Ann Thorac Surg 2001;72:1868-1876
© 2001 The Society of Thoracic Surgeons
Original article: general thoracic
Immunohistochemical analysis of epidermal growth factor receptor family members in stage I non-small cell lung cancer
Wu-Wei Lai, MDa,
Fen-Fen Chen, MD*b,
Ming-Ho Wu, MDa,
Nan-Haw Chow, MDb,
Wu-Chou Su, MDc,
Mi-Chia Ma, PhDd,
Pei-Fang Su, MSd,
Helen Chen, MDe,
Mu-Yen Lin, MDa,
Yau-Lin Tseng, MDa
a Department of Surgery, Division of Thoracic Surgery, National Cheng Kung University, Tainan, Taiwan
b Department of Pathology, National Cheng Kung University, Tainan, Taiwan
c Department of Internal Medicine, Division of Hematology/Oncology, National Cheng Kung University, Tainan, Taiwan
d Department of College of Management Science, National Cheng Kung University, Tainan, Taiwan
e Department of Radio-Oncology, College of Medicine, and Department of Statistics, National Cheng Kung University, Tainan, Taiwan
Accepted for publication August 2, 2001.
* Address reprint requests to Dr Fen-Fen Chen, Department of Pathology, College of Medicine National Cheng Kung University, 138 Sheng Li Rd, Tainan, Taiwan 704
e-mail: fen221{at}mail.ncku.edu.tw
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Abstract
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Background. To elucidate the relationship between the expression of epidermal growth factor receptor family members (ErbB-1, neu/ErbB-2, ErbB-3, and ErbB-4) and tumor recurrence.
Methods. We used immunohistochemistry to examine the expression of four epidermal growth factor receptor family members in 73 patients with stage I non-small cell lung cancer.
Results. Using Cox univariate analysis, we determined that angiolymphatic tumor emboli and non-well-differentiated tumor cells were two significant conventional pathologic predictors of tumor recurrence, and that ErbB-1 and ErbB-3 were also significant predictors. Coexpression of ErbB-1+, -3+, or expression of three or more epidermal growth factor receptor family members had a significant effect on lung cancer recurrence. A stepwise multivariate Cox proportional hazards regression analysis provided a predictive model for tumor recurrence.
Conclusions. The present study shows that in patients with a non-well-differentiated tumor, overexpression of ErbB-3 is a useful marker for predicting tumor recurrence. The present study also confirmed that ErbB-1 expression increased in proportion to the loss of tumor differentiation. The correlation between ErbB-3 and distant metastasis was good.
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Introduction
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The reported average 5-year survival and tumor relapse rates for patients with stage I non-small cell lung cancer (NSCLC) are 64.6% (range, 55% to 72%) and 42.5% (range, 35% to 50%) [1]. This implies that the TNM staging of NSCLC is an acceptable, but not a satisfactory, classification system. At present, postoperative adjuvant radiotherapy or chemotherapy are not routine standard procedures for treating stage I NSCLC. However, advances in molecular and genetic biology have been applied in the development of a set of biologic prognostic factors of recurrence in those patients [2]. We think that methods to identify patients at high risk of recurrence could lead to effective postoperative adjuvant therapy for those patients.
The epidermal growth factor receptor (EGFR, or ErbB-1) subfamily consists of four transmembrane receptor tyrosine kinases, ErbB-1, -2 (HER-2/neu), -3, and -4. These receptors have been implicated in the pathogenesis of various human cancers [3]. Overexpression of ErbB-1, or -2, or -3 has been reported to be an important prognostic factor in NSCLC [4–6]. However, the ability of EGFR family members to form homodimers or heterodimers through the stimulation of their ligands has been demonstrated [7–8]. Coexpression patterns of the EGFR family members deserve to be investigated in pulmonary tumorigenesis. Recently, coexpression of ErbB-2, -3, and -1 in patients with oral squamous cell carcinoma and shortened survival has been explored [9]. However, few studies describing the interactions of EGFR family-member proteins in stage I NSCLC are available. Therefore, in this 10-year follow-up of 73 patients with stage I NSCLC we sought to determine whether immunohistochemical analysis of all the EGFR family members is more useful in predicting recurrence than conventional pathologic predictors.
