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Epidermal Growth Factor Receptor Dependence
in Human Tumors: More Than Just Expression?
CARLOS L. ARTEAGA
Departments of Medicine and Cancer Biology, and Vanderbilt-Ingram Comprehensive Cancer Center,
Vanderbilt University School of Medicine, Nashville, Tennessee, USA
Key Words. EGFR-TKI · ZD1839 (Iressa™) · Prognostic factor · Cancer therapy · Predictive factor
After completing this course, the reader will be able to:
1. Describe the current limitations in measuring levels of EGR receptor (EGFR) expression in tissues.
2. Identify the molecular pathways for signal transduction induced by EGFR activation.
3. Identify the level of expression of EGF in different tumor types.
CME
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A BSTRACT
The epidermal growth factor receptor (EGFR) is a
rational target for antitumor strategies. EGFR signaling
causes increased proliferation, decreased apoptosis, and
enhanced tumor cell motility and neo-angiogenesis. The
EGFR is expressed or highly expressed in a variety of
human tumors of epithelial origin. ZD1839 (Iressa™) is
an orally active, selective EGFR tyrosine kinase
inhibitor, which blocks signal transduction pathways
implicated in proliferation and survival of cancer cells.
The lack of a consistent method of evaluating levels
of EGFR has caused a disparity in reports of the EGFR
as a prognostic factor; however, for some tumors,
EGFR is a strong prognostic indicator associated with
more aggressive disease and reduced survival. So far, no
clear association between EGFR levels and response to
EGFR-targeted agents has been found. Preclinical studies with ZD1839 have noted a relationship between the
two in some cases, but not others.
EGFR signaling may be increased by a number of
mechanisms in addition to high expression levels of
EGFR, including receptor mutations, heterodimerization with other members of this receptor family such as
HER2 (erbB2), increased expression of (autocrine/
paracrine) ligands, and alterations in molecules that
control receptor signaling output. Each of these components could be assessed to give an indication of the
magnitude of EGFR signal amplification. Evaluation of
signaling components downstream from EGFR should
provide information on the activation of the EGFR
pathway.
Until EGFR-based assays predictive of a response to
receptor-targeted therapies are available, there is no
clear justification for stratifying patients by EGFR status or excluding patients with low EGFR levels from trials with ZD1839 or other EGFR inhibitors. The
Oncologist 2002;7(suppl 4):31-39
Correspondence: Carlos L. Arteaga, M.D., Departments of Medicine and Cancer Biology, and Vanderbilt-Ingram Comprehensive
Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232-6307, USA. Telephone: 615-936-3524; Fax: 615936-1790; e-mail: [email protected] Received June 26, 2002; accepted for publication July 25, 2002.
©AlphaMed Press 1083-7159/2002/$5.00/0
The Oncologist 2002;7(suppl 4):31-39
www.TheOncologist.com
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L EARNING O BJECTIVES
EGFR Dependence in Cancer: More Than Just Expression?
32
INTRODUCTION
EGFR Expression in Solid Tumors
The epidermal growth factor receptor (EGFR; HER1;
erbB1) is expressed or highly expressed in a variety of human
tumors including non-small cell lung cancer (NSCLC),
breast, head and neck, gastric, colorectal, esophageal,
prostate, bladder, renal, pancreatic, and ovarian cancers [1].
Activation of the EGFR signaling pathway has many
effects including increased proliferation and angiogenesis,
and decreased apoptosis. These effects are mediated by a
complex series of signaling mechanisms, such as engagement
of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3 kinase (PI3K) pathways (Fig. 1) [2]. High
EGFR expression has been associated with advanced tumor
stage, resistance to standard therapies (hormonal therapy,
chemotherapy, and radiation) [3-5] and, in some tumors, with
poor patient prognosis [6-8].
