Retrospective evaluation of RET biomarker status and outcome to vandetanib in four phase III randomized NSCLC trials.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8045-8045 ◽  
Author(s):  
Adam Platt ◽  
Paul Elvin ◽  
John Morten ◽  
Qunsheng Ji ◽  
Emma Donald ◽  
...  
Keyword(s):  
Protein Expression ◽  
Tumor Cells ◽  
Copy Number ◽  
Fusion Gene ◽  
Gene Copy Number ◽  
Copy Number Gain ◽  
Phase Iii ◽  
Gene Copy ◽  
Ret Gene ◽  
Potential Association

8045 Background: The prevalence of the tumorigenic KIF5B:RET fusion gene in NSCLC tumors has been estimated at 0.2–6% (Jiu et al 2012; Lipson et al 2012). We retrospectively analyzed tumor samples from 4 Phase III NSCLC trials of vandetanib, a TKI that selectively targets RET, VEGFR and EGFR signaling, to determine the prevalence of RET fusions and other RET biomarkers, and any potential association with outcome to vandetanib (V). Methods: The studies evaluated were ZODIAC (NCT00312377; docetaxel ± V 100mg), ZEAL (NCT00418886; pemetrexed ± V 100mg), ZEPHYR (NCT00404924; V 300mg vs placebo) and ZEST (NCT00364351; V 300mg vs erlotinib). RET biomarkers evaluated included RET fusions (including KIF5B:RET) and RET gene copy number (assessed by a 4-probe FISH assay), as well as RET protein expression (by IHC). Results: Of 4089 patients randomized across the 4 studies, 1291 and 1234 had tumor samples available for FISH and IHC analysis, respectively, with evaluable data obtained for 944 and 1102. RET fusions (in >10% of tumor cells) were detected in 7 of 944 samples (vandetanib, n=3; comparator, n=4), at a prevalence of 0.7% (95% CI, 0.3–1.5%). None of the 3 vandetanib-treated RET fusion-positive patients had an objective RECIST response, although there was radiologic evidence of tumor shrinkage in 2. Overall, 2.8% (n=26) of samples had RET amplification (innumerable RET clusters, or ≥7 copies in >10% tumor cells), 8.1% (n=76) had lower RET gene copy number gain (4–6 copies in ≥40% tumor cells) and 8.3% (n=92) were RET expression positive (signal intensity ++ or +++ in >10% of tumor cells). There was no difference in ORR between vandetanib and comparator for the RET amplification-positive subset (both 8.3% [1/12]), the RET copy number gain subset (9.8% [4/41] vs 9.1% [3/33], respectively) or the RET protein expression-positive subset (15.2% [7/46] and 13.6% [6/44], respectively). Conclusions: The prevalence of RET fusions was estimated at 0.7%. There were too few vandetanib-treated patients with RET fusions to make any firm conclusion regarding association with efficacy. Evidence from the other RET biomarkers tested suggested that these do not infer a differential advantage in patients treated with vandetanib. Clinical trial information: NCT00312377; NCT00418886; NCT00404924.

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.

Mechanisms of Bcl-2 Protein Expression in Diffuse Large B-Cell Lymphoma (DLBCL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 26-26
Author(s):  
Pedro Farinha ◽  
Gwyn Bebb ◽  
Reiner Siebert ◽  
Doug Horsman ◽  
Joseph M. Connors ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Expression ◽  
Expression Profiling ◽  
Copy Number ◽  
Gene Copy Number ◽  
Copy Number Gain ◽  
Gene Copy ◽  
Cell Of Origin ◽  
Bcl2 Protein ◽  
Bcl2 Gene