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Material and methods
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Patients
Between July 1988 and December 1997, 235 patients had resection of primary lung malignancy at our hospital. Of these, 73 (31%) (56 men, 17 women; mean age, 63.6 years) were evaluated pathologically as stage I NSCLC (stage IA, n = 21: adenocarcinoma, 11; squamous cell carcinoma, 9; and large cell carcinoma, 1. Stage IB, n = 52: adenocarcinoma, 20; squamous cell carcinoma, 25; large cell carcinoma, 4; adenosquamous cell carcinoma, 2; and poorly differentiated carcinoma, 1). Anatomic resection (lobectomy at least) with complete hilar and mediastinal lymph node dissection was standard procedure in our institute for patients with NSCLC. The procedures for mediastinal lymph node dissection and staging followed the methods and rules described by Naruke [10] and Mountain [11], respectively. As of December 2000, these patients had been followed up for at least 3 years postoperatively or at the date of recurrence. Follow-up data were available for all patients at 3 years. Their characteristics are summarized in Table 1.
Detection of cancer recurrence
Locoregional recurrence was defined as clinically or radiologically demonstrable evidence of tumor at the bronchial surgical stump or within the same lung, pleural space, mediastinum, supraclavicular node, or ipsilateral chest wall [12]. Distant recurrences were diagnosed when there were multiple nodules on the contralateral lung or extrapulmonary metastases with or without nodules on the contralateral lung. Recurrence-free survival was defined as the time between surgery and the first indication of disease recurrence.
Immunohistochemical determination of epidermal growth factor receptor family proteins
The sections for immunohistochemical analysis were deparaffinized through graded alcohols and xylene. Endogenous peroxidase was quenched with 3% hydrogen peroxide in methanol, and nonspecific binding was blocked with normal goat serum. An antigen retrieval method was used. In brief, the tissue sections were immersed in diluted, concentrated antigen-retrieval solution (BioGenex, San Ramon, CA, diluted 1:10) and heated to 100°C in a microwave oven (BioRad H2500 Microwave Processor) at 700 W (100%) for 10 minutes divided into two 5-minute cycles. After heating, the slides were left in the solution to cool for 15 minutes and then were rinsed in phosphate-buffered saline (PBS) (pH 7.4) for another 5 minutes. The sections were incubated overnight at 4°C with EGFR (1005) SC-03 polyclonal antibody (diluted 1:100; Santa Cruz Biotechonology, Inc, Santa Cruz, CA), c-neu (Ab-3) OP15 monoclonal antibody (1:100; Oncogen Research Products, Cambridge, MA), c-erbB-3 (RTJ.2) SC-415 monoclonal antibody (1:100), and c-erbB-4 (C-18) SC-283 polyclonal antibody (1:100; Santa Cruz Biotechonology, Inc) [9]. The immunoreactivity was detected by the streptavidin-biotin-peroxidase complex method (MultiLink SuperSensitive 500 Detection System, BioGenex). The chromogen was 3'-33-diamino-benzidine (0.025%). The sections were counterstained with hematoxylin. The section incubated with PBS instead of primary antibody was used as the negative control, whereas an invasive ductal carcinoma of the breast positive for all four primary antibodies above was used for positive controls.
Tumor cells with membranous and cytoplasmic staining were considered positive, and cells without any immunostaining were considered negative. The slides were reviewed independently by two pathologists who had no knowledge of the clinical outcome. The staining intensity of EGFR family members was ranked into four grades (0 to 3 scale), and percentages of positively stained tumor cells were also recorded. The positive result denotes that more than 50% of the cancer cells were stained with an intensity of at least 1 on a 0 to 3 scale [13].
Statistical analysis
The two-sided Fisher exact test was used to analyze contingency tables, with p less than 0.05 as the criterion for statistical significance. The recurrence-free survival curves were calculated by the Kaplan-Meier product limit estimate, and differences between curves were analyzed by the log-rank test and rechecked by a Cox univariate analysis model. A stepwise multivariate Cox proportional hazards regression analysis [14], and an examination of the partial p value of [-2 (log likelihood ratio)] were used to identify, from the significant predictors derived from the Cox univariate analysis, a useful predictive model of tumor recurrence risk. The partial p of [-2 (log likelihood ratio)] is calculated based on the fact that the [-2 (log likelihood ratio)] approximates 
2 distribution. For example, [-2 log (likelihood ratio)] of a combination of ErbB-1 and ErbB-3 = [-2 log (likelihood of ErbB-1)] - [-2 log (likelihood of ErbB-1 and ErbB-3)]. From the 2 distribution, we can obtain the corresponding partial p. The colinearity among the independent variables of the stepwise multivariate Cox analysis model was examined with Spearman’s correlation method. These analyses were performed with the SPSS 8.0 software package for Windows (SPSS, Inc, Chicago, IL) and Prism 3.0 for Windows (GraphPad Software, Inc, San Diego, CA).
