Analysis of c-ErbB1/Epidermal Growth Factor Receptor and c-ErbB2/HER-2 Expression in Bronchial Dysplasia: Evaluation of Potential Targets for Chemoprevention of Lung Cancer

Merrick, Daniel T.; Kittelson, John; Winterhalder, Ralph; Kotantoulas, Georgia; Ingeberg, Steen; Keith, Robert L.; Kennedy, Timothy C.; Miller, York E.; Franklin, Wilbur A.; Hirsch, Fred R.

doi:10.1158/1078-0432.ccr-05-2291

Cited by 71 publications

(54 citation statements)

References 35 publications

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“…The same study reported that a high copy number correlated with a poor prognosis and that this phenomenon was more frequently observed in patients with squamous cell carcinoma than in patients with other types of carcinoma (13). In addition, the correlation between the expression of ErbB receptor family proteins and different clinical outcomes and therapeutic responses to monoclonal antibodies has also been widely studied, although the results are more heterogeneous (22). EGFR expression is frequently observed in NSCLC patients with brain metastases (23).…”

Section: Discussionmentioning

confidence: 99%

Reproducibility of the EGFR immunohistochemistry scores for tumor samples from patients with advanced non-small cell lung cancer

et al. 2016

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Abstract. Epidermal growth factor receptor (EGFR) is overexpressed in >60% of non-small cell lung cancer (NSCLC) cases. In combination with radiotherapy or chemotherapy, first-line treatments with antibodies against EGFR, including cetuximab and necitumumab, have demonstrated benefits by increasing overall survival (OS), particularly in patients who overexpress EGFR. The present study evaluated the interobserver agreement among three senior pathologists, who were blinded to the clinical outcomes and assessed tumor samples from 85 patients with NSCLC using the H-score method. EGFR immunohistochemistry was performed using a qualitative immunohistochemical kit. The reported (mean ± standard deviation) H-scores from each pathologist were 111±102, 127±103 and 128.53±104.03. The patients with average H-scores ≥1, ≥100, ≥200 and between 250-300 were 85.9, 54.1, 28.2 and 12.9, respectively. Patients who had an average H-score >100 had a shorter OS time compared with those with lower scores. Furthermore, patients with EGFR mutations who were treated with EGFR-tyrosine kinase inhibitors (TKIs) and had an average H-score >100 had a longer OS time compared with those with an average H-score <100. The interobserver concordance for the total H-scores were 0.982, 0.980 and 0.988, and for a positive H-score ≥200, the interobserver concordance was 0.773, 0.710 and 0.675, respectively. The determination of EGFR expression by the H-score method is highly reproducible among pathologists and is a prognostic factor associated with a poor OS in all patients. Additionally, the results of the present study suggest that patients with EGFR mutations that are treated with EGFR-TKIs and present with a high H-score have a longer OS time.

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Section: Discussionmentioning

confidence: 99%

Reproducibility of the EGFR immunohistochemistry scores for tumor samples from patients with advanced non-small cell lung cancer

et al. 2016

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“…One biopsy from each site at which evaluable tissue was available was then immunostained for Ki-67 using the mib-1 monoclonal (DAKO) as described (ref. 15; Fig. 1).…”

Section: Bronchial Epithelial Ki-67 and Lung Cancermentioning

confidence: 94%

“…The Ki-67 antigen is localized to the nucleus, currently incompletely biochemically characterized, and is expressed in all phases of the cell cycle except for G 0 (13). The percentage of epithelial cells expressing Ki-67, or Ki-67 index, is progressively elevated in bronchial preneoplasias of increasing grades of severity up to and including invasive lung cancer and displays large interindividual variation, suggesting that it may reflect differences in response to carcinogens (14,15). Ki-67 index has been characterized in current and ex-smokers by Lee et al (11).…”

Section: Introductionmentioning

confidence: 99%

Bronchial Epithelial Ki-67 Index Is Related to Histology, Smoking, and Gender, but Not Lung Cancer or Chronic Obstructive Pulmonary Disease

