Radioimmunohistochemistry of Epidermal Growth Factor Receptor in Breast Cancer

2002 ◽  
Vol 126 (2) ◽  
pp. 177-181
Author(s):  
Kevin W. Robertson ◽  
Jonathon R. Reeves ◽  
Alison K. Lannigan ◽  
James J. Going ◽  
Timothy G. Cooke ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Cell Lines ◽  
Dynamic Range ◽  
Growth Factor Receptor ◽  
Prognostic Indicators ◽  
Egfr Expression ◽  
Epidermal Growth

Abstract Context.—Conflicting reports of epidermal growth factor receptor (EGFR) expression in breast cancer and inconstant relationships with established prognostic indicators and outcomes suggest difficulties with EGFR measurement. Objective.—To compare EGFR measurement in a panel of cell lines and in breast carcinomas by radioimmunohistochemistry (R-IHC), conventional immunohistochemistry (IHC), and a ligand binding (LB) assay. Design.—Eight EGFR-expressing cell lines and 50 primary breast carcinoma specimens were analyzed for EGFR by IHC, R-IHC, and LB assays. A further 153 primary breast cancer specimens were analyzed by R-IHC alone. Results.—All 3 assays were in good agreement for the cell lines. In the subset of the 50 carcinoma specimens, EGFR was detected by LB assays in 19 (38%) and by IHC in 24 (48%). However, R-IHC detected EGFR in 46 (92%) of 50 and in 186 (92%) of all 203 carcinoma specimens. The LB assay agreed poorly with R-IHC of carcinomas, possibly because the LB assay is sensitive to EGFR-expressing nontumor breast parenchyma in the tissue analyzed. Both IHC and R-IHC on carcinoma specimens agreed better, but 26 carcinoma specimens (52%) in which EGFR was not detectable by IHC had a 10-fold range in receptor level detectable by R-IHC. Conclusion.—To elucidate the role of EGFR or other growth factor receptors in breast cancer requires accurate, sensitive receptor assays. With its dynamic range, R-IHC returned meaningful results over the entire range of expression actually present in breast cancer, which LB assays and IHC failed to do.

scholarly journals Modulation of EGFR Gene Transcription by a Polymorphic Repetitive Sequence – a Link between Genetics and Epigenetics

2000 ◽  
Vol 15 (1) ◽  
pp. 105-110 ◽  
Author(s):  
F. Gebhardt ◽  
H. BÜrger ◽  
B. Brandt
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Model Calculations ◽  
Ca Repeat ◽  
Egfr Gene ◽  
Egfr Expression ◽  
Epidermal Growth

The epidermal growth factor receptor (EGFR) plays a crucial role in growth, differentiation and motility of normal as well as tumor cells. The transduction of extracellular signals to the cytoplasm via the receptor not only depends on ligand binding, but is also determined by the receptor density on the cell surface. Therefore, with regard to cancer diagnosis and therapeutic approaches targeting EGFR it is important to know how the expression level of EGFR is controlled. We found that transcription activity declines with increasing numbers of CA dinucleotides of a highly polymorphic CA repeat in the first intron of the epidermal growth factor receptor gene. In vivo data from cultured cell lines support these findings, although other regulation mechanisms can compensate this effect. In addition, we showed that RNA elongation terminates at a site closely downstream of the simple sequence repeat (SSR) and that there are two separate major transcription start sites. Model calculations for the helical DNA conformation revealed a high bendability in the EGFR polymorphic region, especially if the CA stretch is extended. These data suggest that the CA-SSR can act like a joint, bringing the promoter in proximity to a putative repressor protein bound downstream of the CA-SSR. The data indicate that this polymorphism may be a marker for cancer, linking genetic and epigenetic risk factors. Furthermore, in breast cancer, heterozygous tumors with short CA-SSR showed an elevated EGFR-expression in contrast to tumours with longer CA-SSR. Tumours with loss of heterozygosity in intron 1 of egfr revealed an increased EGFR expression if the longer allele was lost. Moreover, decreased EGFR gene levels were significantly correlated with poor prognosis in breast cancer.

