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Emerging Targeted Therapies for Breast Cancer

Emerging Targeted Therapies for Breast Cancer

ABSTRACT: Targeted therapies offer a new approach to breast cancer treatment. Rather than eliminating both malignant and normal cells nonspecifically, these so-called "rational" therapies exploit second messenger proteins, ligands, and receptors that are known to be upregulated in neoplastic cells, or are implicated in cancer metastasis. This review will highlight a number of these targets and the mechanisms that have been targeted in drug design. We will also describe recently completed and currently ongoing clinical trials investigating targeted therapies and their potential to augment standard breast cancer therapy.

Incremental improvement in the efficacy
of standard chemotherapy
and adjuvant endocrine agents, as
well as earlier detection of new breast
tumors, have together altered breast
cancer diagnosis and treatment during
the past 25 years. Advances in
therapy have led to rising 5-year survival
rates and encouraging reduction
in disease mortality.[1] However, traditional
chemotherapy achieves its
desired effects by targeting all rapidly
dividing cells. Desired antitumor effects
typically come at the expense of
nonmalignant cells, specifically those
in a high rate of turnover in the gastrointestinal
tract and bone marrow.
Therefore, the therapeutic index is significantly
narrowed as efforts to obtain
aggressive tumor eradication are
weighed against achieving a tolerable
side-effect profile.

Greater understanding of the molecular
biology of cancer has allowed
novel additions to the chemotherapeutic
armamentarium-"targeted"
agents that exploit the characteristics
unique to cancer cells for their eradication,
rather than relying on the more
universal "cytodestruction" of standard
chemotherapy. Targeted therapies
therefore maximize the therapeutic
index by improving the efficacy of
the anticancer treatment while also
reducing toxicities to surrounding
noncancerous host cells.

Targeting HER Family
Receptors: Monoclonal
Antibodies

Epidermal growth factor receptor
(EGFR) is a transmembrane tyrosine
kinase receptor important for normal
cellular development, damage repair,
and survival.[2] Each of the four receptors
in the EGFR family-HER1,
HER2/neu/ErbB-2, HER3, and
HER4-has distinct ligand specificity,
but all four possess a homologous
transmembrane portion connected to
an intracellular tyrosine kinase domain.
Once bound to ligand, HER
proteins must form either homodimers
(eg, HER1/HER1) or heterodimers
(eg, HER2/HER3) in order to activate
intracellular phosphorylation. The
only exception is HER2, which has
no naturally existing ligand of its own,
and is present only in low levels in
normal human tissue as compared to
HER1.[3] Instead, it acts as the preferred
cofactor for ligand-bound
HER1, HER3, and HER4 proteins,
increasing the number of initiation
stimuli for downstream signaling[4]
(Figure 1).

In tumor cells, EGFR is upregulated,
resulting in increased activation
of secondary messenger pathways and
cell hyperproliferation.[5] Overampli
fication of the EGFR gene has been
shown in a variety of human cancers
including kidney, bladder, colon, pancreas,
lung, rectum, and breast.[6] In
addition, high levels of EGFR have
been correlated with poor disease
prognosis and lower survival among
cancer patients.[7] Because of its
widespread expression and relevant
role in tumor development, the HER
family receptors were some of the
first targets to be selected for "rational"
drug development.

The HER2/c-erbB2 gene is amplified
in 25% to 30% of invasive breast
tumors.[7] Preclinical experiments
suggest that high levels of HER2 may
forecast a poor prognosis in the same
manner that large tumor size, high
histopathologic grade, and lack of
ER+ and PR+ expression are associated
with negative outcomes in breast
and ovarian cancers. Trastuzumab
(Herceptin) is the first example of successful
targeted therapy for breast cancer
directed against the extracellular
domain of HER2.[8] By blocking
HER2, this recombinant humanized
monoclonal antibody prevents kinasemediated
activation of the ras/raf/
MAPK and PI3K pathways,[9] therefore
inhibiting the mechanisms that
initiate tumor growth.