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Results
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Clinicopathologic characteristics and patient prognosis
Median follow-up was 45 months (range, 2 to 144 months). At last follow-up, 26 patients were alive and free of cancer, 6 patients had died of other causes without evidence of cancer, 7 patients were alive with recurrent cancer, 2 patients had died of other causes with recurrent cancer, and 32 patients had died of cancer. The median tumor-free interval was 41 months (range, 2 to 144 months), the recurrence rate was 56% (41 of 73), and the incidence of recurrence within 3 years postoperatively was 73% (30 of 41). The location of recurrence was initially at a distant site in 19 (19 of 41, 46%), or within the ispilateral hemithorax in 22 (22 of 41, 54%; Table 1). The 5-year survival rate in our series was 60.2% (stage IA, 70%; stage IB, 56%), and the 10-year survival rate was 42.3% (stage IA, 48%; stage IB, 41%). The tumor relapse rate at 5 years was 52% (stage IA, 51%; stage IB, 52%) and at 10 years was 67% (stage IA, 68%; stage IB, 67%).
According to the log-rank test, significant conventional pathologic indicators of recurrence were angiolymphatic tumor emboli and non-well-differentiated tumor cells (Fig 1, A and B). Patients with non-well-differentiated tumor were those with moderately differentiated, poorly differentiated, or undifferentiated tumor (Table 1). Most of the angiolymphatic tumor emboli were non-squamous cell carcinoma (Fisher exact test, two-sided, p = 0.008). However, there were no significant associations between tumor recurrence and histologic subtypes (squamous cell carcinoma versus non-squamous cell carcinoma) (Fig 1C), age, gender, and substage of stage I (Fig 1D). The 5-year recurrence-free percentage of squamous cell carcinoma (56%) tended to be higher compared with non-squamous cell carcinoma (33%), but p = 0.0591 (Fig 1C).
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Fig 1. Analyses of traditional pathologic factors for recurrence in 73 patients with stage I non-small cell lung carcinoma by log-rank test and Cox univariate analysis model. (A) Angiolymphatic tumor emboli (Angio.), (B) tumor differentiation (well-differentiated [WD] versus non-well-differentiated), (C) histology (squamous cell carcinoma versus non-squamous cell carcinoma), (D) substage (IA versus IB).
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Immunohistochemical expression percentage of epidermal growth factor receptor family members and clinical correlation
Immunohistochemical staining for ErbB-1, -2, -3, and -4 was completed for all 73 patients. All histologic types of NSCLC showed expression of EGFR family members. The incidences of the immunoreactivity for these four members were ErbB-1, 66%; ErbB-2, 38%; ErbB-3, 64%; and ErbB-4, 78% (Table 2). The incidences of EGFR family members reported in the literature are shown in the footnotes to Table 2. There were no significant associations between expression rate of EGFR family members and age, sex, or substages of stage I, except that ErbB-1 expression was significantly higher in patients with non-well-differentiated tumor cells (Table 3). Nearly half the patients with ErbB-2 expression had adenocarcinoma. However, neither expression rate (Table 3) nor prognostic value of EGFR family members for recurrence correlated with histologic subtype (squamous versus nonsquamous) (data not shown).
Prognostic value of epidermal growth factor receptor family members and coexpression patterns
These 73 patients with stage I NSCLC were regarded as a group, and the correlations between expression of each EGFR family member and recurrent risk were assessed first with the Kaplan-Meier method and log-rank test. ErbB-1 and ErbB-3 were important predictors of recurrent risk (Fig 2A and C), but ErbB-2 expression showed no correlation with recurrent risk (Fig 2B). Patients with ErbB-3 expression had a significantly higher incidence of distant metastasis (Table 4). When ErbB-1, ErbB-3, and two significant traditional pathologic descriptions mentioned above were placed into a Cox univariate analysis model, significance still held true for these four predictors (Figs 1 and 2).
