Molecular marker analysis of SWOG S0636, a phase II trial of erlotinib and bevacizumab in never-smokers with advanced NSCLC.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7552-7552
Author(s):  
Philip C. Mack ◽  
James Moon ◽  
Howard Jack West ◽  
Wilbur A. Franklin ◽  
Marileila Varella-Garcia ◽  
...  
Keyword(s):  
Protein Expression ◽  
Copy Number ◽  
Gene Copy Number ◽  
Careful Analysis ◽  
Gene Copy ◽  
Activating Mutations ◽  
Molecular Selection ◽  
Never Smokers ◽  
Molecular Marker Analysis ◽  
Nsclc Patients

7552 Background: S0636 investigated the combination of erlotinib and bevacizumab in never-smoking NSCLC patients with confirmed adenocarcinoma histology (H. West ASCO 2011). Patient eligibility was not restricted by molecular selection. Median PFS and OS were encouraging at 8 and 26 months. An analysis of molecular markers was undertaken, focusing initially on the EGFR pathway. Methods: EGFR analysis included gene copy number, mutation and protein expression. Copy number was conducted by FISH using the Colorado scoring system. An immunohistochemistry H score was developed for EGFR protein expression analysis, ranging from 0 to 400. Specimens were evaluable from 42 of the 85 eligible patients. Results: FISH positivity was identified in 17/35 pts (49%), 11 with high polysomy and 6 with true gene amplification. EGFR activating mutations were seen in 10/33 pts (30%). IHC H-score >200 was observed in 17/40 pts (43%). All EGFR markers were significantly correlated with one another. In the EGFR WT subgroup, FISH-positive patients outperformed FISH-negative pts (mPFS 20 vs, 6 months, p=0.06). Conclusions: Careful analysis of EGFR markers (mutation, FISH and IHC) identified S0636 patients with favorable PFS and encouraging trends for OS. EGFR FISH and IHC provided additional predictive information beyond that of EGFR mutation status. Supported in part by DHHS: CA32102 and CA38926, and in part by Genentech. [Table: see text]

Phase II pharmacodynamic trial of erlotinib in advanced non-small cell lung cancer (NSCLC) patients previously treated with platinum-based chemotherapy: FISH results

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7160-7160 ◽  
Author(s):  
E. Felip ◽  
F. Rojo ◽  
M. Reck ◽  
A. Heller ◽  
B. Klughammer ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Copy Number ◽  
Advanced Nsclc ◽  
Gene Copy Number ◽  
Large Cell ◽  
Gene Copy ◽  
Egfr Gene ◽  
Previously Treated ◽  
Never Smokers ◽  
Nsclc Patients

7160 Background: The HER1/EGFR inhibitor erlotinib significantly prolongs survival of patients with previously-treated advanced NSCLC. Methods for selecting patients most likely to derive clinical benefit from erlotinib are not established. Increased HER1/EGFR gene copy number has been suggested as a potential predictive biomarker of clinical benefit, and was investigated in this phase II study. Methods: Advanced NSCLC patients who failed first line chemotherapy were treated with erlotinib monotherapy, 150 mg/d p.o. Each patient underwent tumor biopsy before start of treatment. Tumor HER1/EGFR gene amplification status was assessed using FISH, and classified as positive (amplification, polysomy, high polysomy) or negative (disomy, trisomy). Results: 83 patients were included: median age 56 (range 35–78); sex: male 72%, female 28%; histology: adenocarcinoma 43%, large cell 31%, squamous cell 19%, others 7%; smoking status: 44 current smokers, 28 former smokers, 11 never smokers. Of 73 evaluable patients, 7 (10%) achieved partial response (PR), 28 (38%) had stable disease (SD) and 38 (52%) had disease progression. PRs were observed in 4 males / 3 females; in 5 adenocarcinomas / 1 large cell/ 1 squamous cell; in 2 current / 3 former / 2 never smokers. Erlotinib was well tolerated and no unexpected toxicities were seen. HER1/EGFR gene copy number was evaluated in 53 patients. 15 patients were FISH +, 10 of whom achieved clinical benefit (PR, or SD for ≥12 weeks). Only 5 of 38 FISH - patients had clinical benefit. FISH + patients achieved a longer median time to progression (137 vs 43 days; p = 0.00011; HR 0.35) as well as overall survival (226 vs 115 days; p = 0.3221, HR 0.722). Conclusion: In this study, increased HER1/EGFR gene copy number was associated with a better outcome on erlotinib therapy. [Table: see text] [Table: see text]

scholarly journals Insulin-like Growth Factor Receptor 1 (IGF1R) Gene Copy Number Is Associated With Survival in Operable Non–Small-Cell Lung Cancer: A Comparison Between IGF1R Fluorescent In Situ Hybridization, Protein Expression, and mRNA Expression

2010 ◽  
Vol 28 (13) ◽  
pp. 2174-2180 ◽  
Author(s):  
Rafal Dziadziuszko ◽  
Daniel T. Merrick ◽  
Samir E. Witta ◽  
Adelita D. Mendoza ◽  
Barbara Szostakiewicz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Protein Expression ◽  
Squamous Cell ◽  
Copy Number ◽  
Gene Copy Number ◽  
Growth Factor Receptor ◽  
Gene Copy ◽  
Cell Versus

