Level of HER2 Gene Amplification Predicts Response and Overall Survival in HER2-Positive Advanced Gastric Cancer Treated With Trastuzumab

Purpose Previous studies have highlighted the importance of an appropriate human epidermal growth factor receptor 2 (HER2) evaluation for the proper identification of patients eligible for treatment with anti-HER2 targeted therapies. Today, the relationship remains unclear between the level of HER2 amplification and the outcome of HER2-positive gastric cancer treated with first-line chemotherapy with trastuzumab. The aim of this study was to determine whether the level of HER2 gene amplification determined by the HER2/CEP17 ratio and HER2 gene copy number could significantly predict some benefit in overall survival and response to therapy in advanced gastric cancer treated with trastuzumab-based chemotherapy. Patients and Methods Ninety patients with metastatic gastric cancer treated with first-line trastuzumab-based chemotherapy were studied. The optimal cutoff values for HER2/CEP17 ratio and HER2 gene copy number (GCN) for discriminating positive results in terms of response and prolonged survival were determined using receiver operating characteristic curves analyses. Results In this study, a median HER2/CEP17 ratio of 6.11 (95% CI, 2.27 to 21.90) and a median HER2 gene copy number of 11.90 (95% CI, 3.30 to 43.80) were found. A mean HER2/CEP17 ratio of 4.7 was identified as the optimal cutoff value discriminating sensitive and refractory patients (P = .005). Similarly, the optimal cutoff for predicting survival longer than 12 months was 4.45 (P = .005), and for survival longer than 16 months was 5.15 (P = .004). For HER2 GCN, the optimal cutoff values were 9.4, 10.0, and 9.5, respectively (P = .02). Conclusion The level of HER2 gene amplification significantly predicts sensitivity to therapy and overall survival in advanced gastric cancer treated with trastuzumab-based chemotherapy.

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Predictive Roles of HER2 Gene Amplification and Neutrophil-to-Lymphocyte Ratio on Survival in HER2-Positive Advanced Gastric Cancer Treated With Trastuzumab-Based Chemotherapy

American Journal of Clinical Oncology ◽

10.1097/coc.0000000000000810 ◽

2021 ◽

Vol Publish Ahead of Print ◽

Author(s):

Joo-Hwan Park ◽

Ja Hyun Yeo ◽

Young Saing Kim ◽

Inkeun Park ◽

Hee Kyung Ahn ◽

...

Keyword(s):

Gastric Cancer ◽

Advanced Gastric Cancer ◽

Gene Amplification ◽

Neutrophil To Lymphocyte Ratio ◽

Her2 Gene ◽

Her2 Positive ◽

Lymphocyte Ratio ◽

Her2 Gene Amplification

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CDKL2 Is Associated with HER2 Status and Overall Survival in Gastric Cancer: Comparative Analysis of CDKL2 Protein Expression and Gene Copy Number

BioMed Research International ◽

10.1155/2020/1712723 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Qiong Shao ◽

Fang Wang ◽

Yuxia Xu ◽

Xu Zhang ◽

Wenting Tang ◽

...

Keyword(s):

Gastric Cancer ◽

Overall Survival ◽

Protein Expression ◽

Copy Number ◽

Epithelial Mesenchymal Transition ◽

Mrna Level ◽

Gene Copy Number ◽

Gene Copy ◽

Her2 Status ◽

Mesenchymal Transition

Background. Cyclin-dependent kinase-like 2 (CDKL2) is a member of the CDKL family and recognized as a novel regulator of epithelial-mesenchymal transition of breast cancer cells, but its role has not been explored in gastric cancer (GC). This study was to characterize the CDKL2 protein expression and gene copy number in relation to human epidermal growth factor receptor 2 (HER2) status, clinicopathological features, and overall survival (OS) in GC. Methods. This study detected the CDKL2 protein expression and gene copy number by immunochemistry (IHC) and fluorescent in situ hybridization (FISH), respectively, in 334 GC samples. HER2 status was determined according to established criteria. Associations of the CDKL2 protein expression and gene copy number with OS in GC were evaluated, and the association between CDKL2 mRNA expression and OS in GC was also analyzed using TCGA data. Results. The detection results suggested that 34.1% cases showed high CDKL2 protein expression; 11.4% cases had ≥5 copies of CDKL2 gene or a ratio of CDKL2 to chromosome of ≥2. The CDKL2 protein expression was markedly correlated with its gene copy number. High protein expression and high gene copy number were both significantly associated with positive HER2 status, and they both could predicted a shorter OS, although not as independent markers suggested by the multivariate Cox proportional hazard regression analysis. The TCGA data indicated that higher CDKL2 mRNA level also predicted a shorter OS in GC. Conclusions. The combined detection of the CDKL2 protein level and gene copy number could be of important value in predicting HER2 status and prognosis of patients with GC.

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In situ analysis of FGFR2 mRNA and comparison with FGFR2 gene copy number by dual-color in situ hybridization in a large cohort of gastric cancer patients

Gastric Cancer ◽

10.1007/s10120-017-0758-x ◽

2017 ◽

Vol 21 (3) ◽

pp. 401-412 ◽

Cited By ~ 4

Author(s):

Yasutoshi Kuboki ◽

Christoph A. Schatz ◽

Karl Koechert ◽

Sabine Schubert ◽

Janine Feng ◽

...

