Increased EGFR Gene Copy Number May Predict Favorable Response to Iressa in Lung Cancer

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.

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Exploratory analysis of EGFR FISH criteria in Japanese non-small cell lung cancer patients treated with gefitinib

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.7599 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 7599-7599

Author(s):

K. Kazuo ◽

L. E. Morrison ◽

H. Kimura ◽

T. Sone ◽

T. Araya ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Copy Number ◽

Gene Copy Number ◽

Small Cell ◽

Gene Copy ◽

Control Fish ◽

Small Cell Lung ◽

Egfr Gene

7599 Background: In the phase III Iressa (gefitinib) Survival Evaluation in Lung cancer (ISEL) trial, high epidermal growth factor receptor (EGFR) gene copy number was a predictor of a gefitinib effect on survival in patients (pts) with refractory advanced non-small-cell lung cancer (NSCLC) (hazard ratio 0.61 vs 1.16 for high vs low copy number; p=0.045) [JCO 2006;24:5034–42]. Although EGFR mutation status may predict response to gefitinib in Japanese pts, there is insufficient data to clarify if high EGFR gene copy number assessed by fluorescence in situ hybridization (FISH) is predictive in these pts. This analysis investigated the applicability of both published Colorado FISH criteria (Colorado Univ) and new FISH criteria to Japanese NSCLC pts. Methods: 58 tumor specimens from gefitinib-treated Japanese pts were analyzed using Vysis LSI EGFR and CEP7 (chromosome 7 control) FISH probes. Specimens were classed as FISH+ or - using Colorado and exploratory (EGFR/cell; CEP7/cell; EGFR/CEP7; % of cells with various numbers of EGFR or CEP7 signals) criteria. Results: Of the 58 pts, 17 (29%) had an objective response (OR). Using Colorado criteria, OR was 50% in the 14 FISH+ pts vs 23% in the 44 FISH- pts (2-sided Fisher's exact test p=0.089). There was a trend for an association between FISH+ status and improved survival (log rank p=0.15). Defining FISH+ as specimens with =5% cells containing >5 EGFR signals, OR was significantly better among FISH+ pts vs FISH- pts (p=0.0030; 52% of the 23 FISH+ pts responding vs 14% of the 35 FISH- pts). A survival advantage was not indicated. Defining FISH+ as =74% of cells with EGFR or CEP7 loss (<2 signals) or gain (>2 signals), OR was significantly better among FISH+ pts vs FISH- pts (p=0.043; 45% of the 22 FISH+ pts responding vs 19% of the 36 FISH- pts). Association with survival had marginal significance (log rank p=0.061). Conclusions: These preliminary data have identified loss or gain of EGFR and CEP7 abnormality as promising biomarkers for response to gefitinib in Japanese NSCLC patients. Analysis of these markers for correlation with time to progression is ongoing. Investigation of these potential markers in other cohorts of patients is worthy of further evaluation. [Table: see text]

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

Journal of Clinical Oncology ◽

10.1200/jco.2006.06.3958 ◽

2006 ◽

Vol 24 (31) ◽

pp. 5034-5042 ◽

Cited By ~ 523

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.

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Non-small cell lung cancer: Classical tumor markers versus EGFR gene copy number

Clinica Chimica Acta ◽

10.1016/j.cca.2019.03.335 ◽

2019 ◽

Vol 493 ◽

pp. S159-S160

Author(s):

L. Valiña Amado ◽

M. Enver Sumaya ◽

A. Azkárate Martínez ◽

E. Martínez Font ◽

M.M. Parera Rosselló ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Tumor Markers ◽

Cell Lung Cancer ◽

Copy Number ◽

Gene Copy Number ◽

Small Cell ◽

Gene Copy ◽

Small Cell Lung ◽

Egfr Gene

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RTOG 0324: A phase II study of cetuximab (C225) in combination with chemoradiation (CRT) in patients with stage IIIA/B non-small cell lung cancer (NSCLC)—Association between EGFR gene copy number and patients’ outcome

Journal of Clinical Oncology ◽

10.1200/jco.2008.26.15_suppl.7607 ◽

2008 ◽

Vol 26 (15_suppl) ◽

pp. 7607-7607 ◽

Cited By ~ 2

Author(s):

C. C. Olsen ◽

R. Paulus ◽

R. Komaki ◽

M. Varella-Garcia ◽

R. Dziadziuszko ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Copy Number ◽

Phase Ii Study ◽

Gene Copy Number ◽

Small Cell ◽

Gene Copy ◽

Small Cell Lung ◽

Stage Iiia ◽

Egfr Gene

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Increased MET Gene Copy Number Negatively Affects Survival of Surgically Resected Non–Small-Cell Lung Cancer Patients

Journal of Clinical Oncology ◽

10.1200/jco.2008.19.1635 ◽

2009 ◽

Vol 27 (10) ◽

pp. 1667-1674 ◽

Cited By ~ 368

Author(s):

Federico Cappuzzo ◽

Antonio Marchetti ◽

Margaret Skokan ◽

Elisa Rossi ◽

Sujatha Gajapathy ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Gene Amplification ◽

Cell Lung Cancer ◽

Copy Number ◽

Gene Copy Number ◽

Small Cell ◽

Gene Copy ◽

Small Cell Lung ◽

Egfr Gene

Purpose To investigate the prognostic role of genomic gain for MET and epidermal growth factor receptor (EGFR) genes in surgically resected non–small-cell lung cancer (NSCLC). Patients and Methods This retrospective study included 447 NSCLC patients with available tumor tissue from primary lung tumor and survival data. EGFR and MET status was evaluated by fluorescent in situ hybridization (FISH) in tissue microarray sections. Results EGFR FISH results were obtained in 376 cases. EGFR gene amplification and high polysomy (EGFR FISH+) were observed in 10.4% and 32.4% of cases, respectively. EGFR FISH-positive patients had a nonsignificant shorter survival than EGFR FISH-negative patients (P = .4). Activating EGFR mutations were detected in 9.7% of 144 stage I-II disease with no impact on survival. MET FISH analysis was performed in 435 cases. High MET gene copy number (mean ≥ 5 copies/cell) was observed in 48 cases (MET+, 11.1%), including 18 cases with true gene amplification (4.1%). MET+ status was associated with advanced stage (P = .01), with grade 3 (P = .016) and with EGFR FISH+ result (P < .0001). No patient with activating EGFR mutation resulted MET+. In the whole population, MET-positive patients had shorter survival than MET-negative patients (P = .005). Multivariable model confirmed that MET-negative patients had a significant reduction in the risk of death than MET-positive patients (hazard ratio, 0.66; P = .04). Conclusion MET increased gene copy number is an independent negative prognostic factor in surgically resected NSCLC. EGFR gene gain does not impact survival after resection.

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