Molecular Predictors of Outcome With Gefitinib in a Phase III Placebo-Controlled Study in Advanced Non–Small-Cell Lung Cancer

2006 ◽  
Vol 24 (31) ◽  
pp. 5034-5042 ◽  
Author(s):  
Fred R. Hirsch ◽  
Marileila Varella-Garcia ◽  
Paul A. Bunn ◽  
Wilbur A. Franklin ◽  
Rafal Dziadziuszko ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Protein Expression ◽  
Copy Number ◽  
Gene Copy Number ◽  
Phase Iii ◽  
Egfr Mutations ◽  
Gene Copy ◽  
Egfr Gene ◽  
Low Copy Number ◽  
Gefitinib Treatment

Purpose The phase III Iressa Survival Evaluation in Lung Cancer (ISEL) trial compared gefitinib with placebo in 1,692 patients with refractory advanced non–small-cell lung cancer. We analyzed ISEL tumor biopsy samples to examine relationships between biomarkers and clinical outcome after gefitinib treatment in a placebo-controlled setting. Methods Biomarkers included epidermal growth factor receptor (EGFR) gene copy number by fluorescence in situ hybridization (n = 370); EGFR (n = 379) and phosphorylated Akt (p-Akt) protein expression (n = 382) by immunohistochemistry; and mutations in EGFR (n = 215), KRAS (n = 152), and BRAF (n = 118). Results High EGFR gene copy number was a predictor of a gefitinib-related effect on survival (hazard ratio [HR], 0.61 for high copy number and HR, 1.16 for low copy number; comparison of high v low copy number HR, P = .045). EGFR protein expression was also related to clinical outcome (HR for positive, 0.77; HR for negative, 1.57; comparison of high v low protein expression HR, P = .049). Patients with EGFR mutations had higher response rates than patients without EGFR mutations (37.5% v 2.6%); there were insufficient data for survival analysis. No relationship was observed between p-Akt protein expression and survival outcome, and the limited amount of data collected for KRAS and BRAF mutations prevented any meaningful evaluation of clinical outcomes in relation to these mutations. Conclusion EGFR gene copy number was a predictor of clinical benefit from gefitinib in ISEL. Additional studies are warranted to assess these biomarkers fully for the identification of patients most likely to benefit from gefitinib treatment.

Biomarker Analyses and Final Overall Survival Results From a Phase III, Randomized, Open-Label, First-Line Study of Gefitinib Versus Carboplatin/Paclitaxel in Clinically Selected Patients With Advanced Non–Small-Cell Lung Cancer in Asia (IPASS)

2011 ◽  
Vol 29 (21) ◽  
pp. 2866-2874 ◽  
Author(s):  
Masahiro Fukuoka ◽  
Yi-Long Wu ◽  
Sumitra Thongprasert ◽  
Patrapim Sunpaweravong ◽  
Swan-Swan Leong ◽  
...  
Keyword(s):  
Overall Survival ◽  
Copy Number ◽  
Egfr Mutation ◽  
Gene Copy Number ◽  
Phase Iii ◽  
Egfr Mutations ◽  
Gene Copy ◽  
First Line ◽  
Egfr Gene ◽  
Significant Difference

Purpose The results of the Iressa Pan-Asia Study (IPASS), which compared gefitinib and carboplatin/paclitaxel in previously untreated never-smokers and light ex-smokers with advanced pulmonary adenocarcinoma were published previously. This report presents overall survival (OS) and efficacy according to epidermal growth factor receptor (EGFR) biomarker status. Patients and Methods In all, 1,217 patients were randomly assigned. Biomarkers analyzed were EGFR mutation (amplification mutation refractory system; 437 patients evaluable), EGFR gene copy number (fluorescent in situ hybridization; 406 patients evaluable), and EGFR protein expression (immunohistochemistry; 365 patients evaluable). OS analysis was performed at 78% maturity. A Cox proportional hazards model was used to assess biomarker status by randomly assigned treatment interactions for progression-free survival (PFS) and OS. Results OS (954 deaths) was similar for gefitinib and carboplatin/paclitaxel with no significant difference between treatments overall (hazard ratio [HR], 0.90; 95% CI, 0.79 to 1.02; P = .109) or in EGFR mutation–positive (HR, 1.00; 95% CI, 0.76 to 1.33; P = .990) or EGFR mutation–negative (HR, 1.18; 95% CI, 0.86 to 1.63; P = .309; treatment by EGFR mutation interaction P = .480) subgroups. A high proportion (64.3%) of EGFR mutation–positive patients randomly assigned to carboplatin/paclitaxel received subsequent EGFR tyrosine kinase inhibitors. PFS was significantly longer with gefitinib for patients whose tumors had both high EGFR gene copy number and EGFR mutation (HR, 0.48; 95% CI, 0.34 to 0.67) but significantly shorter when high EGFR gene copy number was not accompanied by EGFR mutation (HR, 3.85; 95% CI, 2.09 to 7.09). Conclusion EGFR mutations are the strongest predictive biomarker for PFS and tumor response to first-line gefitinib versus carboplatin/paclitaxel. The predictive value of EGFR gene copy number was driven by coexisting EGFR mutation (post hoc analysis). Treatment-related differences observed for PFS in the EGFR mutation–positive subgroup were not apparent for OS. OS results were likely confounded by the high proportion of patients crossing over to the alternative treatment.