As a result, EGFR was proposed as a rational target for
antitumor strategies. EGFR-targeted therapies in development
include those that interact with the extracellular ligand-binding
A
Epiregulin β-cellulin
(1, 4)
(1)
TGF-α EGF
(1)
(1)
HB-EGF
(1, 4)
Amphiregulin
(1)
Ligands
Input
layer
1
3
1
2
1
1
1
4
Receptor
dimers
X
B
Src
Cbl
PLCγ
PI3K
Shp2
PKC
Sp1
C
Output
layer
Inhibition of
apoptosis
Akt
Bad
Jun
Fos
Elk
Proliferation Angiogenesis Maturation
Nck
Sos
RAF
MEK
MAPK
S6K
Myc
Grb2
GAP
Ras-GTP
Signal-processing
layer
Shc
Ras-GDP
Vav
Grb7
Adaptors
and
enzymes
Crk
Rac
PAK
JNKK
JNK
Transcription
factors
Egr1
Migration
Cascades
Abl
Adhesion
Invasion
Differentiation
Figure 1. The EGFR signaling network. Adapted from [2] by permission from Nature Reviews Molecular Cell Biology 2001;2:127-137. ©2001
Macmillan Magazines Ltd. A) Input layer. Ligands and dimeric receptor combinations for EGFR represent the input layer. Numbers in each ligand block indicate the respective high-affinity HER receptor among HER1 (1), HER2 (2), HER3 (3) and HER4 (4) (HB-EGF, heparin-binding
EGF). HER3 lacks intrinsic kinase activity (crossed kinase domains). B) Signal-processing layer. Signaling to the adaptor-enzyme layer is shown
only for the EGFR homodimer. Only selected pathways and transcription factors are represented. C) Output layer. Cellular processes accelerated or dysregulated by aberrant EGFR signaling output.
Downloaded from www.TheOncologist.com by on January 16, 2010
domain (monoclonal antibodies, bispecific and single chain
antibodies, immunotoxin conjugates), and those that act
intracellularly, such as the small-molecule EGFR tyrosine
kinase inhibitors (EGFR-TKIs) that compete with ATP to
bind to the receptor’s ATP site. In either case, the pathways
leading to tumor cell proliferation, angiogenesis, metastasis,
and cell survival are disrupted [9, 10]. Of these, one of the
most advanced in clinical development is ZD1839 (Iressa™),
an orally active, selective EGFR-TKI; with a mode of action
distinct from cytotoxic chemotherapy.
While there are increasing data to confirm the antitumor
activity of these agents in clinical trials, there are several
important issues still to be addressed, including how best to
evaluate EGFR expression, whether there is a correlation
between EGFR expression and patient prognosis, and whether
EGFR expression levels can predict response to therapy.
Furthermore, there are many components of the EGFR signaling network (Fig. 1), each of which can modulate EGFR signaling output and thus tumor dependence on it. How these
components relate to tumor progression and/or antitumor
activity of anti-EGFR therapies requires further investigation.
Arteaga
variety of methods, such as fluorescence in situ hybridization
or quantitative PCR, may enable detection of alterations to the
EGFR gene such as amplification, mutation or deletion,
which may, in turn, affect receptor signaling output.
EGFR as a Prognostic Factor
Although EGFR is generally considered to be predictive of poor prognosis in human cancers, conflicting results
have been reported [17]. EGFR has been identified as a
strong prognostic indicator in head and neck, breast, ovarian, cervical, bladder, and esophageal cancers. High EGFR
expression has been shown to correlate with poor survival
in a range of tumors including nasopharyngeal, NSCLC,
ovarian, and breast. In one of these studies, prognostic factors were evaluated in 77 patients with unresectable carcinoma of the pharynx [8]. In a multivariate analysis, EGFR
level was found to be a significant predictor for reduced
time to treatment failure (p = 0.0001) and overall survival
(p = 0.0001). In patients with nasopharyngeal carcinoma, a
significant correlation between high levels of EGFR and
poor survival has also been noted (p = 0.05) [18]. In 108
primary ovarian cancer specimens, 61% scored positive for
EGFR, and a significant correlation was observed between
EGFR expression and shorter overall and progression-free
survival [7]. This study also correlated EGFR status with
resistance to platinum-containing chemotherapy. In addition, several studies have reported that EGFR expression
predicts for a significantly shorter disease-free and overall
survival in patients with breast cancer [19, 20]. However,
its prognostic value in all patient subgroups has not been
consistent among these studies. For example, Tsutsui et al.
