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Annals of Surgical Oncology 10:234-241 (2003)
© 2003 Society of Surgical Oncology

ORIGINAL ARTICLES

Clinical Significance of the Epidermal Growth Factor Receptor and HER2 Receptor in Resectable Gastric Cancer

I. García, MD, F. Vizoso, MD, PhD, A. Martín, MD, L. Sanz, MD, PhD, O. Abdel-Lah, MD, P. Raigoso, MD and J.L. García-Muñiz, MD

From the Servicio de Cirugía General (IG, LS, OA-L, JLG-M, FV, AM), Hospital de Jove, Gijón, Spain; and Servicio de Medicina Nuclear (PR), Hospital Central de Asturias, Oviedo, Spain.

Correspondence: Address correspondence and reprint requests to: Francisco Vizoso, MD, Servicio de Cirugía General, Hospital de Jove, Avda. Eduardo Castro s/n, 33920 Gijón, Asturias, Spain; Fax: +34-985-315710; E-mail: fjvizoso{at}wanadoo.es


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Epidermal growth factor receptor (EGFR or HER1) and its homolog c-erbB-2 (HER2) are membrane receptors. Both EGFR and HER2 genes are overexpressed in a variety of solid human cancers and are related to poor prognosis of the patients. The objective of this work was to evaluate the EGFR and HER2 contents in resectable gastric cancer, their possible relationship with clinicopathologic parameters of tumors, and their prognostic significance.

Methods: This was a prospective analysis of 63 patients with resectable gastric carcinomas, with a mean follow-up period of 40.7 months. Membranous EGFR levels were examined by radioligand binding assays, and cytosolic HER2 levels were examined by means of an immunoenzymatic assay.

Results: There was a wide variability of EGFR (1–1,239 fmol/mg of protein) and HER2 (7–20,863 NHU/mg of protein) levels in tumors. There was no significant correlation between these levels and patient or tumor characteristics. However, high levels of EGFR and HER2 were significantly associated with a shorter overall survival period (P = .03 and P = .02, respectively).

Conclusions: There is a wide variability in membranous EGFR levels and in cytosolic HER2 levels in gastric cancer, which seems to be related to the biological heterogeneity of these tumors. In addition, high tumor EGFR and HER2 levels were associated with an unfavorable outcome in patients with resectable gastric cancer.

Key Words: Gastric cancer • Epidermal growth factor receptor • HER2 • Prognosis


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Epidermal growth factor receptor (EGFR or HER1) and its homologs HER2 (c-erbB-2 or NEU), HER3, and HER4 are glycoproteins that consist of an extracellular domain for binding ligands, a short lipophilic transmembrane domain, and an intracellular domain carrying tyrosine kinase activity.1–3 The receptors of this family are activated by dimerization that can be between identical receptors (homodimerization) or between different members of the same family (heterodimerization).4

Epidermal growth factor (EGF) and transforming growth factor {alpha} are produced locally in many tissues as local growth factors rather than as systemic hormones, and through EGFR they stimulate DNA synthesis and cell growth in various systems, including the gastrointestinal tract.5 It has also been demonstrated that EGFR is important not only in cell proliferation, but also in a number of varied processes likely to be important for tumor progression, such as cell motility, cell adhesion, cell invasion, cell survival, and angiogenesis.6 In addition, there is experimental evidence suggesting that EGFR plays a crucial role in regulating the growth of gastric cancer. Growth inhibition of three human gastric cancer cell lines has occurred, both in vitro and in vivo, with the suppression of EGFR protein levels via an antisense messenger RNA.7,8

HER2 is the only member for which there is no known specific ligand. However, it is the preferred co-receptor to form dimers with EGFR, HER3, or HER4; the heterodimers between HER2 and these other receptors show a greater capacity for translating mitogenic signals than the homodimers, and they are synergetic for cellular transformation.9,10 In addition, a series of observations supports the concept that the overexpression of HER2 plays a direct role in the pathogenesis and clinical aggressiveness of tumors: (1) the introduction of HER2 in healthy cells causes malignant transformation, (2) transgenic mice that express HER2 develop breast tumors, and (3) the monoclonal antibodies directed against HER2 inhibit the growth of tumors that express high levels of this receptor.11–15 Both EGFR and HER2 genes are amplified and overexpressed in a variety of solid human cancers and are related to poor prognosis of the patients.16,17 Expression of EGFR18–30 or HER231–41 has also been demonstrated with several methods in human gastric cancer. In addition, several studies reported that tumor EGFR expression, evaluated by amplification26,27 or immunohistochemical methods,20,25,42 is associated with a poor prognosis in gastric cancer patients. However, there are conflicting results on the hypothesis that the expression of HER2 may be a significant predictor of prognosis in this carcinoma.32–39,41