scholarly journals Estrogen Receptor, Progesterone Receptor, Human Epidermal Growth Factor Receptor 2 (HER2), and Epidermal Growth Factor Receptor Expression and Benefit From Lapatinib in a Randomized Trial of Paclitaxel With Lapatinib or Placebo As First-Line Treatment in HER2-Negative or Unknown Metastatic Breast Cancer

2009 ◽  
Vol 27 (24) ◽  
pp. 3908-3915 ◽  
Author(s):  
Richard S. Finn ◽  
Michael F. Press ◽  
Judy Dering ◽  
Michael Arbushites ◽  
Maria Koehler ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Metastatic Breast Cancer ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Human Epidermal Growth Factor ◽  
Egfr Expression ◽  
Epidermal Growth

PurposeLapatinib is a dual inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) with activity in HER2-amplified metastatic breast cancer (MBC). Its role in non–HER2-amplified MBC remains unclear. EGF30001, a phase III trial of lapatinib and paclitaxel versus paclitaxel and placebo, demonstrated lapatinib does not significantly benefit HER2-negative or HER2-unselected patients with MBC. Published data support interactions between steroid hormone and peptide growth factor signaling. We hypothesized that molecular subgroups may exist within EGF30001 that would benefit from lapatinib.MethodsA blinded, retrospective biomarker evaluation was performed using immunohistochemistry to semiquantitate estrogen (ER), progesterone (PR), and EGFR expression. HER2 amplification was determined by fluorescent in situ hybridization. Effects of these biomarkers on event-free survival (EFS) were examined in patients with available tissue (n = 493).ResultsLapatinib improved median EFS in HER2-amplified, ER- or PR-positive MBC (n = 36; 5.7 v 4.5 months; P = .351); benefit was greater and statistically significant in HER2-amplified, ER-negative, PR-negative MBC (n = 42; 8.3 v 5.0 months; P = .007). In HER2-negative, ER-positive MBC, median EFS improvement varied by degree of PR expression (H-score): no benefit if PR-strong (n = 133; 9.3 v 7.3 months; P = .373), benefit if PR-weak (n = 50; 7.3 v 2.4 months; P = .026), and potential antagonism if PR-negative (n = 40; 3.7 v 7.2 months; P = .004). No benefit was seen in triple-negative MBC (n = 131; median EFS, 4.6 v 4.8 months; P = .255). EGFR expression was not correlated with benefit from lapatinib.ConclusionAlthough subgroups are small, these analyses support the hypothesis that semiquantitative determination of hormone receptor status may be a surrogate for EGFR and/or HER2 dependency.

Young Age at Diagnosis Correlates With Worse Prognosis and Defines a Subset of Breast Cancers With Shared Patterns of Gene Expression

2008 ◽  
Vol 26 (20) ◽  
pp. 3324-3330 ◽  
Author(s):  
Carey K. Anders ◽  
David S. Hsu ◽  
Gloria Broadwater ◽  
Chaitanya R. Acharya ◽  
John A. Foekens ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Young Women ◽  
Growth Factor Receptor ◽  
Breast Cancers ◽  
Egfr Expression ◽  
Her 2 ◽  
Epidermal Growth

Purpose Breast cancer arising in young women is correlated with inferior survival and higher incidence of negative clinicopathologic features. The biology driving this aggressive disease has yet to be defined. Patients and Methods Clinically annotated, microarray data from 784 early-stage breast cancers were identified, and prospectively defined, age-specific cohorts (young: ≤ 45 years, n = 200; older: ≥ 65 years, n = 211) were compared by prognosis, clinicopathologic variables, mRNA expression values, single-gene analysis, and gene set enrichment analysis (GSEA). Univariate and multivariate analyses were performed. Results Using clinicopathologic variables, young women illustrated lower estrogen receptor (ER) positivity (immunohistochemistry [IHC], P = .027), larger tumors (P = .012), higher human epidermal growth factor receptor 2 (HER-2) overexpression (IHC, P = .075), lymph node positivity (P = .008), higher grade tumors (P < .0001), and trends toward inferior disease-free survival (DFS; hazard ratio = 1.32; P = .094). Using genomic expression analysis, tumors arising in young women had significantly lower ERα mRNA (P < .0001), ERβ (P = .02), and progesterone receptor (PR) expression (P < .0001), but higher HER-2 (P < .0001) and epidermal growth factor receptor (EGFR) expression (P < .0001). Exploratory analysis (GSEA) revealed 367 biologically relevant gene sets significantly distinguishing breast tumors arising in young women. Combining clinicopathologic and genomic variables among tumors arising in young women demonstrated that younger age and lower ERβ and higher EGFR mRNA expression were significant predictors of inferior DFS. Conclusion This large-scale genomic analysis illustrates that breast cancer arising in young women is a unique biologic entity driven by unifying oncogenic signaling pathways, is characterized by less hormone sensitivity and higher HER-2/EGFR expression, and warrants further study to offer this poor-prognosis group of women better preventative and therapeutic options.

