Frequent intratumoral heterogeneity of EGFR gene copy gain in non-small cell lung cancer

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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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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EGFR genomic gain in Japanese non-small cell lung cancer patients treated with gefitinib

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.7164 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 7164-7164 ◽

Cited By ~ 2

Author(s):

M. Varella-Garcia ◽

T. Mitsudomi ◽

Y. Yatabe ◽

T. Kosaka ◽

E. Nakajima ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Gene Amplification ◽

Cell Lung Cancer ◽

Egfr Mutation ◽

Response Rate ◽

Small Cell ◽

Gene Copy ◽

Small Cell Lung ◽

Egfr Gene

7164 Background: Increased EGFR gene copy numbers evaluated by fluorescence in situ hybridization (FISH) is excellent predictor of clinical benefit from EGFR tyrosine kinase inhibitors (TKIs) in Caucasian non small-cell lung cancer (NSCLC) patients. This study was performed to verify how this marker performs in Oriental patients. Methods: A cohort of 59 Japanese patients with recurrent NSCLC after surgery was treated with gefitinib 250 mg daily. The cohort included 46% of females, 47% of never-smokers, 68% of patients had prior chemotherapy and 59% had stage III-IV at the time of surgery. Adenocarcinoma was the most common histology (85%). FISH was performed using EGFR /CEP 7 and PathVysion probes (Vysis/Abbott). Specimens were classified as FISH+ when showing gene amplification or high polysomy (≥4 copies of the gene in ≥40% of tumor cells). Effectiveness of gefitinib was concluded when there was 30% tumor shrinkage in imaging studies and/or elevated CEA level decreased to <50% of baseline. Results: FISH results were available in 51 tumors: 35 (69%) were EGFR+ and 29 (57%) were HER2+. There was a significant association between EGFR+ and HER2+ (p = 0.012) and between EGFR FISH+ and of EGFR mutations (p = 0.003). All 9 tumors exhibiting clustered EGFR gene amplification harbored mutations. Response rate assessed in 43 patients was 59% in EGFR+ and 33% in EGFR- (p = 0.11). Gefitinib treatment produced response in 5 (83%) cases with gene amplification and 12 (52%) cases with high polysomy. Response rate was 77% in 22 cases positive for FISH and mutation and 100% in 5 cases with EGFR mutation/FISH- cases. No responses were observed in EGFR WT patients, neither in 9 FISH+ nor in 10 FISH- cases. Survival was not significantly impacted by EGFR (p = 0.42) or HER2 (p = 0.40) FISH status, while EGFR mutation was significantly associated with longer survival (p = 0.005). Conclusion: Patients in this Japanese cohort had more frequently FISH+ status than in the Caucasian populations, which may contribute to higher sensitivity to EGFR TKIs. However, the predictive power of EGFR FISH status for TKI sensitivity seems to be lower supporting significant differences in the mechanisms of EGFR pathway activation in Oriental and Caucasian populations. [Table: see text]

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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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Determination of EGFR gene somatic mutations in tissues and plasma of patients with advanced non-small cell lung cancer

Biomeditsinskaya Khimiya ◽

10.18097/pbmc20166206638 ◽

2016 ◽

Vol 62 (6) ◽

pp. 638-644

Author(s):

O.I. Brovkina ◽

M.G. Gordiev ◽

A.N. Toropovskiy ◽

D.S. Khodyrev ◽

R.F. Enikeev ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Real Time ◽

Cell Lung Cancer ◽

Real Time Pcr ◽

Test System ◽

Small Cell ◽

Egfr Mutations ◽

Small Cell Lung ◽

Egfr Gene

The presence of activating mutations in the EGFR gene influences cell proliferation, angiogenesis, and increases metastatic ability; it has a significant impact on the choice of medical therapy of non-small cell lung cancer (NSCLC). The use of targeted therapy with tyrosine kinase inhibitors requires performance of appropriate genetic tests. The aim of this study was to design a real-time PCR-based diagnostic kit for fast and cheap of EGFR mutations testing in paraffin blocks and plasma, and kit validation using samples from patients with NSCLC, and also comparative estimation of diagnostic features of real-time PCR with wild type blocking and digital PCR for mutation testing in blood plasma. The study included 156 patients with various types of adenocarcinoma differentiation. It was designed a simple and efficient real-time PCR-based method of detecting L858R activating mutation and del19 deletion in the EGFR gene for DNA isolated from paraffin blocks. Kit for EGFR mutations was validated using 411 samples of paraffin blocks. The proposed system showed high efficiency for DNA testing from paraffin blocks: a concordance with results of testing with therascreen® EGFR RGQ PCR Kit (`Qiagen`, Germany) was 100%. It has been shown the possibility of using this test system for the detection of mutations in plasma

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