[20] demonstrated that EGFR was a significant prognostic
factor only for disease-free survival in lymph-node-negative breast cancer patients (p = 0.0241) and overall survival
in node-positive patients (p = 0.0333). Among NSCLCs,
squamous-cell carcinomas were found to be more likely
to be EGFR-positive than non-squamous-cell carcinomas
(p = 0.0121), and an absence of EGFR expression correlated with a longer survival (p = 0.024) [21]. This observation confirmed the results of another study showing that
patients with EGFR-positive NSCLC had shorter median
survival than patients with EGFR-negative tumors [22].
Potentially explaining the association with poor patient
outcome, the expression of EGFR has been linked with
resistance to both hormonal therapies and chemotherapeutic agents. However, the value of EGFR in predicting the
efficacy of cancer drugs is still being evaluated. In one
study of 155 breast cancer patients whose disease was progressing while they were receiving tamoxifen, EGFR
expression was examined by IHC in pretreatment biopsies.
The results of this study confirmed that pretreatment
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Methods of Evaluating EGFR Expression
The causal role of high expression of HER2 in cancer
progression was the basis for the development of trastuzumab
(Herceptin®), a humanized monoclonal antibody against
HER2. This agent has demonstrated clinical benefits in
patients with HER2-positive breast cancer [11]. The U.S.
Food and Drug Administration has approved an immunohistochemical test for HER2 expression, which predicts for
clinical response to trastuzumab [12]. In contrast, the situation
with EGFR-targeted agents is less straightforward. No
method of analysis of EGFR is consistently employed in all
laboratories, making the comparison of results from different
studies difficult. A variety of techniques may be used to evaluate EGFR at the DNA, RNA, and protein levels, as well as
the level of receptor activation in situ.
Immunohistochemistry (IHC) is commonly used to
evaluate EGFR protein levels and is arguably the most convenient method for analysis of clinical samples. However,
there is no standard scoring system, with no consensus
available on the cut-off points between no, low, medium, or
high expression. The method is not strictly quantitative and
is prone to inter-observer scoring error, with the appraisal
of staining intensity being highly subjective. Furthermore,
the choice of antibodies and IHC protocol is not consistent
and may cause the sensitivity of these assays to vary.
However, an advantage of this method is that information
on the cellular distribution of EGFR is obtained. In addition
to total EGFR levels, activated (phosphorylated) EGFR has
been detected in human skin keratinocytes by IHC using
phosphospecific EGFR antibodies. Interestingly, the basal
level of phosphorylated EGFR was eliminated by treatment
with the EGFR-TKI ZD1839 [13]. Similar studies in human
tumors, either untreated or treated with EGFR inhibitors,
have not been reported.
EGFR protein levels may also be quantified by Western
analysis [14] or enzyme immunoassay (EIA) [15], which
measure total receptor protein in tumor specimens, regardless of the expressing cell type and cellular localization of
the receptor. EIA has been used to analyze EGFR in serum
samples from patients with breast cancer. The serum EGFR
level was 7-162 fmol/ml and 126-1,587 fmol/ml in healthy
controls and women with breast cancer, respectively. This
study noted that 67.5% of patients had elevated levels of circulating EGFR, using a cut-off value of 180 fmol/ml [15].
Assessment of the levels of EGF binding in tumors has also
been reported but considerable inter-assay variability has
been observed [16].