Prognostic Significance of Overexpression and Phosphorylation of Epidermal Growth Factor Receptor (EGFR) and the Presence of Truncated EGFRvIII in Locoregionally Advanced Breast Cancer

2007 ◽  
Vol 25 (28) ◽  
pp. 4405-4413 ◽  
Author(s):  
Yago Nieto ◽  
Fatima Nawaz ◽  
Roy B. Jones ◽  
Elizabeth J. Shpall ◽  
Samia Nawaz
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Prognostic Value ◽  
Growth Factor Receptor ◽  
High Dose ◽  
Egfr Expression ◽  
Her 2 ◽  
Epidermal Growth

Purpose The prognostic value of the epidermal growth factor receptor (EGFR) in breast cancer and more specifically, in patients with locoregionally advanced disease, is still undefined. We hypothesized that EGFR status plays a major prognostic role in this setting, through expression, activation, or the presence of its mutated variant EGFRvIII. Patients and Methods We reviewed tumor samples of 225 patients treated uniformly in prospective trials of high-dose chemotherapy for four to nine positive axillary nodes, ≥ 10 positive nodes, or inflammatory carcinoma, and observed for a median of 9 years (range, 3 to 13 years). We analyzed the effect on outcome of expression of EGFR, phosphorylated EGFR (phospho-EGFR), and EGFRvIII, as studied by immunohistochemistry. Results EGFR expression, phospho-EGFR, and mutated EGFRvIII were detected in 43%, 54%, and 4% of the patients, respectively. EGFR expression correlated with negative hormone receptor status, and was associated with significantly worse relapse-free survival (59% v 79%; P < .001) and overall survival (61% v 81%; P = .001) than no expression. There was no association of phospho-EGFR or EGFRvIII with outcome. Multivariate models confirmed the prognostic effect of EGFR independent of other known prognostic variables in this population. The prognostic value of EGFR was most prominent in the human epidermal growth factor receptor 2 (HER-2) –positive and the estrogen receptor/progesterone receptor–negative subgroups. Conclusion EGFR expression, but not phospho-EGFR or EGFRvIII expression, is an independent adverse prognostic factor in patients with high-risk primary breast cancer, particularly when it is coexpressed with HER-2. Our results suggest the potential benefit of dual EGFR/HER-2 receptor targeting in this setting.

Computational Evaluation and In Vitro Validation of New Epidermal Growth Factor Receptor Inhibitors

2020 ◽  
Vol 20 (18) ◽  
pp. 1628-1639
Author(s):  
Sergi Gómez-Ganau ◽  
Josefa Castillo ◽  
Andrés Cervantes ◽  
Jesus Vicente de Julián-Ortiz ◽  
Rafael Gozalbes
Keyword(s):  
Cell Proliferation ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Binding Affinity ◽  
Cell Lines ◽  
Growth Factor Receptor ◽  
Significant Activity ◽  
Epidermal Growth

