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
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.
Available from: Evangelos Tsiambas
- "A study showed that among EGFR-positive primary lung ACs, overall survival was signifi cantly poorer for patients demonstrating high protein levels of those ligands than the others, which characterized by low or negative expression (Tateishi et al. 1990). Almost recently, another study analyzing EGFR gene status by FISH and PCR methods identifi ed a subset of patients who were characterized by simultaneous gene amplifi cation and point mutations (Argiris et al. 2006). "
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ABSTRACT: Epidermal growth factor receptor (EGFR) overexpression is observed in significant proportions of non-small cell lung carcinomas (NSCLC). Furthermore, overactivation of vascular endothelial growth factor (VEGF) leads to increased angiogenesis implicated as an important factor in vascularization of those tumors.
Using tissue microarray technology, forty-paraffin (n = 40) embedded, histologically confirmed primary NSCLCs were cored and re-embedded into a recipient block. Immunohistochemistry was performed for the determination of EGFR and VEGF protein levels which were evaluated by the performance of computerized image analysis. EGFR gene amplification was studied by chromogenic in situ hybridization based on the use of EGFR gene and chromosome 7 centromeric probes.
EGFR overexpression was observed in 23/40 (57.5%) cases and was correlated to the stage of the tumors (p = 0.001), whereas VEGF was overexpressed in 35/40 (87.5%) cases and was correlated to the stage of the tumors (p = 0.005) and to the smoking history of the patients (p = 0.016). Statistical significance was assessed comparing the protein levels of EGFR and VEGF (p = 0.043, k = 0.846). EGFR gene amplification was identified in 2/40 (5%) cases demonstrating no association to its overall protein levels (p = 0.241), whereas chromosome 7 aneuploidy was detected in 7/40 (17.5%) cases correlating to smoking history of the patients (p = 0.013).
A significant subset of NSCLC is characterized by EGFR and VEGF simultaneous overexpression and maybe this is the eligible target group for the application of combined anti-EGFR/VEGF targeted therapies at the basis of genetic deregulation (especially gene amplification for EGFR).
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The objective of this analysis was to examine the relationship between genomic variation and health outcomes in studies performed in non-small cell lung cancer (NSCLC) patients treated with single agent epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) using a systematic review with statistical pooling of data.
We performed a systematic search of the literature using the MEDLINE, BIOSIS, and EMABASE databases from July 1997 to July 2007. Eligible studies were evaluated for quality and clinical, methodological, and statistical heterogeneity. Abstracted data judged to be sufficiently homogenous were pooled using a fixed effect model.
In conclusion, EGFR mutation and protein expression status may provide useful clinical information in terms of the likelihood of tumor response and disease prognosis. EGFR gene copy number and to a lesser extent, EGFR protein expression status, appear to be promising biomarkers for predicting a survival benefit with EGFR-TKI therapy in second line NSCLC, but further evidence is needed.
Available from: Kara Perrow (nee Vine)
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ABSTRACT: The increased incidence of multidrug resistance (MDR) and systemic toxicity to conventional chemotherapeutic agents suggests that alternative avenues need to be explored in the hope of finding new and effective treatments for metastatic disease. Considering natural products have made enormous contributions to many of the anticancer agents used clinically today, the cytotoxic molluscan metabolite tyrindoleninone (1) and its oxidative artifact, 6-bromoisatin (5), were initially used as templates for drug design in this study. Structural modifications to the isatin scaffold afforded a total of 51 isatin-based analogues, 21 of which were new. Cytotoxicity screening of the compounds against a panel of heamatological and epithelial-derived cancer cell lines in vitro, found the di- and tri-bromoisatins to be the most potent, with activity observed in the low micromolar range. Interestingly compound activity was enhanced by up to a factor of 22 after N-alkyl and N-arylalkylation, highlighting the importance of N1 substitution for cytotoxic activity. 5,7-Dibromo-N-(p-methylbenzyl)-isatin (39) was the most active compound overall and exhibited an IC50 value of 490 nM against U937 and Jurkat leukemic cell lines, after 24 h. 5,7-Dibromo-N-(p-trifluoromethylbenzyl)isatin (54) was also of interest, considering the potent cell killing ability displayed against a metastatic breast adenocarcinoma (MDA-MB-231) cell line. Investigation into the molecular mode of action of the N-alkylisatin series of compounds found the p-trifluoromethylbenzyl derivative (54), together with 9 other representative molecules to destabilise microtubules and induce morphological cell shape changes via inhibition of tubulin polymerisation. This resulted in cell cycle arrest at G2/M and activation of the effector caspases 3 and 7, ultimately resulting in apoptotic cell death.Further investigations into the pharmacological profile of compound 54 in vivo, found it to be moderately efficacious (43% reduction in tumour size compared to vehicle control treated mice) in a human breast carcinoma xenograft mouse model. Although histopathological analysis of the bone marrow in situ after acute dosing found only mild haematopoietic suppression, analysis of biodistribution via SPECT imaging found large amounts of activity also in the gut and liver.In an effort to reduce non-target organ up-take and thus increase accumulation of drug in the tumour, the N-benzylisatin 54 was derivatised so as to contain an acid labile imine linker and was conjugated to the targeting protein PAI-2 (a naturally occurring inhibitor of the urokinase plasminogen activation system) via amide bond formation with free lysine residues. The conjugate was found to contain an average of 4 molecules of 54 per protein molecule without affecting PAI-2 activity. Hydrolytic stability of the PAI-2-cytotoxin conjugate at pH 5-7 as determined by UV/Vis spectrophotometry, was directly correlated with the lack of activity observed in vitro, suggesting a need to investigate cleavable linker systems with enhanced lability in the future. Despite this, PAI-2 conjugated to the cytotoxin 5-FUdr through a succinate linker system, showed enhanced and selective uPA-mediated cytotoxicity, in two different breast cancer cell lines which varied in their expression levels of uPA and its receptor. This suggests that PAI-2-cytotoxin based therapies hold potential, in the future, as new therapeutic agents for targeted therapy of uPA positive malignancies, with limited side effects.
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