Gene copy number of epidermal growth factor receptor (EGFR) by fluorescent in situ hybridization (FISH) in head and neck squamous cell carcinomas (HNSCC) is closely correlated with EGFR protein levels assessed by automated quantitative protein analysis (AQUA)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 6023-6023
Author(s):  
P. Weinberger ◽  
A. Psyrri ◽  
P. Kountourakis ◽  
T. Rampias ◽  
C. Sasaki ◽  
...  
Keyword(s):  
In Situ Hybridization ◽  
Protein Expression ◽  
Protein Content ◽  
Gene Amplification ◽  
Copy Number ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Egfr Gene ◽  
Protein Levels

6023 Background: EGFR overexpression correlates with recurrence and with treatment resistance in HNSCC. The mechanisms of EGFR protein overexpression are poorly understood. Nonetheless, previous investigators have not demonstrated a correlation between EGFR gene copy number and protein content, using conventional immunohistochemistry (IHC). The aim of this study was to evaluate the relationship of EGFR gene copy number and protein expression utilizing fluorescence in situ hybridization (FISH) and AQUA, a novel, immunohistochemical method of automated quantitative in situ proteomic analysis which permits subcellular localization. Methods: A tissue microarray composed of 137 HNSCC treated with (chemo)radiation was constructed and analyzed for EGFR copy number by FISH (Vysis/Abbot) and EGFR protein expression (DAKO antibody) using AQUA analysis of EGFR staining scored on a scale of 0–255 and by conventional IHC. Agreement was assessed using kappa. Results: Sixteen (15%) of one-hundred six tumors with FISH results demonstrated EGFR high polysomy and/or gene amplification (FISH+). AQUA demonstrated a range of 3.6–102.2; protein levels assessed by AQUA in the FISH amplified cases were significantly higher (p =0.008) than in the FISH non- amplified ones. Using the EGFR 75th percentile as a cut-off, AQUA and FISH showed significant agreement (percentage of overall agreement 82%, kappa=0.458, p=0.003). To the contrary there was no concordance between FISH and conventional IHC results in this series. Conclusions: The discrepancy between EGFR gene amplification rate and protein expression by IHC reported previously may be due to the limitations and nonquantitative nature of conventional IHC. EGFR protein content correlates with gene copy number if protein content is quantitated and automatically analyzed, as with AQUA. No significant financial relationships to disclose.

Protein expression (PE) and increased IGF1R gene copy number (GCN) in small cell lung cancer (SCLC).

2010 ◽  
Vol 28 (15_suppl) ◽  
pp. 10584-10584
Author(s):  
A. Badzio ◽  
M. W. Wynes ◽  
R. Dziadziuszko ◽  
D. Merrick ◽  
M. Pardo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Protein Expression ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Copy Number ◽  
Gene Copy Number ◽  
Small Cell ◽  
Gene Copy ◽  
Small Cell Lung

Prognostic value of epidermal growth factor receptor gene amplification in surgically resected non-adenocarcinoma lung cancer patients.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e18553-e18553
Author(s):  
Yaewon Yang ◽  
Hyun Chang ◽  
Jong-Seok Lee ◽  
YuJung Kim ◽  
Sang-hoon Jheon ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Copy Number ◽  
Gene Copy Number ◽  
Growth Factor Receptor ◽  
Gene Copy ◽  
Egfr Gene ◽  
Epidermal Growth

e18553 Background: The purpose of this study is to investigate the prognostic role of genomoic gain and expression for epidermal growth factor receptor (EGFR) gene in surgically resected non-adenocarcinoma of non-small-cell lung cancer (NA-NSCLC). Methods: This retrospective study included 115 NA-NSCLC consecutive patients with available tumor tissue and survival data, median follow up period of 6.4 years. EGFR gene copy number and protein expression was evaluated using by fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC) in tissue microarray sections, respectively. Results: Among 115 patients, 99 patients (86.1 %) were with squamous cell carcinoma histology. EGFR gene amplification and high polysomy (EGFR FISH+) were observed in 57 (49.6%) and 45 (39.1%) patients, respectively. Patients with EGFR FISH+ had significantly shorter overall survival [median, 41 months vs. not reached (>70 months), P = 0.011]. Multivariable model confirmed that patients with EGFR FISH+ had a significantly greater risk of death than those with EGFR FISH-negative after adjusting pathologic staging, presence of pleural invasion, venous invasion and adjuvant chemotherapy (hazard ratio = 2.11, 95% confidence interval 1.23-3.61, P = 0.006). EGFR IHC expression did not associate with overall survival in same group. Conclusions: EGFR increased gene copy number is an independent negative prognostic factor in surgically resected NA-NSCLC.

