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Epidermal Growth Factor Receptor Dependence in Human Tumors: More Than Just Expression?

Departments of Medicine and Cancer Biology, and Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA

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: 615-936-1790; e-mail: Carlos.Arteaga{at}mcmail.vanderbilt.edu

	LEARNING OBJECTIVES

Top Learning Objectives Abstract Introduction Conclusions References

 
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.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction Conclusions References

 
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^TM) 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.

Key Words. EGFR-TKI • ZD1839 (Iressa^TM) • Prognostic factor • Cancer therapy • Predictive factor

	INTRODUCTION

Top Learning Objectives Abstract Introduction Conclusions References

 
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].

View larger version (50K): [in this window] [in a new window]   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.

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.

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 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 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].

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 EGFR-targeted 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].

View larger version (35K): [in this window] [in a new window]   Figure 2. Multiple mechanisms of increased EGFR activation. Abbreviations: EGF = epidermal growth factor; R = receptor; S = substrate; TGF- = transforming growth factor-; K = tyrosine kinase; pY = phosphorylated tyrosine residue.

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 [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 cross-talk 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].

View larger version (22K): [in this window] [in a new window]   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.

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 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

Top Learning Objectives Abstract Introduction Conclusions References

 
The prognostic significance of EGFR expression in cancer and, more importantly, its ability to predict response to anti-EGFR 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

Top Learning Objectives Abstract Introduction Conclusions References

 
At the time of publication, this paper discusses the unlabeled usage of ZD1839 (Iressa).

	REFERENCES

Top Learning Objectives Abstract Introduction Conclusions References

 

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