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© 2000 American Society for Clinical Oncology c-erbB-2 Is of Independent Prognostic Relevance in Gastric Cancer and Is Associated With the Expression of Tumor-Associated Protease SystemsFrom the Department of Surgery, Klinikum Grosshadern, Ludwig Maximilians University of Munich; Institute of Pathology and Cytology, Deggendorf, Germany; and Department of Tumorbiology, M.D. Anderson Cancer Center, Houston, TX. Address reprint requests to Markus Maria Heiss, MD, Associate Professor, Department of Surgery, Klinikum Grosshadern, Ludwig Maximilians University of Munich, 81377 Munich, Germany; email heiss{at}gch.med.uni-muenchen.de
PURPOSE: The c-erbB-2 gene (encoding the protein p185) is overexpressed in diverse human cancers and has been implicated to be of prognostic value in gastric cancer. Recent studies suggest a role of p185 in tumor progression by specifically promoting the invasive capacity of tumor cells. Therefore, the present study was conducted with the following three objectives: (1) to support the prognostic value of c-erbB-2 in gastric cancer in a large prospective series using a monoclonal antibody and a highly sensitive immunohistochemical method; (2) to determine the association of c-erbB-2 expression with the expression of invasion-related genes; and (3) to perform the first overall multivariate analysis including c-erbB-2 and the invasion-related tumor-associated protease systems.
PATIENTS AND METHODS: In a consecutive prospective series of 203 gastric cancer patients (median follow-up, 42 months), expression of c-erbB-2 and a panel of tumor-associated proteases and inhibitors by tumor cells were evaluated semiquantitatively (score 0 to 3) and analyzed for correlation (
RESULTS: Kaplan-Meier analysis (log-rank statistics) revealed a significant association of increasing expression of c-erbB-2 with shorter disease-free (P = .0023) and overall survival (P = .0160). High amounts of p185 were significantly associated with a high expression of urokinase-type plasminogen activator (uPA) (P < .010), uPA-receptor (P = .030), type-1 plasminogen activator inhibitor (PAI) (P < .010), type-2 PAI (P = .021), cathepsin D (P = .036), matrix metalloproteinase-2 (P = .024), CONCLUSION: c-erbB-2 is confirmed as a new independent, functional prognostic parameter for overall survival in gastric cancer, even when a panel of invasion-related factors, including the strong prognostic parameter PAI-1, are considered. The significant correlation of p185 with several tumor-associated proteases supports the hypothesis that c-erbB-2 is a promoter of invasion and metastasis. This strongly suggests that c-erbB-2 may be a promising target for anti-invasive therapy in gastric cancer.
THE c-erbB-2 GENE (also known as HER2/neu), located on human the chromosome 17 at q21, is related to the oncogene v-erbB of the avian erythroblastosis virus and encodes a transmembrane glycoprotein of Mr 185.000 (p185). This receptor, although unable to bind epidermal growth factor (EGF), has been shown to be extensively homologous to EGF-receptor (EGF-R)1 and, like EGF-R, to have intrinsic tyrosine kinase activity.2 The c-erbB-2 gene has been found to be amplified in 10% to 30% of human breast, ovarian, and gastric cancers,3,4 the gastric cancer cell line MKN-7,5 and other diverse tumor types including lung adenocarcinoma, uterine cervix carcinoma, and squamous cell carcinoma of the head and neck.6-9 Therefore, the protein encoded by the c-erbB-2 gene has been suggested to be a growth factor receptor potentially involved in the growth and progression of malignant cells, despite the fact that the ligand to p185 remains to be identified.