Abstract Background: Bcl-2 protein expression is an important biomarker in DLBCL. Gene expression profiling also has prognostic relevance in DLBCL, establishing cell-of-origin (GCB vs non-GCB) as an important predictor of survival. Using tissue microarrays (TMA), immunohistochemical staining can be used to provide biomarker data that correlates closely with the results of gene expression profiling in predicting outcome (Hans et al, Blood 103; 275–82: 2004). The t(14;18) can be detected in DLBCL, with frequencies varying between 5–40%. The aim of this study was to clarify the different mechanisms leading to Bcl-2 expression in a cohort of patients with DLBCL. Methods: The study group consisted of 94 patients with de novo DLBCL, all with a clonal karyotype at diagnosis and treated with curative intent. A TMA was constructed with duplicate 0.6mm cores and stained for Bcl-2, CD10, Bcl-6, MUM1 and FOXP1. Cases were called positive if more than 30% of the tumor cells expressed a given protein. Cases were defined as GCB if they were CD10+. Non-GCB was defined as CD10−, MUM1+ and/or FOXP1+. Cytogenetic studies were performed routinely and locus-specific FISH was performed using commercially available Vysis probes (dual-color LSI IGH/BCL2) to detect the t(14;18). Unbalanced increases in BCL2 gene copy number were determined by comparison of BCL2 and IGH signals and correlation with the karyotype. Results: The IPI was highly predictive of overall survival (OS) (p < 0.00001). The t(14;18) was detected by both routine cytogenetics and FISH in 24 (25%) cases, but did not predict survival (p = 0.78). None of the non-GCB cases harbored a t(14;18). The t(14;18) and isolated BCL2 copy number gain were mutually exclusive. Expression of Bcl-2 protein and GCB-type immunostaining profile each predicted OS (p = 0.008 and 0.03, respectively). Expression of Bcl-2 was imperfectly correlated with either the t(14;18) or a non-GCB immunostaining profile, but was highly correlated with cases harboring an increased gene copy number for BCL2 (see Table, χ2 p=0.005). Increased BCL2 gene copy number did not predict OS (p = 0.43), a not unexpected finding as it accounts for only a proportion of Bcl-2 protein-positive cases. Cases lacking both the t(14;18) and increased BCL2 copy number were deemed cytogenetically “normal”, accounting for 47 cases. These were distributed between the GCB (42%) and non-GCB cases (62%). Of the cytogenetically “normal” cases, 35% of the GCB and 63% of the non-GCB expressed Bcl-2 protein. BCL2 Probe Result GCB(55) Non-GCB(39) n Bcl2 protein + n Bcl2 protein + t(14;18)(q32;21) 24 18 0 0 ⇑ Gene Copy# 8 6 15 14 “Normal” 23 8 24 15 Conclusions: We conclude that multiple mechanisms are responsible for Bcl-2 expression in DLBCL. Non-GCB cases do not harbor the t(14;18), more commonly have isolated BCL2 gene copy number gain and have a higher percentage of cytogenetically “normal” BCL2 protein-positive cases. The latter finding suggests a prominent role for transcriptional up-regulation of the BCL2 gene resulting from constitutive activation of NF- κB. DLBCL cases with a t(14;18) are always GCB and never show isolated BCL2 gene copy number gains, suggesting that these two events are mutually exclusive. The impact of other mechanisms (e.g. epigenetic changes, promoter hypomethylation) deregulating BCL2 expression requires further study. Bcl-2 protein expression and cell-of-origin (GCB vs non-GCB) are predictive biomarkers in DLBCL.

Fibroblast growth factor receptor 1 (FGFR1) gene copy number gain in adenocarcinoma and squamous cell carcinoma of the lung.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7552-7552 ◽  
Author(s):  
Ximing Tang ◽  
Yuwen Xue ◽  
Xinying Su ◽  
Nusrat Harun ◽  
Yiran Cai ◽  
...  
Keyword(s):  
Protein Expression ◽  
Squamous Cell ◽  
Copy Number ◽  
Gene Copy Number ◽  
Copy Number Gain ◽  
Smoking History ◽  
Gene Copy ◽  
Primary Tumors ◽  
Cell Lung Carcinoma ◽  
Fgfr1 Gene

7552 Background: FGFR-1 is a novel target for therapy in non-small cell lung carcinoma (NSCLC). FGFR1 gene has been shown to be amplified in ~20% of squamous cell carcinomas (SCC) of the lung. The frequency of FGFR1 copy number gain (CNG) and gene amplification (GA) in lung adenocarcinoma (AC) is unknown, and the clinicopathological and molecular characteristics of the NSCLC tumors with FGFR1gene increase have not been fully described. Methods: We examined FGFR1 gene copy number (GCN) by fluorescent in-situ hybridization (FISH) and FGFR1 protein expression by immunohistochemistry in 475 surgically resected NSCLCs (162 SCCs, and 313 ACs) stages I-III in tissue microarrays. Three FGFR1 FISH categories were identified: a) no CNG; b) CNG, defined as ≥4 gene copies in ≥40% of cells; c) GA, defined as ratio of copies of FGFR1:CEP8 ≥2 or presence of tight gene clusters in ≥10% of cells. FGFR1 protein expression in the cytoplasm and membrane of tumor cells was quantified using H score. Results: FGFR1 GA was detected only in SCCs (14 cases, 9%). CNG was detected in both SCC (39 cases, 24%) and AC (80 cases, 26%). In AC, significantly higher frequency of CNG was detected in patients with smoking history (P=0.008) and in tumors with low differentiated histology (P=0.0005). No correlation was detected between FGFR1 CNG and mutation of KRAS and EGFR in AC. In SCC, tumors with FGFR1 CNG/GA had higher cytoplasmic FGFR1 protein expression than those with no copy changes (49±39 vs. 26±21, P<0.001), and the protein expression correlated with GCN (R=0.55; P<0.001). In multivariate analysis, patients with stage I/II SCCs having FGFR1 gene copy ≥6 or GA showed a significantly better overall survival (HR=0.26; 95% CI: 0.08-0.84, P=0.02) than patients with <6 gene copy, after adjusting for smoking, gender and tumor size. An increase on FGFR1copy number was detected in 8/45 (18%) brain metastasis compared with primary tumors. Conclusions: In NSCLC, FGFR1 GA occurs only is a small subset of SCCs (9%), whereas CNG is a relatively frequent phenomenon in both SCC (24%) and ACs (25%). FGFR1 copies ≥6 or GA is associated with better outcome in patients with surgically resected stages I/II SCCs of the lung.