Levels of the EGFR RNA transcript, which do not necessarily reflect the levels of protein that will be produced, can be
assessed by Northern analysis and reverse transcriptase-polymerase chain reaction (RT-PCR). Analysis of DNA through a
33
34
Relationship Between EGFR Expression and Activity of Agents
Targeting EGFR
Sensitivity to anti-EGFR agents might not simply
depend on the number of EGFRs. Taking the EGFR-TKI
ZD1839 as an example, some studies have demonstrated a
relationship between relative EGFR expression and activity
of ZD1839 [29, 30], whereas others have reported no such
effect [31-33]. These studies involved cell lines derived
from a variety of carcinomas. Meye et al. [29] investigated
the effect of ZD1839 in four bladder cancer cell lines, each
expressing a different level of EGFR. The concentration
required to inhibit ligand-independent growth 50% (IC50)
ranged from 1.8 to 9.7 µM in these cell lines and correlated
with EGFR protein and transcript level. Similarly, Janmaat
et al. [30] found a correlation between EGFR expression
and ZD1839-induced growth inhibition in cell lines derived
from vulval squamous-cell carcinoma (A431) and NSCLC.
However, the linear correlation was less pronounced within
the series of NSCLC cell lines. Similar levels of growth
inhibition were achieved in two cell lines derived from head
and neck squamous-cell carcinoma and melanoma, despite
their different levels of EGFR expression [31]. In a study
using human tumor xenografts, ZD1839 caused growth
inhibition of tumors and markedly enhanced the activity of
a number of cytotoxic agents, but, interestingly, neither the
growth inhibition nor the degree of potentiation of
chemotherapy were dependent on high levels of EGFR
expression [32, 33].
Clinical studies have demonstrated activity of EGFRtargeted agents in patients who were not recruited on the
basis of their tumor EGFR expression. Patients in phase I
and II studies with ZD1839 were not selected on the basis
of EGFR levels [34]. Moasser et al. [35] reported in vitro
data with ZD1839 against a panel of breast cancer cell lines
with a wide range of EGFR levels, further suggesting that
high EGFR expression does not dictate sensitivity to
ZD1839 [35]. In contrast, trials of the small-molecule
EGFR-TKI OSI-774 and the monoclonal antibody C225
have been carried out in patients selected as EGFR-positive
by IHC [36, 37]. The phase II trial of OSI-774 found that
objective tumor response and stable disease were not associated with more EGFR-positive cells in tumor sections or
more intense EGFR staining [36].
Alternative Mechanisms by which EGFR Drive Is Increased
In addition to high expression of EGFR as a mechanism
for increased receptor signaling output, this transduction
pathway can be upregulated via alternative mechanisms
including activating EGFR mutations, increased coexpression of receptor ligands, and heterodimerization with HER2
as well as with heterologous receptor systems (Fig. 2) [38].
Increased (Autocrine) Receptor Ligands
EGFR signals may be enhanced by increased levels of
receptor ligands (such as EGF, amphiregulin, or transforming growth factor-α [TGF-α]). Coexpression of
EGFR and one or more of its ligands might result in activation of an autocrine system leading to dysregulated
EGFR action and uncontrolled tumor growth [1, 39-42].
Indeed, in a study of 173 patients with invasive ductal
breast carcinoma, a multivariate analysis found that coexpression of EGFR and TGF-α had the most significant
effect on survival compared, for example, with coexpression of EGFR and HER2 [43]. EGF expression has also
been correlated with poor prognosis in patients with breast
cancer [44]. Among EGFR-positive primary lung adenocarcinomas, overall survival was significantly worse for
patients with high levels of expression of EGF or TGF-α
compared with EGFR-positive cancers that were EGF- and
TGF-α negative [45].