The mechanisms by which c-erbB-2 could contribute to malignant progression are still to be clarified. However, two studies, one of Yu and Hung10 and one of Tan et al11 have provided compelling evidence for a p185-dependent upregulation of invasion and metastasis in NIH3T3- and MDA-MB-435 breast cancer cells. Stable transfection of NIH3T3 with an activated HER2/neu enhanced the invasive capacity both in vitro and in vivo, and this could be countered by anti-p185neu antibodies.10,11 Moreover, MDA-MB-435 cells made to overexpress p185 were significantly more metastatic to the lungs in a mouse model than were nontransfected cells, and this was accompanied by a higher in vitro invasiveness. Strikingly, this enhancement of metastasis-related properties was not associated with increased tumor cell growth and transformation, but with increased secretion and activity of the basement-membrane degrading type-4 collagenases matrix metalloproteinase (MMP)-2 and MMP-9.10,11 Another invasion-related molecule, the 55-kd protease urokinase-type plasminogen activator (uPA), has been shown to be upregulated in c-erbB-2 transfected in lung cancer and NIH3T3 cells, and this was associated with enhanced extracellular matrix degradation.12 uPA, together with uPA-receptor (uPA-R) and the specific inhibitor type-1 plasminogen activator inhibitor (PAI-1), is a major causal factor in tumor invasion and metastasis and is an independent prognostic parameter in diverse tumor types.13-18 Other proteolytic factors interacting with the uPA system (such as cathepsin D, The prognostic and therapeutic value of c-erbB-2 has been shown primarily in breast cancer. Patients with overexpression of the c-erbB-2 gene have a significantly lower relapse-free and overall survival than patients without overexpression of c-erbB-2, and high levels of p185 expression correlates positively with lymph node metastasis.4,8,20-22 Recently, treatment with anti-p185 antibodies and anti-p185 immunoliposomes has been introduced as a promising new therapeutic strategy in breast cancer.23 In gastrointestinal tumors and especially in gastric cancer, evidence also exists that c-erbB-2 is overexpressed, and some studies indicate that c-erbB-2 is a prognostic factor in gastric cancer.24-26 However, other studies have failed to find an association with prognosis.27-30 All of these predominantly immunohistochemical studies used polyclonal antibodies directed against different domains of p185 protein, generally reported only a low percentage of reactive tumors (ranging between 9% and 38%), and restricted the evaluation to the staining of the cell membrane.
Here, in a large prospective series of 203 patients, we investigated the prognostic value of an immunohistochemical staining for p185 in gastric cancer using a monoclonal antibody and a highly sensitive immunoperoxidase method. Considering the potential causal involvement of c-erbB-2 in invasion and metastasis through the upregulation of proteolytic enzymes as discussed above, a second objective of this study was to compare the expression of p185 with the expression of diverse tumor-associated proteases and inhibitors that had been analyzed extensively in the same series of patients in earlier publications (the uPA system, cathepsin D, MMP-2,
Patients and Tumors A consecutive prospective series of 247 patients underwent surgery for primary gastric cancer at the Department of Surgery, Klinikum Grosshadern, Ludwig-Maximilians University of Munich (Munich, Germany) between February 1989 and October 1991. Two hundred three of these patients could be tumor-resected. The mean age was 63.8 years (SD, ± 10.4 years; range, 22 to 87 years), and the male/female ratio was 1.14 (108 men/95 women). Of 203 patients, 70% (143) were curatively resected (R0), including radical lymph node dissection (compartment I and II). The remaining 30% of cases were given palliative resection, 22 with microscopic (R1) and 38 with macroscopic tumor residues (R2). Tumor-node-metastasis classification of the resected tumors revealed that 14.8% were International Union Against Cancer (UICC) stage Ia, 12.8% were stage Ib, 14.3% were stage II, 19.2% were stage IIIa, 13.8% were stage IIIb, and 25.1% were stage IV. According to Laurén’s classification, 108 tumors (53.2%) were intestinal, 86 (42.4%) were diffuse, and nine (4.4%) were mixed-type carcinomas. Four tumors were well-differentiated (G1), 68 were G2, and 131 were poorly differentiated (G3). Lymphangiosis carcinomatosa was present in 159 of 203 cases. Borrmann’s classification showed 26 class I, 106 class II, 25 class III, and 46 class IV tumors. In 92 cases, tumors were located at the cardia and/or the fundus, and, in 111 cases, tumors were located at the corpus and/or the antrum. Twelve patients were given intraoperative radiation therapy (all curatively resected, 28 Gy). Neoadjuvant and adjuvant chemotherapy were applied to three and 11 patients, respectively. Five patients received chemotherapy after noncurative resection. Prospective follow-up was done 6, 12, 18, and 24 months after surgery and in 1-year intervals thereafter. It included physical examination, abdominal ultrasound, gastroscopy, chest x-ray, hematology, blood chemistry, and screening for the tumor markers CEA, Ca 19-9, and Ca 72-4. If tumor recurrence was suspected, we recommended confirmation of the diagnosis by biopsy or explorative surgery. However, imaging procedures were accepted for the diagnosis of a recurrence if this could not be achieved. Causes of death were evaluated clinically.