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Fig 2. Analyses of prognostic value of each epidermal growth factor receptor family members for recurrence in 73 patients with stage I non-small-cell lung carcinoma by log-rank test and Cox univariate analysis model. (A) ErbB-1. (B) ErbB-2. (C) ErbB-3. (D) ErbB-4.
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When we examined the expression patterns of EGFR family members in our 73 patients, we saw a pattern (Fig 3A). The distribution of EGFR family-member expression was (a) patients with no expression, 8% (6 of 73); (b) with one member, 12% (9 of 73); (c) two members, 23% (17 of 73); (d) three members, 37% (27 of 73); and (e) four members, 20% (14 of 73) (Fig 3B). We analyzed the relationship between these coexpression patterns and tumor recurrent risk by using a Kaplan-Meier product limit estimate to calculate the recurrence-free percentage and the log-rank test to examine the differences between curves. Only the ErbB-1+, -3+ combination provided a significant pair (Fig 4A). The incidence of this significant pair was 49% (36 of 73, Table 2).
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Fig 3. (A) Expression patterns of epidermal growth factor receptor family members in 73 patients with stage I non-small-cell lung carcinoma. (B) Graph of number of epidermal growth factor receptor family members expressed in the 73 patients.
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Fig 4. Kaplan-Meier recurrence-free survival estimates stratified by (A) combined ErbB-1+, -3+, (B) expression of three or more members of epidermal growth factor receptor family, (C) expression of ErbB-1+, -2+, -3+ or ErbB-1+, -3+, -4+. Difference between curves was analyzed by log-rank test and Cox univariate analysis.
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Expression of three or more members of the EGFR family occurred in 57% (41 of 73) of the patients in the present study (Fig 3B), which significantly correlated with tumor recurrence risk during the follow-up period (Fig 4B). These two findings allow us to describe a subset of patients with a higher incidence of tumor recurrence than other patients (Fig 4C).
Establishing predictive models for the risk of tumor recurrence by a stepwise multivariate cox proportional hazards regression analysis model
Using Cox univariate analysis, we derived a panel of significant independent prognostic factors for the risk of tumor recurrence (Table 5). This panel consists of conventional pathologic factors and EGFR family members, and the relative importance of each is ranked from high to low based on its [-2 (log likelihood)]. Stepwise multivariate Cox proportional hazards regression analysis and examination of the partial p value of [-2 (log likelihood ratio)] allowed us to identify three important predictive models for the risk of tumor recurrence (Table 6). It is important to note that there was no strong colinearity among the independent variables of the multivariate analysis model. The low Spearman correlation coefficients and p values more than 0.05 are given in parentheses. The first model predicts a high incidence of recurrence for patients with combined angiolymphatic tumor emboli and non-well-differentiated tumor (Spearman correlation coefficient = 0.002, p = 0.986), the second for patients with both angiolymphatic tumor emboli and ErbB-1 expression (Spearman correlation coefficient = 0.205, p = 0.082), and the third for patients who have non-well-differentiated tumor cells with ErbB-3 expression (Spearman correlation coefficient = 0.033, p = 0.782).
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Table 5. Independent Prognostic Factors for Tumor Recurrence in Stage I Non-Small Cell Lung Cancer Derived From the Cox Univariate Analysis Model
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Table 6. Useful Predictive Model for the Risk of Tumor Recurrence in Stage I Non-Small Cell Lung Cancer by Stepwise Multivariate Cox Proportional Hazards Regression Analysis
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Comment
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The reported average 5-year survival rate for patients with stage I NSCLC is 64.6% (range, 55% to 72%) [1, 11]. The results of the present study show a 5-year survival rate of 60.2% (44 of 73) (stage IA, 70%; stage IB, 56%). A variety of clinical and pathologic features have been recognized as important determinants of clinical outcome of stage I NSCLC. The tumor size (T1 versus T2) and histologic subtype (squamous cell carcinoma versus nonsquamous cell carcinoma) have been the most widely studied. The correlation between postoperative recurrences and the tumor size or histologic subtype has not been consistent across studies [1, 15–16], and neither factor was a significant predictor in the present study (Fig 1C and D). However, in agreement with other reports [15–17], we found two significant conventional pathologic indicators, angiolymphatic tumor emboli and tumor differentiation status (Fig 1A and B). Furthermore, the accuracy of predicting the recurrence risk using these two factors in combination was significantly greater than when either one was used alone and was regarded as a more powerful predictive model by stepwise multivariate Cox analysis (Table 6). Nevertheless, only 19% of our patients were positive for angiolymphatic tumor emboli (Table 1), which means that this predictive model is not general enough for most patients with stage I NSCLC.