Heterodimerization with HER2 and Cross-Talk with
Heterologous Receptors
Homodimers of EGFR signal weakly, in part due to
receptor downregulation and degradation after ligand-mediated activation [2]. The EGFR-homologous HER2 receptor,
which is highly expressed in several human cancers, can
potentiate EGFR function by increasing EGF binding affinity, stabilizing and recycling EGFR-HER2 heterodimers,
and expanding the repertoire of receptor-associated substrates and signaling responses [46, 47]. Cancers with high
expression of either EGFR or HER2 have a better prognosis
than cancers that have high expression of both receptors
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expression of the receptor predicted for a lower response
rate to tamoxifen (p = 0.046) [4]. However, other reports,
such as the study of tamoxifen therapy in estrogen-receptor-positive breast cancer patients [23], have not supported
the predictive value of EGFR status for antiestrogen resistance. There is increasing evidence demonstrating that
growth factor pathways are highly interactive with estrogen
receptor signaling in the control of breast cancer growth
[24]. In tamoxifen-resistant breast cancer cell lines, antiestrogenic resistance is associated with upregulation of the
EGFR pathway [25]. Hence, EGFR-TKIs such as ZD1839
have the potential to treat endocrine-resistant tumors and
might abrogate acquired resistance when used early in
combination with antiestrogens [25, 26]. High expression
of EGFR has also been associated with resistance to radiotherapy [3], and recent studies have confirmed the capacity
of EGFR downregulation to modify the cellular response to
radiation [27, 28].
EGFR Dependence in Cancer: More Than Just Expression?
Arteaga
35
1
Increased expression
of EGFR protein
2
R
R
R
pY
pY
pY
pY
K
K
K
K
K
5
Ligand/
autocrine
loop
S
K
pY
S
pY
pY
pY
Mutant
EGFR
R
S
S
pY pY
K
R
Mitogenic
signals
pY
R
R
K
pY pY
pY
K
pY pY
pY
pY
pY
S
S
pY
TGF-α
EGF
R
R
pY
K
pY
pY
K
K
Phosphatase
K
K
K
R R
R
R
pY
S S
pY
pY
3
Heterodimerization
and cross-talk
Figure 2. Multiple mechanisms of increased EGFR activation. Abbreviations: EGF = epidermal growth factor; R = receptor; S = substrate;
TGF-α = transforming growth factor-α; K = tyrosine kinase; pY = phosphorylated tyrosine residue.
[48-51]. In 83 patients with resected NSCLC, coexpression
of both EGFR and HER2 was a better predictor of treatment
failure and poor survival than EGFR expression alone [52].
Furthermore, high expression of HER2 can counteract the
efficacy of EGFR-TKIs in EGFR-expressing tumor cells
[53]. Finally, EGFR-TKIs block HER2 phosphorylation by
inhibiting EGFR-mediated transactivation of HER2 in
tumor cells that highly express HER2 [35, 54, 55]. Taken
together, these studies strongly support EGFR-HER2 crosstalk in vivo, and high expression of HER2 as a mechanism
that can potentiate EGFR signals and EGFR-mediated
tumor progression.
In addition, the EGFR can cross-talk with heterologous
receptors activated by neurotransmitters, lymphokines, and
stress inducers [56-58]. G-protein-coupled receptors
(GPCRs) can exert positive effects on EGFR signaling in
several ways, including the activation of matrix metalloproteinases, which cleave membrane-tethered EGFR ligands that can then bind and activate EGFR [2]. In addition,
GPCRs indirectly activate Src, which can phosphorylate the
EGFR at tyrosines other than those autophosphorylated by
EGFR tyrosine kinase [57]. Steroid hormones can also influence EGFR signaling by activating the transcription of genes
encoding EGFR ligands (Fig. 3). Conversely, estrogen can
transactivate EGFR via the GPCR GPR30, potentially
explaining the EGF-like effect of estrogen [59].
EGFR Mutations
The best described and most common EGFR mutation,
EGFRvIII, involves deletion of exons 2 to 7 and loss of
residues 6 to 276 in the receptor’s ectodomain. This mutant
yields a constitutively active receptor that is not downregulated by endocytosis and is potently transforming [60]. This
mutant receptor is detected in 40% of high-grade gliomas,
where it frequently exhibits gene amplification, and less
frequently in NSCLC, breast, and ovarian cancers [61-63].