Immunohistochemical Staining The mouse-derived monoclonal antibody directed against the peptide sequence TAENPEYLGLDVPV in the carboxy-domain of human p185 (#OP15, clone 3B5, immunoglobulin [Ig] G 1, 0.1 mg/mL, 1:600; Oncogene Science, Manhasset, NY) was incubated overnight at 4°C. This was followed by incubation with horse-derived bridging antibody (7.5 µg/mL, 30 minutes) and the Vectastain ABC elite complex for 30 minutes (Vectastain, Burlingame, CA). After washing in PBS, the enzyme substrate aminoethylcarbazole (Sigma Chemical Co) was added for 15 minutes. Finally, the slides were counterstained with hematoxylin. One section of each tumor treated with nonspecific IgG and one section treated with antibody MLG/7S (Nordic, Tilburg, Netherlands) directed against murine IgG instead of the primary antibody in equimolar protein concentration served as negative controls. A section of a routinely processed mamma carcinoma with known strong expression of c-erbB-2 served as a positive control. All slides were coded and evaluated, without knowledge of the patient and the clinical status, by an experienced pathologist as a blinded observer (R.B.). Analysis of staining was restricted to the reactions observed in tumor cells. Staining of stromal cells was not considered and, in fact, not observed (see Results). Based on our previous experiences with the scoring of this method,15,19,31-34 which had revealed a reproducible quantificability of stained tumor cells and a significant correlation with staining intensity, we classified the staining results semiquantitatively into four groups according to number of positively stained tumor cells (score 0 = negative; score 1 = 30% or fewer positive tumor cells; score 2 = 30% to 70% positive cells; score 3 = 70% or more positive tumor cells (Fig 1). The scores were determined without regard to the staining patterns observed in the individual tumor cells. The staining for tumor-associated proteases and inhibitors was performed using the protocols and antibodies described previously.15,19,31-34
Statistical Analysis  2 analysis was performed to determine the correlations between expected and detected frequencies, considering the following parameters: expression of c-erbB-2, uPA, uPA-R, PAI-1, PAI-2, cathepsin D, MMP-2,  -1-antichymotrypsin, -2-macroglobulin, -1-antitrypsin, t-PA, plasminogen, -2-antiplasmin, and antithrombin III (score 0 to 3); Laurén’s classification (intestinal v diffuse/mixed); lymphangiosis and vessel infiltration (presence v absence); and pT, pN, M, UICC, G, and Borrmann stages (as established). The Bonferroni-Holm correction for n tests was performed for all tests that gave significant 2 results within this collective. The first correction was performed for the most significant P value; this P value was multiplied by n. The second significant P value was multiplied by (n-1), and so forth. For significance the corrected P value had to be below an alpha level of 0.05.35 Group-oriented life-table curves were calculated with Kaplan-Meier analysis and compared with the Mantel-Cox log-rank statistics.36 To correct the univariate prognostic relevance of c-erbB-2 for its correlation with established risk factors in gastric cancer and tumor-associated proteases, multivariate analysis was performed using the Cox proportional hazard model.37 Parameters considered for multivariate analysis were those as stated for 2 analysis, intended surgical curability (curative v not curative), and operative procedure (extended v not extended). Tumor localization was considered as cardia/fundus versus corpus/antrum, and tumor diameter was considered as a continuous variable. The parameters were entered into the multivariate model after a significant univariate P value had been calculated. A second multivariate analysis with the same variables was performed with the c-erbB-2 expression dichotomized (score 0/1 v 2/3), as Kaplan-Meier analysis suggested a cut between these groups. All statistics were performed two-sided at a significance level of P = .05, using the BMDP statistical software.38
Of 203 patients, 14 died in the hospital, and 189 were observed every 6 months postoperatively, for a median of 42 months (range, 5 to 65 months). One hundred thirty-nine of the patients had been curatively (R0) resected. Of all 189 patients, three were lost from follow-up. One hundred two patients died, 93 with malignant disease but one not causative. In the 139 curatively resected patients, 48 recurrences occurred, 11 appearing as peritoneal carcinosis, 24 as locoregional recurrence, and 13 as distant metastasis (seven liver, two bone, one brain, and one generalized metastasis). The expression of c-erbB-2, examined in 189 tumors, appeared as predominantly membraneous staining or cytoplasmic staining with a clear membraneous component. Well-differentiated tumors tended to have a more obvious membraneous staining pattern and higher staining intensities; whereas, in poorly differentiated tumors, membrane staining was less pronounced, and the staining seemed to be less intense. However, the differences were not statistically significant (see below). Seventeen of the 189 tumors investigated were negative for the expression of c-erbB-2 in tumor cells and scored as 0.71; these tumors were classified as score 1, 79 tumors were classified as score 2, and 22 were classified as score 3. Staining examples are given in Fig 1. Stromal cells and normal epithelial cells adjacent to the tumor tissue were negative. Intestinal metaplasias and the margins of adenomas that were observed in the tissue sections investigated were positive for p185 but had a weaker staining intensity compared with the corresponding carcinomas.
