Elsevier

Human Pathology

Volume 40, Issue 3, March 2009, Pages 356-365
Human Pathology

Original contribution
The predictive value of epidermal growth factor receptor tests in patients with pulmonary adenocarcinoma: review of current “best evidence” with meta-analysis

https://doi.org/10.1016/j.humpath.2008.08.008Get rights and content

Summary

Epidermal growth factor receptor signaling pathway plays an important role in pulmonary adenocarcinoma biology. Targeted therapy with tyrosine kinase inhibitors like gefitinib and erlotinib are being used in selected patients with variable response rates. Several RCT and other studies have evaluated the value of various tests such as immunohistochemistry, polymerase chain reaction, and fluorescent in situ hybridization for epidermal growth factor receptor detection. The clinical validity and applicability of these tests remain controversial. Evidence-based pathology promotes the use of systematic review of the literature and meta-analysis rather than subjective appraisal of the literature. We performed a systematic review of the literature to identify the “best evidence” regarding the use of these tests. The data were analyzed using Comprehensive meta-analysis software (Biostat, Inc, Englewood, NJ). Most of the information regarding epidermal growth factor receptor tests has been published in retrospective case series with few double-blind and prospective RCT. Estimated positive predictive values of immunohistochemistry, polymerase chain reaction, and fluorescent in situ hybridization range from 6.5% to 82%%, 7% to 100%, and 11% to 89%, respectively. Meta-analysis of nearly 5000 cases in the literature estimates that all 3 tests significantly predict response to gefitinib in patients with lung cancer. It shows lack of heterogeneity within the study results, although the current best evidence is limited by variations in study methodologies, patient ethnicity, test interpretation criteria, and variable definitions of treatment response. There is only one study evaluating the value of epidermal growth factor receptor tests in predicting response to erlotinib. Further studies are needed to clarify the predictive value of epidermal growth factor receptor tests in patients with pulmonary adenocarcinoma.

Introduction

Lung cancer is a leading cause of cancer-related deaths with less than 15% five-year survival [1]. Benefits of conventional platinum-based chemotherapy are modest in patients with advanced-stage disease [2], [3]. Inhibitors of epidermal growth factor receptors (EGFR) are being used as a second- or third-line targeted therapy for patients with advanced pulmonary adenocarcinoma [4]. EGFR is a member of the erbB family of tyrosine kinase receptor proteins. The overexpression or mutation in the tyrosine kinase domain leads to inappropriate activation of the ras-antiapoptotic cascade in 43% to 89% of the non–small cell carcinomas (NSCLC) of the lung [5]. Tyrosine kinase inhibitors (TKI) such as gefitinib (Iressa, AstraZeneca, Macclesfield, UK) and erlotinib (Tarceva, OSI/Genentech, Boulder, CO/South San Francisco, CA) interfere with this signaling pathway and result in objective responses in 10% to 27% of patients with NSCLC after failure of chemotherapy [6].

The prognostic value of EGFR overexpression in patients with pulmonary adenocarcinoma is controversial. For example, Ohsaki et al [7] have reported an association between detection of EGFR overexpression and poor prognosis, whereas Rusch et al [8] have not reported prognostic correlation. Specific EGFR mutations of exons 18 to 21 have been associated with good prognosis irrespective of TKI therapy in multiple studies [9], [10], [11], [12]. EGFR mutations are more frequently observed in nonsmoking Asian women with adenocarcinoma showing bronchioloalveolar histology; however, these clinical parameters have limited value in selecting patients likely to benefit from TKI [13], [14], [15]. Various tests such as immunohistochemistry (IHC), polymerase chain reaction (PCR), and fluorescent in situ hybridization (FISH) have been used to assess the overexpression or mutation in EGFR in an attempt to identify the subset of patients who may benefit from gefitinib or erlotinib therapy with conflicting results. For example, initial studies by Parra et al [16] failed to demonstrate a predictive value of EGFR overexpression detected by IHC in patients with pulmonary adenocarcinoma treated with TKI therapy. In contrast, 2 recent placebo-controlled trials by Hirsch et al [15] and Tsao et al [17] showed that IHC had a predictive value in selecting patients who may benefit from TKI therapy. The predictive value of EGFR mutation detected by PCR in patients with pulmonary adenocarcinoma in selecting patients who may benefit from TKI therapy has been reported by Mitsudomi et al [10] who reported response to TKI therapy in 72% of the patients with EGFR mutation, whereas only 7.6% of patients without mutations responded to TKI therapy; similar findings were reported by Han et al [11] who reported response to TKI in 88% of patients with EGFR mutations, whereas only 14% of patients without EGFR mutations responded to TKI therapy. On the other hand, Cappuzzo et al [18] were not able to confirm this finding. Increased EGFR copy number as detected by FISH has shown correlation with response to gefitinib, disease-free, and overall survival in the majority of the studies [18], [19].

Evidence-based pathology promotes the use of an analytical approach to the evaluation of the information published in the medical literature and its applicability for individual patient care [20], [21]. It relies on systematic review of the literature, classification of information into levels of accuracy in an attempt to identify the “best” current evidence, and the use of meta-analysis for the integration of best evidence into diagnostic rules, guidelines, or algorithms that can help guide the treatment of individual patients [22], [23], [24]. We performed a systematic review of the literature to identify current “best evidence” regarding the clinical value of the various EGFR tests as predictors of management in patients with pulmonary adenocarcinoma and evaluated the data using meta-analysis.

Section snippets

Materials and methods

The English language medical literature was reviewed using the Pubmed database (United States National Medical Library) and the search terms “pulmonary adenocarcinoma”, “EGFR” “IHC”, “PCR”, “FISH”, “gefitinib” and “erlotinib.” Only randomized controlled trials (RCT) and case series that evaluated the use of IHC, PCR, and/or FISH in human tissue to determine response in patients with primary pulmonary adenocarcinoma to TKI therapy were included in the analysis. Studies that carried out these

Results

Systematic review of the literature revealed 233 publications analyzing various aspects of EGFR biology and/or erlotinib or gefitinib therapy in patients with pulmonary adenocarcinoma. Twenty-six of these studies including nearly 4270 patients fulfilled our selection criteria and compared the response and/or survival rates in patients with pulmonary adenocarcinoma treated with gefitinib therapy and positive and negative EGFR test results (Table 1). An additional study evaluated the response and

Discussion

The possibility of treating lung cancer patient with targeted therapies has elicited a great deal of interest in oncology, and several clinical trials have evaluated the use of TKI, anti-angiogenesis, and other drugs such as Herceptin [46]. The use of TKI drugs has generated particular interest as selected patients with metastatic NSCLC can respond dramatically to gefitinib or erlotinib therapy for periods of up to 18 months [9], [47]. However, as the overall response rate to these expensive

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