Trastuzumab is currently used in
the treatment of metastatic breast cancer,
either alone[10] or in the presence
of taxane chemotherapy.[11]
Other phase II clinical trials have
shown efficacy when trastuzumab was
used with vinorelbine (Navelbine)[12]
and gemcitabine (Gemzar).[13] Another
recently completed phase III trial
demonstrated that the combination of
trastuzumab and paclitaxel with carboplatin
(Paraplatin) resulted in improved
response rate and time to
progression as compared to trastuzumab
and paclitaxel alone in women newly
diagnosed with HER2-overexpressing
breast cancers.[14] The successes
of trastuzumab offer encouraging
proof of principle for further
targeted therapy development: by
identifying unique characteristics of
tumor cells, the tumor phenotype can
be abrogated without major adverse
effects on nonmalignant cells. The low
but clinically relevant incidence of
trastuzumab-associated cardiomyopathy
is a notable exception.[15]

Tumors with higher levels of HER2
by immunohistochemistry (IHC) (ie,
3+ score) or with HER2 gene amplification
using fluorescence in situ hybridization
(FISH) have been shown
to respond more convincingly to trastuzumab
than those with less HER2
expression (IHC 2+ score). Initial
phase II studies testing single-agent
trastuzumab enrolled women with any
HER2 expression at all, IHC 2+ or 3+
score.[16] While overall response to
trastuzumab varied from 15% to 38%,
the clinical benefit rate increased to
48% when only examining tumors that
scored IHC 3+ for HER2 expression.
In the absence of HER2 gene amplification,
patients with tumors that exhibit
IHC 2+ overexpression of HER2
do not appear to derive benefit from
trastuzumab.[17]

However, even among IHC 3+ tumors,
barely 50% respond to trastuzumab.[
18] Of those patients who
benefit initially from treatment with
trastuzumab, most progress again
within 9 months.[17] A newer antibody,
pertuzumab, has shown promising
preclinical efficacy in breast
cancer cell lines, and is currently being
tested in phase I clinical trials. In
contrast to trastuzumab's exclusive
specificity for HER2, pertuzumab
blocks all HER-mediated signal transduction
by interfering with transmembrane
receptor dimerization.[19]
Combined treatment with both antibodies
is proposed to exhibit synergistic
inhibition of EGFR signal
transduction, while increasing the
number of HER2-expressing tumors
that will respond to anti-HER therapies.[
19,20]

In hopes of further improving the
scope and efficacy of HER-targeted
agents, a number of other anti-EGFR
monoclonal antibodies are currently
in development. For example, cetuximab
(Erbitux) is a recombinant chimeric
antibody directed against
EGFR/HER1 receptor with an affinity
greater than twice that of any of its
natural ligands. Cetuximab has been
shown to induce dimerization, internalization,
and downregulation of the EGFR.[21] It has been shown to successfully
inhibit tumor growth in many
cancer lines including head and neck,
colorectal, and pancreatic cancer.[22]
While preclinical results in breast cancer
cells were also promising, a small
study of 13 women treated with paclitaxel
and cetuximab did not demonstrate
any promising antitumor activity
and did encounter significant dermatologic
toxicity (personal communication,
A. Seidman, 2005).

In contrast to the aforementioned
human-engineered antibodies, geldanamycin
is a naturally occurring ansamycin
antibiotic also under
investigation as a potential HER2-
targeted agent (Figure 2). Produced
by the bacteria Streptomyces hygroscopicus
during fermentation, geldanamycin
has been shown to inhibit
tumor growth in rodent fibroblasts by
inhibiting intracellular tyrosine kinase
phosphorylation.[23] Geldanamycin
and its derivative, 17-N-allylamino-
17-demethoxy geldanamycin (17-
AAG), appear to block tyrosine kinase
activity by inhibiting Hsp-90, a ubiquitous
chaperone protein that stabilizes
signaling proteins including
EGFR.[24] Preclinical studies show
that geldanamycin significantly inhibits
tumor cell lines that overexpress
HER-2, and in mouse xenografts, trastuzumab
and 17-AAG demonstrated
more superior tumor inhibition than
either agent alone (unpublished data,
D. Solit).

Currently, 17-AAG in combination
with trastuzumab is being studied in a
phase I/II trial at Memorial Sloan-
Kettering Cancer Center (MSKCC)
in patients with advanced breast cancer.
This trial will examine the extent
to which the mechanisms of action of
the two drugs acting in concert can
slow tumor growth, and will also determine
the activity of 17-AAG alone
in trastuzumab-resistant tumors.