Correlation With Established Tumor Characteristics
No correlation was detected for pN stage, M stage, Borrmann’s classification, lymphangiosis carcinomatosa, tumor localization and diameter, and sex. Despite the overall impression that well-differentiated tumors seemed to have stronger staining intensities that were emphasized at the cell membranes, no significant correlation between high c-erbB-2 expression and Laurén’s intestinal-type tumors or well-differentiated types (G status) was found.
Correlation With Tumor-Associated Proteases
Analysis of Univariate Prognostic Impact of Expression of c-erbB-2
Analysis of Multivariate Prognostic Impact of Expression of c-erbB-2 In the multivariate analysis model applied (Cox proportional hazard), the established risk factors in gastric cancer (pT, pN, M, and G stage, surgical curability, necessity of extended resections, Laurén, Borrmann, lymphangiosis carcinomatosa, vessel infiltration, and tumor localization and diameter) and components of the uPA system (uPA, uPA-R, PAI-1, and PAI-2), cathepsin D, MMP-2, -1-antichymotrypsin, -2-macroglobulin, -1-antitrypsin, t-PA, plasminogen, -2-antiplasmin, and antithrombin III19 were considered, in addition to c-erbB-2, if they were univariately significant in the individual analysis. For disease-free survival, pT stage, PAI-1, and pN stage were the dominant independent parameters. For overall survival, c-erbB-2 was found to be a new independent prognostic factor in both curatively resected patients (n = 139; P = .049; relative risk, 1.54; 95% CI, 1.08 to 1.67) and in all 189 patients (P = .028; relative risk, 1.33; 95% CI, 1.28 to 1.38), in addition to surgical curability, pT stage, pN stage, and PAI-1 (Table 2). In univariate Kaplan Meier analysis, because an especially low survival probability was seen for patients with c-erbB-2 score 2 and 3 (Figs 2, 3, and 4), we performed a second multivariate analysis with the staining for c-erbB-2 expression dichotomized. The relative risk was even more pronounced for patients with c-erbB-2 expression scores of 2 and 3 (overall survival, R0 patients: P = .03; relative risk, 2.11; 95% CI, 1.64 to 2.57; overall survival, all patients: P = .04, relative risk, 1.55; 95% CI, 1.41 to 1.71, independent covariables as in the previous analysis). These results indicates that these patients are especially high at risk.