The aims of this study were (1) to analyze the EGFR and HER2 contents in tumors from patients with resectable gastric cancer; (2) to assess the relationships of these receptor tumor contents with clinicopathologic characteristics from tumors; and (3) to evaluate the prognosis value of both membrane receptors in these patients.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
This prospective study included a series of 63 patients with primary gastric adenocarcinoma who consecutively underwent surgical resection of their tumors (R0 according to International Union Against Cancer [UICC] criteria43). None of these patients received systemic therapy. Samples of gastric carcinomas were obtained from all patients. Age ranged from 42 to 85 years (average, 68.6 years). Patient characteristics regarding age, sex, tumor location, histological type, histological grade, tumor stage, lymph node involvement, and vascular, neural, or lymphatic invasion are listed in Table 1. Each case was staged according to the tumor-node-metastasis classification criteria advocated by the UICC.43 The histological type of the tumors was determined according to Lauren’s criteria.44


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  		TABLE 1. EGFR tumor content in 63 gastric carcinomas: correlation with clinicopathologic parameters
 
All patients were evaluated for disease recurrence and survival status by clinical and biological examinations (blood counts, liver tests, and serum carcinoembryonic antigen), upper gastrointestinal endoscopic assessment, and diagnostic imaging (chest radiograph, ultrasonography, computed tomography, or magnetic resonance imaging) every 3 months during the first year and once 6 months thereafter. The mean follow-up period was 40.7 months (range, 2–97 months) for all patients. Thirty-six (57.1%) of the 63 patients died because of recurrence during the study period.

Tissue Processing
Samples were removed from tumors; grossly necrotic tissue was avoided. Immediately after surgical resection, samples were processed for pathologic examination while the remainder was washed with a cold saline solution, divided into aliquots, rapidly transported on ice to the laboratory, and stored at -70°C pending biochemical studies.

Specimens from neoplastic tissues were processed at the same time. They were pulverized with a microdismembrator (Braun, Melsungen, Germany) at -70°C and homogenized in Tris hydrochloride buffer (Tris 10 mmol/L, EDTA 1.5 mmol/L, 10% glycerol, and .1% monothioglycerol) at pH 7.4. Homogenates were centrifuged at 800 x g for 10 minutes at 4°C, and the supernatant was ultracentrifuged at 100,000 x g for 60 minutes at 4°C. The obtained membrane pellets were homogenized in a glass/Teflon (DuPont, Wilmington, DE) potter; they were then resuspended in Tris buffer and stored at -70°C until analysis.

EGFR Assay
EGFR assays were performed by radioligand binding at a single saturation dose by using a commercially available kit (Vienna Lab, Vienna, Austria). For EGFR Scatchard assay, EGF {alpha} was obtained from male mouse submaxillary glands and enzymatically radioiodinated with solid phase-coupled lactoperoxidase/glucose oxidase (Enzymobeads, Bio-Rad, San Jose, CA). With this method, the product is purified by chromatography on a C18 reversed-phase column.45 The control for normal tissue consists of lyophilized human placenta membranes stabilized with bovine serum albumin. The control for tumor tissue is breast carcinoma, as previously described.45,46 Briefly, 75-µl aliquots of cell membrane preparation are incubated with 125I-EGF at a concentration of .5 nM in the absence (total binding) or presence (unspecific binding) of a 200-fold excess of unlabeled EGF in a competitive manner. After incubation, free EGF is separated from receptor-bound EGF by the addition of precipitation reagents (gamma-globulin and polyethylene glycol) and low-speed centrifugation. Bound 125I-EGF is determined by gamma counting. Subtracting unspecific binding from total binding yields specific binding, from which the concentration of EGF is calculated as femtomoles per milligram of protein. The protein concentration was determined by the Bradford method.47

HER2 Assay
The oncoprotein p185 was analyzed in cytosolic samples by an enzyme-linked immunosorbent assay (Oncogene Research Products, San Diego, CA) that uses two mouse monoclonal antibodies, one for the antigen capture and another for the detection (TA1 and NB3), against the extracellular domain of the molecule.48 The analytical sensitivity of the method was 1.75 NHU/mL. The intra-assay and interassay coefficients of variation for concentrations of 33 and 194 NHU/mL of p185 were 4.3% and 2.4% (n = 16) and 12.8% and 9% (n = 19), respectively. The results were expressed as NHU/mg of homogenate proteins. Protein content was quantified with the Bradford method.47

Statistical Analysis
EGFR and HER2 contents were expressed as median (range). Patients were subdivided into groups on the basis of different clinical and pathologic parameters. Comparison of the EGFR or HER2 contents between groups was made with Mann-Whitney and Kruskal-Wallis tests. Differences in percentages of positivities were calculated with the {chi}2 test. Probabilities of relapse-free and overall survival were calculated with the Kaplan-Meier method.49 Differences between curves were evaluated with the log-rank test.50 Differences were considered significant at P < .05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
There was a wide variability of EGFR (1–1,239 fmol/mg of protein) and HER2 (7–20,863 NHU/mg of protein) levels in neoplastic tissues from patients with resectable gastric cancer (R0 according to UICC criteria43). Figure 1 shows the distribution of these receptor contents in tumors.