Keyword(s):

Gastric Cancer ◽

In Situ Hybridization ◽

Cancer Patients ◽

Copy Number ◽

Gene Copy Number ◽

In Situ Analysis ◽

Gene Copy ◽

Fgfr2 Gene ◽

Gastric Cancer Patients

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Comparison of HER2 gene amplification assessed by fluorescence in situ hybridization and HER2 protein expression assessed by immunohistochemistry in gastric cancer

Oncology Reports ◽

10.3892/or.15.1.65 ◽

2006 ◽

Cited By ~ 19

Author(s):

Tomonori Yano ◽

Toshihiko Doi ◽

Atsushi Ohtsu ◽

Narikazu Boku ◽

Kaoru Hashizume ◽

...

Keyword(s):

Gastric Cancer ◽

In Situ Hybridization ◽

Protein Expression ◽

Fluorescence In Situ Hybridization ◽

Gene Amplification ◽

Her2 Gene ◽

Her2 Protein ◽

Her2 Gene Amplification

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MET Gene High Copy Number (Amplification/Polysomy) Identified in Melanoma for Potential Targeted Therapy

American Journal of Clinical Pathology ◽

10.1093/ajcp/aqab171 ◽

2021 ◽

Author(s):

Nisha S Ramani ◽

Ajaykumar C Morani ◽

Shengle Zhang

Keyword(s):

Targeted Therapy ◽

Gene Amplification ◽

Copy Number ◽

Kinase Inhibitors ◽

Gene Copy Number ◽

Tissue Microarrays ◽

High Copy Number ◽

Gene Copy ◽

Aberrant Expression ◽

Mesenchymal Epithelial Transition Factor

Abstract Objectives Aberrant expression of the mesenchymal epithelial transition factor (MET) gene has been observed in several malignancies, and drugs targeting the MET gene have been implicated in clinical trials with promising results. Hence, MET is a potentially targetable oncogenic driver. We explored the frequency of MET gene high copy number in melanomas and carcinomas. Methods The study group included 135 patients. Tissue microarrays were constructed with 19 melanomas and 116 carcinomas diagnosed from 2010 to 2012. We screened MET gene copy number by fluorescence in situ hybridization analysis using probes for MET gene and CEP7 as control. Results We found MET gene amplification in 2 (11%) of 19 melanoma cases, whereas 5 (26%) of 19 melanoma cases showed polysomy. For carcinomas, there was no MET gene amplification identified. However, 8 (7%) of 116 cases showed polysomy. Conclusions In our study, MET gene amplification was identified in 11% of melanomas and is relatively concordant with few reported studies. However, about 26% of the additional melanoma cases showed MET gene polysomy, which has not been reported as per our knowledge. If these results are validated with further orthogonal studies, more of the melanoma cases could potentially benefit from targeted therapy with MET tyrosine kinase inhibitors.

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Genome-wide gene copy number and expression analysis of primary gastric tumors and gastric cancer cell lines

BMC Cancer ◽

10.1186/1471-2407-10-73 ◽

2010 ◽

Vol 10 (1) ◽

Cited By ~ 38

Author(s):

Siina Junnila ◽

Arto Kokkola ◽

Marja-Liisa Karjalainen-Lindsberg ◽

Pauli Puolakkainen ◽

Outi Monni

Keyword(s):

Gastric Cancer ◽

Cell Lines ◽

Cancer Cell ◽

Expression Analysis ◽

Copy Number ◽

Gastric Cancer Cell ◽

Gene Copy Number ◽

Gene Copy ◽

Genome Wide ◽

Gastric Cancer Cell Lines

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Resistance to methotrexate due to gene amplification in a patient with acute leukemia.

Journal of Clinical Oncology ◽

10.1200/jco.1984.2.1.16 ◽

1984 ◽

Vol 2 (1) ◽

pp. 16-20 ◽

Cited By ~ 92

Author(s):

M D Carman ◽

J H Schornagel ◽

R S Rivest ◽

S Srimatkandada ◽

C S Portlock ◽

...

Keyword(s):

Gene Amplification ◽

Copy Number ◽

Cdna Probe ◽

Leukemia Cell ◽

Gene Copy Number ◽

Leukemia Cell Line ◽

Gene Copy ◽

Acute Myelocytic Leukemia ◽

Human Leukemia ◽

Dot Blot

A patient is described with acute myelocytic leukemia refractory to conventional therapy, who also became highly resistant to methotrexate (MTX) after repeated courses of this drug. Leukemia cells from this patient were found to contain an elevated level of dihydrofolate reductase (DHFR) activity, with no change in the affinity of the enzyme for MTX. A sensitive "dot blot" assay revealed a fourfold increase in the gene copy number of DHFR. Southern blot analysis with a human DHFR cDNA probe confirmed this increase in the gene copy number, and demonstrated a similar restriction pattern with Eco R1, Hind III, and Pst 1 as seen with a highly amplified human leukemia cell line, K562. Additional DHFR fragments were detected, not seen in the K562 blot, suggesting the presence of pseudogenes, or a result of gene rearrangements occurring as part of the amplification process. Resistance to MTX in this patient was therefore ascribed to gene amplification and overproduction of DHFR.

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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)

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.6023 ◽

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.

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

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e18553 ◽

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.

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