In the present investigation, we demonstrate that immunohistochemical assessment of the expression of the c-erbB-2 gene is an independent biologic risk factor in a large prospective series of gastric cancer patients that, at present, has a median follow-up of 42 months. In addition, our study shows for the first time a positive and significant association between the expression of c-erbB-2 and the expression of uPA-R, uPA, PAI-1, PAI-2 (the uPA system), cathepsin D, MMP-2, -1-antichymotrypsin, and -2-macroglobulin. Many of these protease systems have been repeatedly shown to be causally involved in invasion and metastasis.13,39-43 Furthermore, this is the first prospectively observed series of patients in which an overall multivariate analysis involving c-erbB-2, a broad pattern of tumor-associated proteases, and the established risk factors has been performed. Our results are consistent with other prospective and retrospective studies that suggested that c-erbB-2 is a prognostic parameter in gastric cancer. Yonemura et al44,45 found immunoreactivity for c-erbB-2 (using a polyclonal antibody) to be of independent prognostic value in series of 260 and 189 gastric cancers. Staining intensity for c-erbB-2 was correlated with tumor size, serosal invasion, and lymph node metastasis, a fact that was confirmed by a third study from the same group.46 Uchino et al24 confirmed the correlation between p185 immunohistochemistry and 10-year survival in a retrospective study using a preliminary series of 106 and a second series of 108 gastric cancer patients. Mizutani et al26 reported a significantly poorer prognosis for patients with early gastric cancer who were p185 positive in immunohistochemistry (using a polyclonal antibody) in a series of 226 patients. Additional reports27,47-49 also indicated a prognostic impact of the immunohistochemical assessment of p185 expression in 82, 87, 58, and 128 patients. In all of these studies, a relatively small percentage of c-erbB-2–positive cases (range, 9% to 38%) was observed. Generally, a low incidence of an event can lower the statistical power of a study considerably and can easily lead to a false-negative result,50 a fact that potentially could be one reason why some studies of immunohistochemistry for c-erbB-2 in gastric cancer did not see a significant prognostic impact.28-30,51 Two major explanations can be given for the considerable discrepancy in c-erbB-2 expression between previous studies (up to 38% positive cases) and our study (91% positive cases). First, in contrast to all of the previous studies in gastric cancer, we used a monoclonal antibody against p185 together with a highly sensitive streptavidin-biotin-elite kit. This could have resulted in a higher overall sensitivity for p185. Second, the previous studies restricted their evaluation to membrane staining only, excluding staining that appeared cytoplasmatic. The rationale for doing so was the fact that overexpression of c-erbB-2 in gastric cancer mainly seems to be caused by amplification of the gene, which has been reported to correlate to membrane staining.4,52,53 However, because membrane staining can project to the cytoplasm in the two-dimensional limitation of the microscopic picture, in our opinion, a definite distinction between an exclusively cytoplasmatic and a mainly membraneous staining can not be made in many cases. Furthermore, there have been reports of truncated or secreted forms of the erb-B-2 receptor that are not anchored in the cell membrane1,25 and that could have been detected immunohistochemically as a nonmembraneous staining pattern. The biologic function of these truncated forms is not yet known, but some authors speculate that the accumulation of truncated receptors is associated with the appearance of the transformed phenotype.1 In view of these facts, we decided not to restrict our scoring system to membrane staining and, therefore, also considered other staining patterns as positive. Nevertheless, as reported by others,48,54 we can confirm that, albeit not statistically significant, the membrane-type staining pattern appeared more frequently in well-differentiated and intestinal gastric cancers.
Our results demonstrating a positive statistical correlation between the staining intensities for the ErbB-2 receptor and the proteases or protease inhibitors uPA, uPA-R, PAI-1, PAI-2, cathepsin D, MMP-2,
Regardless of the mechanism by which upregulation of p185 and proteolytic enzymes coincide, our observations propose that c-erbB-2 may be a promising new target for an antimetastatic therapy in gastric cancer. For breast cancer, the application of anti-p185 antibodies has recently been introduced as a promising and efficacious strategy in experimental phase I and II trials,4,23,62-64 and parallel promising tools, such as bispecific p185/Fc In summary, our present study demonstrates that even in the context of PAI-1 as an established strong biologic risk factor and a pattern of other tumor-associated proteases, the tyrosine kinase receptor p185 is an independent prognostic parameter in gastric cancer that correlates with the expression of invasion-related genes. This opens up the exciting possibility to consider c-erbB-2 as a biologic target for anti-invasive therapy not only in breast cancer, but also in gastric cancer.
We thank Dr rer. nat. Mathias Schmidt (Department of Clinical Investigations, M.D. Anderson Cancer Center, Houston, TX, now Asta Medica, Frankfurt, Germany) for his invaluable input and Prof Judith Johnson (Institute of Immunology, Ludwig Maximilians University of Munich, Germany) for critically reviewing the manuscript. We further thank Andreas Reiner, Alexander Villinger, and Hansjoerg Hufnagel for their excellent help with the manuscript.
Rudolf Babic was supported by the Wilhelm Sander Stiftung, Neustadt, Germany. H.A. and R.B. share first authorship.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
RI antibodies