Role of EGFR but not HER2 or HER3 gene copy number in predicting sensitivity of head and neck squamous cell carcinoma (SCCHN) cell lines to EGFR tyrosine kinase inhibitors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 6063-6063
Author(s):  
M. Varella-Garcia ◽  
K. Acheson ◽  
G. B. Marshall ◽  
R. M. McCormack ◽  
A. Ryan ◽  
...  
Keyword(s):  
Protein Expression ◽  
Cell Lines ◽  
Copy Number ◽  
Kinase Inhibitors ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Sensitive Cell ◽  
Egfr Gene ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Egfr Tkis

6063 Background: EGFR gene copy number has previously been reported to predict for improved overall survival in NSCLC patients treated with gefitinib (IRESSA) or erlotinib compared with placebo [JCO 2006;24:5034–42 & N Engl J Med 2005;353:133–44]. The utility of EGFR gene copy number as a predictive biomarker in other tumour types such as squamous cell carcinoma of the head and neck (SCCHN) is currently under clinical investigation. The present study examined a panel of 20 SCCHN cell lines to identify potential biomarkers predicting in vitro sensitivity to EGFR tyrosine kinase inhibitors (TKIs). Methods: A panel of 20 SCCHN cell lines was screened for sensitivity to gefitinib, vandetanib or erlotinib using a viable cell number endpoint, with G150 values determined for each cell line (inhibitor concentration required to give 50% growth inhibition). Cell lines were blinded and assessed for EGFR, HER2 and HER3 protein expression by ELISA, mutation status by dye-terminator sequencing, and gene copy number by fluorescence in situ hybridisation (FISH). Results: A broad range in sensitivity was observed for all compounds across the panel of 20 SCCHN cell lines (G150 ranging from 0.001uM to =10uM). 12 cell lines were positive for EGFR genomic gain. Sensitivity (GI50 <1uM) to all EGFR TKIs was seen in 11 lines and resistance (GI50 >8uM) in 5 lines. Of the sensitive cell lines, 9 were positive for EGFR genomic gain compared with only 1 of the resistant lines. Furthermore, EGFR protein expression also had a direct association with EGFR TKI sensitivity. In contrast, only 4 cell lines were positive for HER2 or HER3 genomic gain and there was no correlation with sensitivity. The most sensitive cell line was positive for EGFR genomic gain and was the only line to have an EGFR TK mutation (S768I in exon 20). Conclusions: EGFR gene copy number and protein expression appeared to have predictive value in identifying SCCHN cell lines sensitive to EGFR TKIs. No significant financial relationships to disclose.

Alterations of insulin-like growth factor-1 receptor gene copy number and protein expression are common in non-small cell lung cancer

2014 ◽  
Vol 67 (11) ◽  
pp. 985-991 ◽  
Author(s):  
T N Tran ◽  
C I Selinger ◽  
B Yu ◽  
C C Ng ◽  
M R J Kohonen-Corish ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Protein Expression ◽  
Copy Number ◽  
Gene Copy Number ◽  
Small Cell ◽  
Clinicopathological Features ◽  
Gene Copy ◽  
Small Cell Lung ◽  
Mutational Status ◽  
Node Metastases

AimsInsulin-like growth factor-1 receptor (IGF1R) is a tyrosine kinase membrane receptor involved in tumourigenesis that may be a potential therapeutic target. We aimed to investigate the incidence and prognostic significance of alterations in IGF1R copy number, and IGF1R protein expression in resected primary non-small cell lung cancer (NSCLC), and lymph node metastases.MethodsIGF1R gene copy number status was evaluated by chromogenic silver in situ hybridisation and IGF1R protein expression was evaluated by immunohistochemistry in tissue microarray sections from a retrospective cohort of 309 surgically resected NSCLCs and results were compared with clinicopathological features, including EGFR and KRAS mutational status and patient survival.ResultsIGF1R gene copy number status was positive (high polysomy or amplification) in 29.2% of NSCLC, and 12.1% exhibited IGF1R gene amplification. High IGF1R expression was found in 28.3%. There was a modest correlation between IGF1R gene copy number and protein expression (r=0.2, p<0.05). Alterations of IGF1R gene copy number and protein expression in primary tumours were significantly associated with alterations in lymph node metastases (p<0.01). High IGF1R gene copy number and protein expression was significantly higher in squamous cell carcinomas (SCC) compared with other subtypes of NSCLC (p<0.05). There were no other associations between IGF1R status and other clinicopathological features including patient age, gender, smoking status, tumour size, stage, grade, EGFR or KRAS mutational status or overall survival.ConclusionsHigh IGF1R gene copy number and protein overexpression are frequent in NSCLC, particularly in SCCs, but they are not prognostically relevant.

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