Miller

Blatchford

Hyun

et al. 2007

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Purpose: To determine whether increased bronchial epithelial proliferation is associated with histology, smoking status, gender, age, chronic obstructive pulmonary disease (COPD), or lung cancer. Experimental Design: Cross-sectional study of 113 subjects undergoing white light and autofluorescence bronchoscopy: 27 never smokers; 27 current or ex-smokers with normal spirometry; 31 current or exsmokers with COPD; and 28 current, ex-, or never smokers with lung cancer. Ki-67 expresssion was determined by immunohistochemistry on all evaluable biopsy sites without carcinoma. Relationships between Ki-67 index (percentage of epithelial cells expressing Ki-67), demographic variables, smoking, histology, and the presence of COPD and/or lung cancer were determined. Results: Results for both maximal and mean Ki-67 index are similar, so only the former are reported. Average maximal Ki-67 index was higher in current smokers than either ex-smokers or never smokers (48.0% versus 30.6% versus 22.6%; P < 0.001). Males had higher Ki-67 index than females (39.9% versus 23.6%; P < 0.001). Compared with subjects without disease (Ki-67 index = 30.0%), maximal Ki-67 index was not significantly elevated (P = 0.44) in subjects with either lung cancer (Ki-67 = 39.1%) or COPD (Ki-67 = 38.9%). Conclusions: Smoking status, bronchial histology, and gender were significantly associated with Ki-67 index. No increase in Ki-67 index was found in the nonmalignant epithelium of patients with lung cancer or COPD. Although Ki-67 index may provide insight into the short-term effects of chemoprevention agents on cell proliferation, its lack of association with lung cancer or COPD raises question regarding its utility as a lung cancer risk biomarker. (Cancer Epidemiol Biomarkers Prev

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“…EGFR is highly expressed in a variety of human tumors, including NSCLC, and is implicated in tumor development (Grandis and Sok, 2004;Merrick et al, 2006). The overexpression of EGFR has been observed in both premalignant lesions and malignant tumors of the lung, and occurs in 40-80% of patients with NSCLC (Salomon et al, 1995;Grandis and Sok, 2004;Merrick et al, 2006).…”

Section: Egfr and Her2 Overexpressionmentioning

confidence: 99%

“…The overexpression of EGFR has been observed in both premalignant lesions and malignant tumors of the lung, and occurs in 40-80% of patients with NSCLC (Salomon et al, 1995;Grandis and Sok, 2004;Merrick et al, 2006). EGFR overexpression was suggested to result primarily from epigenetic causes, including transcriptional activation; however, gene amplification and oncogenic viruses can also have an important function (Wong et al, 1992;Rubin Grandis et al, 1996a, b;Grandis and Sok, 2004).…”

Section: Egfr and Her2 Overexpressionmentioning

confidence: 99%

Predictive value of EGFR and HER2 overexpression in advanced non-small-cell lung cancer

2009

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Epidermal growth factor receptor (EGFR) and HER2 are cell surface receptor tyrosine kinases (TKs) that transduce growth signals through dimerization with HER family receptors. The heterodimerization of EGFR with HER2 induces a more potent activation of EGFR TK than does EGFR homodimerization. When tumor cells overexpress both EGFR and HER2, they exhibit aggressive tumor cell growth, owing to the increased potential for EGFR/HER2 heterodimerization and signaling. Gefitinib and erlotinib are EGFR TK inhibitors (EGFR TKIs) and have antitumor activity in 8-18% of patients with advanced non-small-cell lung cancer (NSCLC). Certain patient subsets are particularly responsive to EGFR TKIs. Analyses of biomarkers from patients in clinical studies of EGFR TKIs show correlations between objective tumor response and EGFR overexpression, as detected by immunohistochemistry and increased gene copy number measured by fluorescence in situ hybridization analysis. Furthermore, NSCLC tumors that overexpress both EGFR and HER2 are more sensitive to EGFR TKIs than are tumors that overexpress EGFR but are HER2 negative. Therefore, the measurement of EGFR and HER2 protein expression and the gene copy number in NSCLC tumors may have a prognostic value in NSCLC and a predictive value for identifying patients likely to benefit from an EGFR TKI. These considerations suggest that the simultaneous inhibition of EGFR and HER2 may warrant further study in patients with NSCLC.

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Analysis of c-ErbB1/Epidermal Growth Factor Receptor and c-ErbB2/HER-2 Expression in Bronchial Dysplasia: Evaluation of Potential Targets for Chemoprevention of Lung Cancer

Cited by 71 publications

References 35 publications

Reproducibility of the EGFR immunohistochemistry scores for tumor samples from patients with advanced non-small cell lung cancer

Reproducibility of the EGFR immunohistochemistry scores for tumor samples from patients with advanced non-small cell lung cancer

Bronchial Epithelial Ki-67 Index Is Related to Histology, Smoking, and Gender, but Not Lung Cancer or Chronic Obstructive Pulmonary Disease

Predictive value of EGFR and HER2 overexpression in advanced non-small-cell lung cancer

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