Combined analysis of molecular and clinical predictors of gefitinib activity in advanced non-small cell lung cancer: epidermal growth factor receptor mutations do not tell the whole story.
ABSTRACT Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have been introduced in the standard therapy of non-small-cell lung cancer (NSCLC), but they benefit a minority of patients. The study of molecular markers may identify the subset of patients who are the most appropriate to treat with these agents.
We analyzed 43 patients with advanced NSCLC who were treated with gefitinib, an oral EGFR tyrosine kinase inhibitor, were included in analysis. We evaluated EGFR in tumor tissue by using immunohistochemistry and fluorescence in situ hybridization. We also studied downstream molecules (AKT, ERK, p38 MAPK) and their activation status and the presence of EGFR mutations in tumor tissue in exons 18-21.
Three patients had tumors with EGFR mutations, all of which had EGFR gene amplification with a ratio of 2 or greater (p= 0.001). There was no correlation between EGFR protein expression and gene amplification. Six patients (14%) achieved an objective response and nine (21%) had stable disease; the median survival was 162 days. EGFR mutations, high levels of AKT protein expression, rash of any grade, and no history of smoking were predictive of disease control (objective response plus stable disease). Only 3 of 15 patients (20%) with disease control had an EGFR mutation. On multivariate analysis, rash and AKT were independent predictors of disease control. Patients with rash survived longer than patients without rash.
EGFR mutation-positive tumors are present in a small fraction of patients who achieve disease control with gefitinib. Other molecular markers, such as AKT, need to be further evaluated. Clinical parameters remain major determinants of gefitinib activity in NSCLC.
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ABSTRACT: The aim of this study was to assess the role of skin rash in predicting the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and the prognosis of patients with non-small cell lung cancer (NSCLC). We systematically searched for eligible articles investigating the association between rash and the efficacy of EGFR-TKIs and the prognosis of patients with NSCLC. The summary risk ratio (RR) and hazard ratio (HR) were calculated using meta-analysis. We identified 33 eligible trials involving 6,798 patients. We used two different standards to group the patients [standard 1: rash vs. no rash, standard 2: rash (≥ stage 2) vs. rash (stage 0, 1)]. For standard 1, the objective response rate (ORR) and disease control rate (DCR) of the rash group were significantly higher than the no rash group [RR = 3.28; 95% CI: 2.41-4.47(corrected RR = 2.225, 95% CI: 1.658-2.986); RR = 1.96, 95% CI: 1.58-2.43]. The same results were observed for standard 2. For standards 1 and 2, the progression-free survival (PFS) (HR = 0.45, 95% CI: 0.37-0.53; HR = 0.57, 95% CI: 0.50-0.65) and overall survival (OS) (HR = 0.40, 95% CI: 0.28-0.52; HR = 0.53, 95% CI: 0.35-0.71) of the rash group were significantly longer than the control group, and the same results were observed in the subgroup analysis. skin rash after EGFR-TKI treatment may be an efficient clinical marker for predicting the response of patients with NSCLC to EGFR-TKIs. Furthermore, skin rash is also the prognostic factor of patients with NSCLC. Patients with skin rash have a longer PFS and OS.PLoS ONE 01/2013; 8(1):e55128. · 3.53 Impact Factor
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ABSTRACT: 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.Human pathology 11/2008; 40(3):356-65. · 3.03 Impact Factor
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ABSTRACT: Objective.-To establish evidence-based recommendations for the molecular analysis of lung cancers that are required to guide EGFR- and ALK-directed therapies, addressing which patients and samples should be tested, and when and how testing should be performed. Participants.-Three cochairs without conflicts of interest were selected, one from each of the 3 sponsoring professional societies: College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Writing and advisory panels were constituted from additional experts from these societies. Evidence.-Three unbiased literature searches of electronic databases were performed to capture articles published from January 2004 through February 2012, yielding 1533 articles whose abstracts were screened to identify 521 pertinent articles that were then reviewed in detail for their relevance to the recommendations. Evidence was formally graded for each recommendation. Consensus Process.-Initial recommendations were formulated by the cochairs and panel members at a public meeting. Each guideline section was assigned to at least 2 panelists. Drafts were circulated to the writing panel (version 1), advisory panel (version 2), and the public (version 3) before submission (version 4). Conclusions.-The 37 guideline items address 14 subjects, including 15 recommendations (evidence grade A/B). The major recommendations are to use testing for EGFR mutations and ALK fusions to guide patient selection for therapy with an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) inhibitor, respectively, in all patients with advanced-stage adenocarcinoma, regardless of sex, race, smoking history, or other clinical risk factors, and to prioritize EGFR and ALK testing over other molecular predictive tests. As scientific discoveries and clinical practice outpace the completion of randomized clinical trials, evidence-based guidelines developed by expert practitioners are vital for communicating emerging clinical standards. Already, new treatments targeting genetic alterations in other, less common driver oncogenes are being evaluated in lung cancer, and testing for these may be addressed in future versions of these guidelines.Archives of pathology & laboratory medicine 04/2013; · 2.78 Impact Factor