ErbB-1, encoded by the protooncogen erb-b1, is an important contributing factor in driving uncontrolled tumor growth [4]. We found that ErbB-1 expression increased parallel to the loss of tumor differentiation (Table 3). Combined angiolymphatic tumor emboli and ErbB-1 expression, therefore, might be as useful as combined angiolymphatic tumor emboli and non-well-differentiated tumors in predicting the risk of tumor recurrence. At present, however, the examination of EGFR family member expression is not a routine practice, but the description of tumor cell differentiation is. If overexpression of ErbB-3 is a useful marker for predicting the probability of tumor recurrence in patients with non-well-differentiated stage I NSCLC (Table 6), as our stepwise multivariate Cox analysis model suggests, perhaps we should consider routinely testing for it. This result may have potential for helping clinicians determine appropriate treatment strategies for patients with stage I NSCLC. In addition, the correlation of ErbB-3 with distant metastasis is consistent with the finding of Lemoine and colleagues [18] that overexpression of ErbB-3 is associated with lymph node metastases in human breast cancers.
We proved the predictive significance of combined ErbB-1+, -3+ expression for the risk of tumor recurrence (Fig 4A), but the ErbB-1+, -3+ was not significantly important when combined with either angiolymphatic tumor emboli or non-well-differentiated tumor in the stepwise multivariate Cox analysis model. However, this study did confirm that EGFR family members can be detected in diverse combinations in patients with stage I NSCLC. In addition, univariate analysis also showed a significant correlation in the risk of tumor recurrence with expression of three or more members of the EGFR family and a subset of patients with expression of (ErbB-1+, -2+, -3+) or (ErbB-1+, -3+, -4+). In light of our findings, it is interesting to note that Xia and associates [9] report that patients with oral squamous cell carcinoma and concomitant expression of ErbB-2+, -3+, and -1+ had a shortened survival. Zhang and associates [7] showed that ErbB-1 or -2 coexpression with ErbB-3 or -4 is required for the transformation of NIH 3T3 cells in the presence of heregulin. Kim and colleagues [19] showed that the binding of epidermal growth factor to ErbB-1 resulted in the activation of protein tyrosine kinase activity and the phosphorylation of the ErbB-3 protein on tyrosine residues. The phosphorylated ErbB-3 protein then tightly binds with and activates the phosphatidylinositol 3-kinase (PI3-kinase) enzyme, a signaling molecule shown to be involved in mitogenic activity and cytoskeletal rearrangement [20]. Expression of ErbB-2 has been long regarded as an important prognostic factor and was found in two large series of patients with stage I NSCLC [5, 15]. However, the present study and two other large cohort studies [1, 21] showed that ErbB-2 was not an important predictor of tumor recurrence. The results suggested that ErbB-2 and its related pathway might not be relevant in the early stage of pulmonary carcinogenesis. It is also of interest that Tateishi and associates [22] showed ErbB-2 expression to be correlated with more advanced disease in a group of lung cancer patients with adenocarcinoma.
Taken together, ErbB-1 expression increased relative to the loss of tumor differentiation, and ErbB-3 expression was also well correlated with distant metastasis. Among patients with non-well-differentiated stage I NSCLC, overexpression of ErbB-3 was a useful predictor of tumor recurrence. To determine the molecular mechanism, biologic relevance of EGFR family member coexpression, and the value of postoperative adjuvant therapy in this subgroup of patients, a prospective clinical study with a large cohort and an elaborate experimental model is required.
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Acknowledgments
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This study was supported in part by research grants from National Cheng Kung University Hospital (NCKUH #89–020 and #89–053) and the National Science Council of the Republic of China (NSC #89–2314-B-006–108).
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Abstract
Introduction