ZD1839 has been shown to inhibit autophosphorylation of
EGFRvIII in NR6M cells in culture [64]. In principle,
EGFR antibodies raised against extracellular receptor epitopes deleted in this mutant would not be expected to have
activity in this setting.
Assessment of Operative EGFR Signaling
Further research is required to assess the link between
EGFR signaling in situ (rather than EGFR expression
alone) and the prediction of both patient outcome and
response to anti-EGFR therapies. These investigations
should include the assessment of EGFR phosphorylation in
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pY
pY K
K
pY
pY
pY
R R
4
K
pY
pY
S
R
K
R
S
K
EGFR Dependence in Cancer: More Than Just Expression?
36
LPA, thrombin,
ET, etc.
Steroid
hormone
HB-EGF
+
α
β γ
Inactive
erbB
MMP
G protein
P
P
+
+
Ca2+
Pyk2
Src
Ras
MAPK
Transcription
erbB ligand gene
Figure 3. Cross-talk of EGFR with G-protein coupled receptors and steroid receptors [2]. Reprinted by permission from Nature Reviews
Molecular Cell Biology 2001;2:127-137. ©2001 Macmillan Magazines Ltd.
vivo and its biochemical response as a function of treatment
with receptor-targeted therapies. Evaluation of markers
downstream from EGFR (e.g., MAPK, PI3K/Akt, the proliferation marker Ki67) might also give an indication of surrogate markers of EGFR inactivation and its association
with response or lack of response to treatment.
Studies of the pharmacodynamic effects of ZD1839 can be
used to determine optimal biologic doses to be used in clinical
trials. A study of ZD1839 given over a 28-day period to cancer
patients assessed a range of signaling, proliferation, and maturation markers in patients’ skin, a highly EGFR-expressing tissue. End points indicative of EGFR inactivation in the skin were
found at all dose levels in the range 150-1,000 mg/day [13]. In
part due to this observation, two doses of ZD1839 (250 and
500 mg/day) well below the maximum tolerated dose were chosen for phase II efficacy trials. These trials reported good tolerability and clinical activity of both doses of ZD1839 in patients
with NSCLC [65-66]. Preliminary results have shown that evaluation of these markers is feasible in serial tumor biopsies [67].
Measurement of proliferation (by Ki67 IHC) and levels of
apoptosis (by TUNEL) gave the most reproducible results and
the best indication of ZD1839 activity. Early evidence suggests
that ZD1839 can inhibit EGFR signaling in the vicinity of
tumors and may increase levels of tumor cell apoptosis [67].
CONCLUSIONS
The prognostic significance of EGFR expression in cancer
and, more importantly, its ability to predict response to antiEGFR therapies, are subjects of active research. Increased levels of receptor ligands, coexpression of EGFR mutants, and
cross-talk with HER2 or other receptors are mechanisms that
can enhance EGFR signaling output and potentially alter the
response to EGFR inhibitors. These factors will certainly modify the treatment-predictive value of future EGFR-based assays.
Clearly, the current methods to measure EGFR levels in tumors
are not quantitative and cannot be endorsed as predictive of
either patient prognosis or response to treatment. Thus, until
EGFR (or other) assays that can predict response to anti-EGFR
therapies are available, there is no compelling reason to exclude
patients with low or negative EGFR levels from trials with
EGFR inhibitors, as long as there is evidence for EGFR expression in the tumor type(s) tested by these trials. By the same
token, it is essential that tissues/blocks from all patients enrolled
in these trials are saved and retrospectively examined with
quantitative EGFR assays for correlation of these data with
clinical response to EGFR inhibitors.
ACKNOWLEDGMENT
At the time of publication, this paper discusses the unlabeled usage of ZD1839 (Iressa).
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Steroid
hormone
receptor
Arteaga
37
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Epidermal Growth Factor Receptor Dependence in Human Tumors: More Than
Just Expression?
Carlos L. Arteaga
Oncologist 2002;7;31-39
DOI: 10.1634/theoncologist.7-suppl_4-31
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