Targeting EGFR: Anti-EGFR
Tyrosine Kinase Inhibitors

Tyrosine kinase inhibitors (TKIs)
are the second main strategy for targeting
HER-mediated signaling.
These small-molecule inhibitors are
modeled after imatinib mesylate
(Gleevec), a well-validated TKI directed
against the bcr-abl translocation
that drives the development of
95% of chronic myeloid leukemias.
By inhibiting the constitutive tyrosine
kinase activity of this oncogene, imatinib
therapy alone is sufficient to stop
the malignant transformation of cells
in chronic myeloid leukemia.[25]
Likewise, a TKI bound to the intracellular
ATP-binding pocket of the
EGFR disrupts downstream phosphorylation
and signaling pathways in
solid tumor cell lines. By design, anti-
EGFR TKIs offer potential advantages
over anti-EGFR antibodies, as they
are several-fold smaller (~400 Daltons,
as compared to ~150,000-Dalton
monoclonal antibodies) and
therefore provide improved tumor
penetration. In addition, they are administered
orally rather than by intravenous
infusion.[26] However, TKIs
are less specific for malignant cells,
and can cause mild to moderate toxicities
including skin rash and diarrhea,
as well as edema and headaches.[27]

Anti-EGFR TKIs have been moderately
successful in achieving significant
clinical response among patients
with solid tumors. Gefitinib (Iressa)
is a reversible TKI that has demonstrated
safety and tolerability in doseescalation
studies of a variety of solid
tumors,[28-30] including preclinical
breast cancer tumor models.[31] Large
multicenter phase II trials confirmed
antitumor activity in patients with advanced
non-small-cell lung cancer
(NSCLC),[32,33] motivating the US
Food and Drug Administration (FDA)
to approve gefitinib as third-line treatment
for patients with NSCLC following
failure of both docetaxel
(Taxotere)- and platinum-based therapies.
Further studies by Lynch et al
demonstrated that patients with particular
mutations within the EGFR
gene experience a more rapid, dramatic
response when taking gefitinib,
suggesting a more specific niche for
TKIs that may improve their efficacy
in treating patients with NSCLC.[34]

Emerging understanding of the biology
underlying hormone-dependent
breast cancers demonstrates crucial
"cross-talk" between EGFR-mediated
and estrogen receptor pathways,
suggesting a possible role for gefitinib
in the treatment of breast cancer
as well. Shou et al found that while
breast cancer cells overexpressing
HER2 seemed resistant to tamoxifen's
ER-inhibitory effects, using gefitinib
in addition to tamoxifen enhanced
antitumor effects, presumably by inhibiting
HER2-mediated EGFR phosphorylation
and cross-activation of ER
signaling pathways.[35]

Three recent phase II studies in
women with metastatic breast cancer
demonstrated very slight clinical response
or disease stabilization with
gefitinib monotherapy. For example,
Albain et al reported a partial response
in 1 of 63 women enrolled in the trial,
and stable disease in 8 others. However,
24% (15 patients) continued to
receive treatment after the required 2
months for participation regardless of
outcome, and 5 of 12 patients reported
improvement in bone pain,[36] offering
some encouragement for further
investigation of its use for breast cancer.
The recent FDA approval of erlotinib
(Tarceva) a second anti-EGFR
TKI, for the treatment of refractory
stage IIIB or IV non-small-cell lung
cancer, provides motivation for the
investigation of this TKI for use in
breast cancer as well.[37]

Targeting Angiogenesis

Angiogenesis is another necessary
aspect of cancer development. As tumors
grow, they are increasingly dependent
on new blood vessel
formation for adequate oxygen and
nutrients. A highly conserved, homodimeric
member of the PDGF super-
family, vascular endothelial
growth factor (VEGF) is the most potent
and specific glycoprotein driving
tumor angiogenesis.[38] This heparinbinding
glycoprotein also mediates
vascular permeability and induces endothelial
migration. VEGF catalyzes
signal transduction pathways very
similar to those of EGFR by binding
one of three extracellular tyrosine kinase
receptors: flt-1 (VEGFR-1), KDR
(VEGFR-2), or flt-4 (VEGFR-3). Intracellular
signaling results in neovascular
formation (Figure 3). In tumor
cells, overexpression of VEGF results
in abnormal, leaky vessels, with blind
sacs and variations in flow as compared
to normal vasculature.[39]

Bevacizumab (Avastin) is a recombinant
monoclonal antibody that binds
directly to VEGF so that it is unable
to bind any of its usual VEGF-Rs,
thereby inhibiting angiogenesis. Preclinical
studies with bevacizumab confirmed
that VEGF does result in a
reduction of tumor microvessel density,
as well as a delay in tumor growth.[40] Other studies in murine
models affirm that antiangiogenic
agents will potentiate the antitumor
effects of standard chemotherapy.[41]

VEGF is highly expressed in the
majority of cancers, including breast
cancer.[42,43] In both node-positive
and node-negative breast cancers,
VEGF has been found to serve as a
marker of larger tumors, p53 mutations,
and poor tumor differentiation.[
44] Phase I clinical trials
demonstrate that bevacizumab is well
tolerated, in comparison to many cytotoxic
chemotherapies. Common side
effects include hypertension, epistaxis,
and proteinuria. More serious side
effects such as thromboembolism and
pulmonary hypertension are rare.[45]

