
Study Phase Therapy Primary endpoint Estimated enrollment Status
NCT00614978 (Jules Bordet Inst.) [113] I Lapatinib + TMZ MTD & DLT 18 Recruiting
NCT00470847 (Dana Farber) [114] I Lapatinib + RT MTD & feasibility 39 Recruiting
NCT00263588 (Glaxo-SmithKline) [115] II Lapatinib alone RR 220 Completed
EGF107671 (Glaxo-SmithKline) [116] II Lapatinib + CAP or Lapatinib + TOP RR 55 Recruiting
Abbreviations: TMZ = temozolomide; MTD = maximum tolerated dose; DLT = dose limiting toxicity; RT = radiation therapy; RR = response rate;
CAP = capecitabine; TOP = topotecan; NCI = National Cancer Institute.
are still low with lapatinib monotherapy and new approaches
deserve clinical testing. As a matter of fact, the activity of
lapatinib against HER2-positive CNS disease has prompted
many ongoing trials of lapatinib monotherapy for less heavily
pretreated patients, lapatinib combined with brain irradiation,
and combination therapy with cytotoxic agents able to cross
the BBB (Table 4). In addition, the ongoing ALTTO (Adju-
vant Lapatinib and/or Trastuzumab Treatment Optimisation)
trial will provide important insight regarding the incidence
of CNS metastases with lapatinib therapy for early HER2-
positive BC. ALTTO is a four-arm phase III adjuvant study
comparing the activity of lapatinib alone vs. trastuzumab
alone vs. trastuzumab followed by lapatinib vs. lapatinib
administered concomitantly with trastuzumab. The primary
endpoint of this study is to compare disease-free survival
between the four treatment arms; the incidence of BM is a
prespecified secondary endpoint.
4. Conclusions
Although trastuzumab is a landmark advance in the treat-
ment of HER2-positive BC, it does not prevent intracranial
seeding and is largely ineffective for established CNS dis-
ease. Today, women with HER2-positive BM are surviving
longer, as a result of aggressive local therapy and improved
systemic disease control. The development of novel sys-
temic therapies for BM faces many daunting obstacles. To
be successful, systemic agents must cross the BBB, evade
efflux mechanisms, penetrate the local tumor microenvi-
ronment, and eradicate malignant clones resistant to prior
therapies. Lapatinib is the first of a new wave of exciting
small molecules directed against the HER2 signaling axis that
will hopefully further improve the outcome of women with
HER2-positive BM. As the early clinical experience with lap-
atinib illustrates, the radiographic evaluation of CNS activity
in the context of remodeling changes induced by prior CNS-
directed therapies is problematic. Uniform prospectively
defined benchmarks for CNS response and symptomatic ben-
efit are sorely needed, along with a renewed commitment
among clinicians, patients, and industry sponsors to develop
well-designed clinical trials that can appropriately define the
role of these novel agents in the management of HER2-
positive brain metastases.
Reviewers
Dr. Romuald Le Scodan, Centre René Huguenin, Depart-
ment of Radiation Oncology, 35 rue Dailly, F-92210 Saint
Cloud, France.
Dr. Joseph Gligorov, APHP Tenon, University of Paris
VI, Dept. of Medical Oncology CancerEst, 4 rue de la Chine,
FR-75970 Paris Cedex 20, France.
Conflict of interest statement
Dr. Piccart-Gebhart has acted as a consultant and received
honoraria from Roche and Glaxo-SmithKline.
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Biography
Gianluca Tomasello, was born in Reggio Calabria, Italy,
in 1976. He received his M.D. degree (2001) and specialty
(2007) in Medical Oncology at the University of Parma, Italy.
From November 2001 to November 2003 he was resident in
Radiation Oncology at the University of Parma. From Octo-
ber 2007 to September 2008 he was clinical research fellow
at the Jules Bordet Institute in Brussels, Belgium under the
supervision of Prof. M. Piccart-Gebhart. During this fellow-
ship his main activity was focused on phase III studies of
adjuvant therapy in HER2-positive early breast cancer. He
is currently staff oncologist at the Department of Oncol-
ogy, Istituti Ospitalieri of Cremona, Italy, and member of the
American Society of Clinical Oncology (ASCO). His main
research fields include breast, gastro-intestinal and genito-
urinary cancers.
Page 12
  • Source
    • "[32] Each treatment group had excellent local control (89% vs. 90%, P = 0.78) and required low rates of salvage WBRT (10 vs. 8%, P = 0.48, for 2-4 vs. 5-10 metastases, respectively). [30] Most series have documented an excellent rate of local control with the use of SRS alone [23,33] or in combination with WBRT. [34,20] In the recently published EORTC 22952 trial, SRS alone produced a local control rate greater than surgery alone with a local control rate at 1-year of 69% versus 41% for surgery, which improved to 81% when SRS was combined with WBRT. "
    [Show abstract] [Hide abstract] ABSTRACT: As local and systemic control of breast cancer improves, metastasis to the brain remains a common event requiring a specialized management approach. Women diagnosed with breast cancer who develop brain metastases have superior overall survival compared to patients with other forms of metastatic carcinoma. This article summarizes some of the unique aspects of care for patients with breast cancer metastases to the brain.