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  		FIG. 1. Distribution of membranous epidermal growth factor receptor (EGFR) (A) and cytosolic c-erbB-2 (B) contents in 63 gastric carcinomas (prot, protein).

 
Tables 1 and 2 show the distribution of EGFR and HER2 levels, respectively, in 63 tumors in relation to patient and tumor characteristics, including age, sex, tumor location, stage, tumor grade, histological type, vascular invasion, neural invasion, lymphatic invasion, and lymph node involvement. Statistical analysis showed that there was no correlation between tumor EGFR or HER2 content and patient or tumor characteristics (Table 2).


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  		TABLE 2. HER2 cytosolic tumor content in 63 gastric carcinomas: correlation with clinicopathologic parameters
 
The potential association between EGFR and HER2 contents in neoplastic tissues and overall survival was prospectively evaluated in the 63 patients included in this study. First, these patients were dichotomized according to the median value of the tumor levels of these proteins. According to these cutoff points, high levels of EGFR and HER2 were significantly associated with a shorter overall survival (P = .03 and P = .02, respectively; Figs. 2 and 3). Then the patients were divided into four groups according to the different combinations of cutoff points of both factors. Statistical analysis demonstrated that there were significant differences between overall survival curves determined for these four patient subgroups (P = .04; Fig. 4), showing that the subgroup of patients with low tumor levels of both EGFR and HER2 had a higher probability of overall survival than the other patient subgroups.



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  		FIG. 2. Overall survival as a function of tumor levels of membranous epidermal growth factor receptor (EGFR) in 63 patients with resectable gastric carcinomas.

 


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  		FIG. 4. Overall survival as a function of membranous levels of epidermal growth factor receptor (EGFR) and cytosolic HER2. The cutoff point was defined as the median value of the distribution of tumor EGFR levels (10.7 fmol/mg of protein) and HER2 levels (420 NHU/mg of protein).

 


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  		FIG. 3. Overall survival as a function of tumor levels of cytosolic HER2 in 63 patients with resectable gastric carcinomas.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The results of this work demonstrate a wide variability of EGFR and HER2 content in resectable gastric carcinomas. In addition, high tumor levels of these proteins were significantly associated with a shorter overall survival of patients.

It has previously been reported, by use of radioligand binding assays, that membranous EGFR levels in gastric carcinomas are significantly higher than those found in adjacent gastric mucosa samples.24,28,30 Likewise, cytosolic HER2 levels were also reported, by use of immunoenzymatic assay, to be higher in tumors than in paired adjacent nonneoplastic gastric mucosa.40 Thus, these findings suggest that EGFR and HER2 seem to be associated with specific molecular changes related to neoplastic transformation in gastric epithelium.

Expression of EGFR in human gastric cancer has also been demonstrated by using several methods, including immunohistochemistry,18–20,25,29 Western and Northern blotting,19,21 and measurement of EGFR transcripts.22,23,26,27 Our data, showing a significant association between high EGFR levels (measured with an immunoradiometric method) and a shorter overall survival of patients with resectable gastric carcinomas, suggest a role of this cellular transmembrane receptor in tumor aggressiveness. This is in accordance with previous reports showing a positive and significant relationship between the expression of EGFR and several parameters indicative of an aggressive phenotype in gastric carcinomas, such as the depth of tumor invasion,19,27 high tumor stage,30 poor differentiation grade,20,42 high proliferating activity of cancerous cells,20,25 and the occurrence of lymph node metastases.25 In addition, there are different studies reporting a significant relationship between the expression of this membrane protein, examined immunohistochemically20,25,42 or by an in situ hybridization26,27 method, and poor prognosis of gastric cancer patients. Nevertheless, we consider that further studies evaluating EGFR activation by examining phospho-EGFR may be of interest to evaluate the regulation of EGFR in gastric cancer.