Background: The Epidermal Growth Factor Receptor (EGFR) is a transmembrane protein that acts as a receptor of extracellular protein ligands of the epidermal growth factor (EGF/ErbB) family. It has been shown that EGFR is overexpressed by many tumours and correlates with poor prognosis. Therefore, EGFR can be considered as a very interesting therapeutic target for the treatment of a large variety of cancers such as lung, ovarian, endometrial, gastric, bladder and breast cancers, cervical adenocarcinoma, malignant melanoma and glioblastoma. Methods: We have followed a structure-based virtual screening (SBVS) procedure with a library composed of several commercial collections of chemicals (615,462 compounds in total) and the 3D structure of EGFR obtained from the Protein Data Bank (PDB code: 1M17). The docking results from this campaign were then ranked according to the theoretical binding affinity of these molecules to EGFR, and compared with the binding affinity of erlotinib, a well-known EGFR inhibitor. A total of 23 top-rated commercial compounds displaying potential binding affinities similar or even better than erlotinib were selected for experimental evaluation. In vitro assays in different cell lines were performed. A preliminary test was carried out with a simple and standard quick cell proliferation assay kit, and six compounds showed significant activity when compared to positive control. Then, viability and cell proliferation of these compounds were further tested using a protocol based on propidium iodide (PI) and flow cytometry in HCT116, Caco-2 and H358 cell lines. Results: The whole six compounds displayed good effects when compared with erlotinib at 30 μM. When reducing the concentration to 10μM, the activity of the 6 compounds depends on the cell line used: the six compounds showed inhibitory activity with HCT116, two compounds showed inhibition with Caco-2, and three compounds showed inhibitory effects with H358. At 2 μM, one compound showed inhibiting effects close to those from erlotinib. Conclusion: Therefore, these compounds could be considered as potential primary hits, acting as promising starting points to expand the therapeutic options against a wide range of cancers.

Recent Advances on Epidermal Growth Factor Receptor as a Molecular Target for Breast Cancer Therapeutics

2020 ◽  
Vol 21 ◽  
Author(s):  
Swathi R. Shetty ◽  
Ragini Yeeravalli ◽  
Tanya Bera ◽  
Amitava Das
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Critical Role ◽  
Growth Factor Receptor ◽  
Type I ◽  
Egfr Inhibition ◽  
Epidermal Growth

: Epidermal growth factor receptor (EGFR), a type-I transmembrane protein with intrinsic tyrosine kinase activity is activated by peptide growth factors such as EGF, epigen, amphiregulin, etc. EGFR plays a vital role in regulating cell growth, migration, and differentiation in various tissue-specific cancers. It has been reported to be overexpressed in lung, head, and neck, colon, brain, pancreatic, and breast cancer that trigger tumor progression and drug resistance. EGFR overexpression alters the signaling pathway and induces cell division, invasion, and cell survival. Our prior studies demonstrated that EGFR inhibition modulates chemosensitivity in breast cancer stem cells thereby serving as a potential drug target for breast cancer mitigation. Tyrosine kinase inhibitors (Lapatinib, Neratinib) and monoclonal antibodies (Trastuzumab) targeting EGFR have been developed and approved by the US FDA for clinical use against breast cancer. This review highlights the critical role of EGFR in breast cancer progression and enumerates the various approaches being undertaken to inhibit aggressive breast cancers by suppressing the downstream pathways. Further, the mechanisms of action of potential molecules at various stages of drug development as well as clinically approved drugs for breast cancer treatment are illustrated.

scholarly journals HER2-positive breast cancer and tyrosine kinase inhibitors: the time is now

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Ilana Schlam ◽  
Sandra M. Swain
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Her2 Positive ◽  
Epidermal Growth ◽  
Positive Breast Cancer

AbstractHuman epidermal growth factor receptor 2 (HER2) positive breast cancer accounts for 20–25% of all breast cancers. Multiple HER2-targeted therapies have been developed over the last few years, including the tyrosine kinase inhibitors (TKI) lapatinib, neratinib, tucatinib, and pyrotinib. These drugs target HER2 and other receptors of the epidermal growth factor receptor family, therefore each has unique efficacy and adverse event profile. HER2-directed TKIs have been studied in the early stage and advanced settings and have shown promising responses. There is increasing interest in utilizing these drugs in combination with chemotherapy and /or other HER2-directed agents in patients with central nervous system involvement, TKIs have shown to be effective in this setting for which treatment options have been previously limited and the prognosis remains poor. The aim of this review is to summarize currently approved TKIs for HER2+ breast, key clinical trials, and their use in current clinical practice.

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