    Full-text · Article · Apr 2015 · Indian journal of medical and paediatric oncology
  • Source
    • "Interestingly, the use of trastuzumab in the adjuvant setting or metastatic setting prior to the development of brain metastasis did not affected prognosis once patients had developed brain metastasis. It has been thought that trastuzumab is unable to penetrate the blood–brain barrier (BBB) and can better control extracranial metastases, which would lead to an increased risk of brain metastases in patients with HER2-positive breast cancer and a decreased risk of extracranial distant metastases [12,141516. However, Tamura analyzed the PET scan images of patients with HER2-positive breast cancer who were given 64Cu-DOTA-trastuzumab and determined that the compound reached brain metastases through the BBB [17]. "
    [Show abstract] [Hide abstract] ABSTRACT: The clinical course and prognostic factors of HER2-positive breast cancer patients with brain metastases are not well known because of the relatively small population. The aim of this study was to determine prognostic factors associated with HER2-positive patients who develop brain metastases. This retrospective study assessed the largest dataset to date of 432 HER2-positive patients who were diagnosed with brain metastases from 24 institutions of the Japan Clinical Oncology Group, Breast Cancer Study Group. The median age of the 432 patients was 54 years (range, 20–86 years). Of the patients, 162 patients (37.5 %) had ER-positive/HER2-positive (ER+HER2+) breast cancer, and 270 (62.5 %) had ER-negative/HER2-positive (ER−HER2+) breast cancer. The median brain metastasis-free survival period from primary breast cancer was 33.5 months in both groups. The median survival after developing brain metastasis was 16.5 and 11.5 months in the ER+HER2+ and ER−HER2+ groups, respectively, (p = 0.117). Patients with >3 brain metastases had significantly shorter overall survival in both ER+HER2+ (p HER2+ (p = 0.018) groups. Treatment with trastuzumab before developing brain metastases was not associated with survival duration after developing brain metastases (p = 0.571). However, patients treated with both trastuzumab and lapatinib after developing metastasis had significantly longer survival than patients treated with trastuzumab alone, lapatinib alone, or no HER2-targeting agent (p HER2-positive patients with brain metastases, regardless of the use of trastuzumab before developing brain metastasis, treatment with both trastuzumab and lapatinib might improve survival.
    Full-text · Article · Dec 2014 · Breast Cancer Research and Treatment
  • Source
    • "The reasons for this increased incidence include the more frequent use of sensitive detection methods such as contrast-enhanced magnetic resonance imaging (MRI), increased awareness among patients and clinicians, and improvements in systemic therapies that prolong survival4567. Another possible reason is that adjuvant and systemic therapy with a drug having low penetrance through the blood– brain barrier (BBB), such as trastuzumab, may—while decreasing the risk of distant metastases in general and prolonging overall survival—lead to an increased risk of brain metastases in breast cancer patients [8, 9]. A meta-analysis revealed adjuvant trastuzumab therapy to be associated with a significantly increased risk of the central nervous system (CNS) being the site of first recurrence in HER2-positive breast cancer patients [9]. "
    [Show abstract] [Hide abstract] ABSTRACT: To define prognostic factors for breast cancer patients with brain metastases, compare their clinical courses and prognoses according to breast cancer subtypes, and analyze the causes of death in such patients. We retrospectively analyzed 1,466 patients diagnosed with brain metastases between April 1, 2001 and December 31, 2012, from 24 institutions of the Japan Clinical Oncology Group. Overall, 1,256 patients with brain metastases were included. The median overall survival (OS) was 8.7 months (95 % confidence interval [CI] 7.8-9.6 months). Univariate and multivariate analyses revealed that patients diagnosed with brain metastasis within 6 months of metastatic breast cancer diagnoses, asymptomatic brain disease, or HER2-positive/estrogen receptor-positive tumors had increased OS. Median OS after the development of brain metastases was 9.3 months (95 % CI 7.2-11.3) for the luminal type, 16.5 months (95 % CI 11.9-21.1) for the luminal-HER2 type, 11.5 months (95 % CI 9.1-13.8) for the HER2 type, and 4.9 months (95 % CI 3.9-5.9) for the triple-negative type. Luminal-HER2 type patients had significantly longer OS than patients with the luminal type (hazard ratio [HR] = 1.50, P < 0.0001) and triple-negative type (HR = 1.97, P < 0.0001); no significant differences were noted compared to HER2-type patients (HR = 1.19, P = 0.117). The prognosis and clinical course of patients with brain metastasis from breast cancer before and after developing brain metastases vary according to subtype. Focusing on the subtypes of breast cancer can optimize the prevention, early detection, and improved treatment of brain metastases.
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