PurposeThe purpose of this study was to characterize insulin-like growth factor-1 receptor (IGF1R) protein expression, mRNA expression, and gene copy number in surgically resected non–small-cell lung cancers (NSCLC) in relation to epidermal growth factor receptor (EGFR) protein expression, patient characteristics, and prognosis.Patients and MethodsOne hundred eighty-nine patients with NSCLC who underwent curative pulmonary resection were studied (median follow-up, 5.3 years). IGF1R protein expression was evaluated by immunohistochemistry (IHC) with two anti-IGF1R antibodies (n = 179). EGFR protein expression was assessed with PharmDx kit. IGF1R gene expression was evaluated using quantitative reverse transcription polymerase chain reaction (qRT-PCR) from 114 corresponding fresh-frozen samples. IGF1R gene copy number was assessed by fluorescent in situ hybridization using customized probes (n = 181).ResultsIGF1R IHC score was higher in squamous cell carcinomas versus other histologies (P < .001) and associated with stage (P = .03) but not survival (P = .46). IGF1R and EGFR protein expression showed significant correlation (r = 0.30; P < .001). IGF1R gene expression by qRT-PCR was higher in squamous cell versus other histologies (P = .006) and did not associate with other clinical features nor survival (P = .73). Employing criteria previously established for EGFR copy number, patients with IGF1R amplification/high polysomy (n = 48; 27%) had 3-year survival of 58%, patients with low polysomy (n = 87; 48%) had 3-year survival of 47% and patients with trisomy/disomy (n = 46; 25%) had 3-year survival of 35%, respectively (P = .024). Prognostic value of high IGF1R gene copy number was confirmed in multivariate analysis.ConclusionIGF1R protein expression is higher in squamous cell versus other histologies and correlates with EGFR expression. IGF1R protein and gene expression does not associate with survival, whereas high IGF1R gene copy number harbors positive prognostic value.

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

Androgen Receptor Gene Copy Number and Protein Expression in Treatment-Naïve Prostate Cancer

2017 ◽  
Vol 99 (2) ◽  
pp. 222-228 ◽  
Author(s):  
Filip Poelaert ◽  
Candy Kumps ◽  
Nicolaas Lumen ◽  
Stephanie Verschuere ◽  
Louis Libbrecht ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Protein Expression ◽  
Copy Number ◽  
Receptor Gene ◽  
Gene Copy Number ◽  
Androgen Receptor Gene ◽  
Gene Copy ◽  
Treatment Naïve

EGFR mutations (muts), IHC and FISH status, and chromosome 7 gene copy number combined with pAkt expression as potential predictors of survival in non-small cell lung cancer (NSCLC) patients (pts) treated with gefitinib (GEF)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7182-7182 ◽  
Author(s):  
V. M. Villaflor ◽  
L. Buckingham ◽  
M. Gale ◽  
J. Coon ◽  
A. M. Mauer ◽  
...  
Keyword(s):  
Copy Number ◽  
Gene Copy Number ◽  
Chromosome 7 ◽  
Egfr Mutations ◽  
Gene Copy ◽  
Double Positive ◽  
Specific Pcr ◽  
Copy Numbers ◽  
Kaplan Meier ◽  
Nsclc Patients

7182 Background: EGFR and pAkt expression by immunohistochemistry (IHC), muts, and FISH status have been identified as possible molecular predictors for GEF efficacy in NSCLC (Cappuzzo, et. al, JNCI, 2005). The goal of this study was to independently evaluate these findings regarding survival (surv), and to assess the predictive value of mean chromosome 7 copy number/cell (C7). Methods: 150 consecutive Expanded Access Trial pts with >1 week GEF therapy were included for analysis. IHC (present vs not detected) was performed for 87 pts, and 58 pts were analyzed for muts by SSCP, mut-specific PCR, and sequencing. Tissue from 81 pts was evaluated for EGFR and C7 gene copy numbers by fluorescence in situ hybridization (FISH). Results: 150 pts (77 female, 73 male; median (md) age 67; 85 adenocarcinoma) received GEF; md follow-up was 5.8 months (mo). Overall response was 8% (2 CR, 10 PR); 56 pts had stable disease. Md Kaplan-Meier surv was 5.9 mo. IHC revealed that 47/87 pts (54%) had EGFR+, and 36/75 pts (48%) had pAkt + tumors. pAkt+ pts had significantly (sig) longer surv than pAkt− pts (11.4 vs 5.8 mo, p < .05). High polysomy was seen in 36/81 pts (44%) who were designated FISH+; 45 pts were FISH−. EGFR IHC and FISH positivity were not sig associated with surv. C7 was defined as low (<3.6, 63 pts) or high (≥3.6, 18 pts); md surv was 6.6 and 17.1 mo, respectively, p < .01. Muts were found in 17/58 tumors (29%). Md surv for pts with and without muts was 23.8 and 7.9 mo, respectively, p < .07. EGFR IHC− pAkt− pts (18 pts) had sig shorter surv than 57 pts with any pos value (4.7 vs 8.8 mo, p < .02). Double-positive pts had sig longer surv than pts with any neg value. Conclusions: These findings resemble but do not duplicate those reported by Cappuzzo, et al. Additionally, high C7, alone or combined with pAKT, may be an important predictor for GEF efficacy in NSCLC. Further studies of C7, a technically simple and reproducible FISH assay, are warranted. [Table: see text] [Table: see text]

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.

Sign in / Sign up

Export Citation Format

Share Document