Because of its generally favorable
tolerability, it has been readily combined
with other chemotherapies in
hopes of augmenting antitumor response,
including a phase II trial in
patients with previously treated metastatic
breast cancer where using bevacizumab
with vinorelbine resulted in
a 31% objective response rate.[46] In
a recent study in previously untreated
women with inflammatory breast cancer
treated with bevacizumab and vinorelbine,
reduced VEGF levels were
demonstrated, as well as a decrease in
vascular permeability and endothelial
cell proliferation as seen on dynamic
contrast enhanced MRI.[47]

A large prospective randomized
phase III trial recently compared
capecitabine (Xeloda) alone or in
combination with bevacizumab in
anthracycline- and taxane-pretreated
metastatic breast cancer. The
combination increased the response
rate (19.8% vs 9.1%, P = .001), yet
there was no improvement in median
time to progression or survival.[
48] In May 2004, the Eastern
Cooperative Oncology Group completed
accrual for a phase III trial
(study E2100) examining the addition
of bevacizumab to weekly paclitaxel,
as compared to paclitaxel
alone for women with metastatic
breast cancer. It is hoped that the
results will demonstrate that this
standard breast cancer therapy can
be further augmented with the addition
of bevacizumab.

Recent evidence suggests that
HER2 and VEGF signaling pathways
also rely on "cross-talk" phosphorylation
in human breast cancers in much
the same way as the EGFR pathway
has been linked to ER steroid hormone
molecular signaling.[49] Gefitinib
has been shown to inhibit
production of tumor necrosis factor-
alpha, bFGF, and VEGF in several
human epithelial cancer cell lines.[50]
Therefore, inhibition of both pathways
is hypothesized to result in synergistic
antitumor effects. A recently completed
phase II trial at MSKCC and
University of California-San Francisco
examined the use of bevacizumab
and erlotinib for their combined
effects in metastatic breast cancer.

Targeting Cyclooxygenase-2

Cyclooxygenase-2 (COX-2) is an
inducible enzyme responsible for the
rate-limiting conversion of arachidonic
acid to prostaglandins in a variety of
cellular perturbations such as inflammation
and tissue damage.[51] Deregulation
of COX-2 and downstream
prostaglandins have also been demonstrated
in tumorigenesis, and elevated
COX-2 has been measured in a variety
of epithelial carcinomas including colorectal,[
52] lung,[53] esophageal,[54]
and breast tumors.[55] Elevated levels
of COX-2 mRNA, COX-2 protein, and
PGE2 in colorectal carcinoma cells was
linked to the activation of the HER2/
HER3 pathway in colorectal carcinoma
cells-an EGFR family pathway
discussed above for its association with
breast cancer pathogenesis.[56] Once
again, "cross-talk" between the HER2
and COX-2 pathways appears to be
associated with the development of
breast cancer tumors expressing the
HER2-neu oncogene.

COX-2-selective inhibitors, such
as celecoxib (Celebrex), have been
shown to delay incidence of mammary
tumors in transgenic mice
overexpressing HER-2.[57] The
mechanism of action by which
COX-2 inhibitors slow tumor progression
is still not well understood,
but recently Chang et al proposed
that by blocking PGE2, a potent inducer
of angiogenesis and angiogenic
regulatory proteins such as
VEGF, COX-2 inhibitors cause apoptosis
of the tumor microvasculature
as well as tumor mass reduction.
Chang et al suggested that,
along with VEGF, COX-2 may
therefore be another crucial component
of the "angiogenic switch,"
necessary for tumor vessel formation.[
56] Preclinical studies using a
transgenic mouse model demonstrate
a decrease in primary mammary
tumor burden due to decreased
tumor proliferation, as well as an
increase in the induction of apoptosis
when treated with COX-2 inhibitors.[
57] Oral administration of
celecoxib also demonstrated decreased
expression of proangiogenic
VEGF.

Based on these in vivo studies, an
exploratory open phase I clinical trial
using celecoxib (either 200 or 400 mg
twice daily, orally) in breast cancer
patients prior to surgery are currently
under way (MSKCC 03-027). COX-
2 expression, downstream signaling,
as well as aromatase activity are all
being examined (Figure 4). In another
preliminary phase II trial at Ohio
State University, celecoxib at two different
doses is being studied as remission
maintenance therapy after four
to six cycles of chemotherapy (Cancer
and Leukemia Group B 40105).

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