Elevated PDGFRB gene copy number gain as prognostic in resected malignant pleural mesothelioma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7078-7078
Author(s):  
Anne S. Tsao ◽  
Nusrat Harun ◽  
Junya Fujimoto ◽  
Vikki Devito ◽  
J. Jack Lee ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Tumor Cells ◽  
Malignant Pleural Mesothelioma ◽  
Copy Number ◽  
Gene Copy Number ◽  
Copy Number Gain ◽  
Gene Copy ◽  
Pleural Mesothelioma ◽  
Patient Demographics ◽  
Gene Copy Number Gain

7078 Background: PDGF/PDGFR pathway has been implicated in malignant pleural mesothelioma (MPM) carcinogenesis. We sought to evaluate the incidence of PDGFRB gene copy number gain (CNG) and PDGFR pathway protein expression by immunohistochemistry (IHC) in the tumor cell cytoplasm, membrane, nucleus, and stroma, and correlate it to patient clinical outcome. Methods: 88 archived tumor blocks from resected MPM with full clinical information were used to perform the analyses. IHC biomarkers for PDGFRα,β and p-PDGFRβ, and fluorescence in situ hybridization were performed for analysis of PDGFRB gene CNG. Spearman’s rank correlation, Wilcoxon rank-sum test or Kruskal-Wallis test, BLiP plots, and Kaplan-Meier method were used to assess the biomarkers and their correlation to clinical outcome. Results: There were several correlations identified between the IHC biomarkers; however, none associated with patient demographics or histology subtype, with the exception of high cytoplasmic PDGFRα occurring in patients with no prior known asbestos exposure (p=0.029). In the CNG analysis, PDGFRB gene CNG in > 10% of tumor cells had lower cytoplasmic p-PDGFRβ (p=0.029), while PDGFRB gene CNG in > 40% of tumor cells had a higher cytoplasmic PDGFRβ (p=0.04). PDGFRB gene CNG status did not associate with patient demographics or tumor characteristics. Patients with PDGFRB CNG > 40% of tumor cells had an improved relapse-free survival (RFS) [HR 0.25 (95% CI 0.09, 0.72), p=0.0096]. In the patients with PDGFRB CNG > 40% of cells, the addition of chemotherapy appeared to also improve RFS (p=0.017). In the multi-covariate analyses for RFS, there was no association with any IHC biomarker. In the overall survival (OS) analysis, having PDGFRB gene CNG > 40% of tumor cells correlated with an improved OS [HR 0.32 (95% CI 0.11, 0.89), p=0.029] and the addition of peri-operative chemotherapy led to a trend towards improved OS (p=0.089). Conclusions: PDGFRB CNG > 40% of tumor cells is a potential prognostic biomarker in surgically resected MPM tumors. Adding chemotherapy to patients with PDGFRB CNG > 40% of cells improved RFS and led to a trend towards improved OS. Future validation of this biomarker in prospective trials is needed.

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.

scholarly journals Top-level MET gene copy number gain defines a subtype of poorly differentiated pulmonary adenocarcinomas with poor prognosis

2020 ◽  
Vol 9 (3) ◽  
pp. 603-616 ◽  
Author(s):  
Tobias Raphael Overbeck ◽  
Dana Alina Cron ◽  
Katja Schmitz ◽  
Achim Rittmeyer ◽  
Wolfgang Körber ◽  
...  
Keyword(s):  
Copy Number ◽  
Poor Prognosis ◽  
Gene Copy Number ◽  
Copy Number Gain ◽  
Gene Copy ◽  
Poorly Differentiated ◽  
Gene Copy Number Gain
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