Gene amplification and protein overexpression of HER2 have also been reported in gastric carcinomas.31–39 However, the prevalence of HER2 immunoreactivity, as determined by immunohistochemical studies,31–35,38,39 slot blot hybridization,36 or automated fluorescence in situ hybridization,37 varied widely in several series (from 8.6% to 43%). In addition, overexpression or amplification of the HER2 protein has been reported to be related to poor33,35–37,39,41 and good prognosis32 or to be without any effect on prognosis34,38 in gastric carcinomas. All of these discrepancies with the determination of the HER2 status and its clinical significance may be due to problems of selecting the best methodology, standardizing the methods, and determining the correct cutoff points. Nevertheless, measurement of the oncoprotein content by immunoenzymatic assay, such as it was determined in this study, may be a useful standardized method for evaluating the clinical significance of this oncogene product in malignant tumors. In addition, one consideration that points to the value of direct measurement of HER2 protein content is that its overexpression in human tumors may also occur without gene amplification involving other mechanisms, such as upregulation of HER2 transcription.51

However, few studies evaluated the cytosolic content of HER2 in human carcinomas. The HER2 proteins of the cytoplasmic and membranous types were confirmed to be 185-kDa whole molecules by immunoblotting.34 It has been suggested that because proteins are synthesized in the ribosomes, the antibody may detect cytoplasmic precursors of the final product.52 In addition, we previously reported a significant positive relation between membranous and cytosolic HER2 protein contents in gastric carcinomas.40 Although the biological and clinical significance of cytoplasmic HER2 tumor content in gastric carcinomas remains to be elucidated, our results show that high cytosolic content of HER2 is associated with a poor prognosis of patients. In addition, our data suggest that the combination of EGFR and HER2 tumor values may contribute to a more precise prognostic evaluation of patients with resectable gastric carcinomas.

It is also remarkable to consider that both cellular transmembrane receptor contents might be good biological markers for selecting candidates for possible therapy by an HER2- or EGFR-targeting strategy. Thus, it has been demonstrated that trastuzumab (Herceptin, Genentech, Vacaville, CA), a monoclonal antibody against the p185HER2 protein, has therapeutic efficacy in HER2-overexpressing tumors.13,15 In addition, it has recently been demonstrated that HER2 expression in gastric cancer is one of the factors related to cisplatin sensitivity and that anti-HER2 antisense oligonucleotides induced increased sensitivity to cisplatin.53 Similarly, one of the most promising current strategies in cancer therapy involves the use of a variety of methods for inhibiting the action of EGFR on its stimulatory ligands, including enzyme inhibitors, antibodies, and antisense oligonucleotides.6,54

In conclusion, the results of this work showed a wide variability of EGFR and HER2 contents in gastric carcinomas, and this seems to correspond to the biological heterogeneity of these tumors. Our data also suggest a role of both transmembrane proteins in tumor progression of gastric cancer. In our opinion, further studies are needed to confirm the potential value of EGFR and HER2 contents as prognostic factors in resectable gastric cancer, as well as to investigate the possible value of these tumor contents for identifying gastric cancer patients who are candidates for therapies based on EGFR and/or HER2 inhibition.


   Footnotes
 
Epidermal growth factor receptor (EGFR) and HER2 are membrane receptors that are overexpressed by a variety of human cancers. We report a variability in membranous EGFR and in cytosolic HER2 levels in gastric cancer. High tumor EGFR and HER2 levels were associated with an unfavorable prognosis.

Received for publication May 8, 2002. Accepted for publication October 18, 2002.


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 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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J. Matsubara, Y. Yamada, Y. Hirashima, D. Takahari, N. T. Okita, K. Kato, T. Hamaguchi, K. Shirao, Y. Shimada, and T. Shimoda
Impact of Insulin-Like Growth Factor Type 1 Receptor, Epidermal Growth Factor Receptor, and HER2 Expressions on Outcomes of Patients with Gastric Cancer
Clin. Cancer Res., May 15, 2008; 14(10): 3022 - 3029.
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L. Lim, M. Michael, G. B. Mann, and T. Leong
Adjuvant Therapy in Gastric Cancer
J. Clin. Oncol., September 1, 2005; 23(25): 6220 - 6232.
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M. F. McCarty, J. Wey, O. Stoeltzing, W. Liu, F. Fan, C. Bucana, P. F. Mansfield, A. J. Ryan, and L. M. Ellis
ZD6474, a vascular endothelial growth factor receptor tyrosine kinase inhibitor with additional activity against epidermal growth factor receptor tyrosine kinase, inhibits orthotopic growth and angiogenesis of gastric cancer
Mol. Cancer Ther., September 1, 2004; 3(9): 1041 - 1048.
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S. J. Kim, H. Uehara, S. Yazici, R. R. Langley, J. He, R. Tsan, D. Fan, J. J. Killion, and I. J. Fidler
Simultaneous Blockade of Platelet-Derived Growth Factor-Receptor and Epidermal Growth Factor-Receptor Signaling and Systemic Administration of Paclitaxel as Therapy for Human Prostate Cancer Metastasis in Bone of Nude Mice
Cancer Res., June 15, 2004; 64(12): 4201 - 4208.
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O. Tikhomirov and G. Carpenter
Ligand-induced, p38-dependent Apoptosis in Cells Expressing High Levels of Epidermal Growth Factor Receptor and ErbB-2
J. Biol. Chem., March 26, 2004; 279(13): 12988 - 12996.
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