Egfr
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Egfr -Epidermal growth factor receptor
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Pubmed
Treatment with aromatase inhibitors stimulates the expression of epidermal growth factor receptor-1 and neuregulin 1 in ER positive/HER-2/neu non-amplified primary breast cancers.
Journal: The Journal of steroid biochemistry and molecular biology
July/5/2017
Description

While estrogens have been shown to modulate EGFR/HER-1 and HER-2/neu expression in experimental systems, the effects of estrogen deprivation on expression levels of the HER-receptors and the neuregulin (NRG)1 ligand in breast cancers remain unknown. Here, we measured EGFR/HER-1-4 and NRG1 mRNA in ER positive tumors from 85 postmenopausal breast cancer patients before and after two weeks (n=64) and three months (n=85) of primary treatment with an aromatase inhibitor (AI). In tumors lacking HER-2/neu amplification, quantitative real-time PCR analyses revealed EGFR/HER-1 and NRG1 to vary significantly between the three time points (before therapy, after 2 weeks and after 3 months on treatment; P≤0.001 for both). Pair-wise comparison revealed a significant increase in EGFR/HER-1 already during the first two weeks of treatment (P=0.049) with a further increase for both EGFR/HER-1 and NRG1 after 3 months on treatment (P≤0.001 and P=0.001 for both comparing values at 3 months to values at baseline and 2 weeks respectively). No difference between tumors responding versus non-responders was recorded. Further, no significant change in any parameter was observed among HER-2/neu amplified tumors. Analyzing components of the HER-2/neu PI3K/Akt downstream pathway, the PIK3CA H1047R mutation was associated with treatment response (P=0.035); however no association between either AKT phosphorylation status or PIK3CA gene mutations and EGFR/HER-1 or NRG1 expression levels were observed. Our results indicate primary AI treatment to modulate expression of HER-family members and the growth factor NRG1 in HER-2/neu non-amplified breast cancers in vivo. Potential implications to long term sensitivity warrants further investigations.

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Pubmed
Clinical and molecular characteristics of non-small-cell lung cancer (NSCLC) harboring EGFR mutation: results of the nationwide French Cooperative Thoracic Intergroup (IFCT) program.
Journal: Annals of oncology : official journal of the European Society for Medical Oncology
November/7/2017
Description

UNASSIGNED

EGFR mutations cause inconsistent response to EGFR tyrosine-kinase inhibitors (TKI). To better understand these features, we reviewed all cases of EGFR-mutated non-small-cell lung cancer collected in the Biomarkers France database.

UNASSIGNED

Of 17 664 patients, 1837 (11%) with EGFR-mutated non-small-cell lung cancer were retrospectively analyzed for clinical and molecular characteristics. Results were correlated with survival and treatment response for the 848 stage IV patients.

UNASSIGNED

EGFR exon 18, 19, 20 and 21 mutations were found in 102 (5.5%), 931 (51%), 102 (5.5%) and 702 (38%) patients, respectively. Over 50% of exon 18 and 20 mutated patients were smokers. The median follow-up was 51.7 months. EGFR mutation type was prognostic of overall survival (OS) versus wild-type {exon 19: hazard ratio (HR)=0.51 [95% confidence interval (CI): 0.41-0.64], P < 0.0001; exon 21: HR = 0.76 (95% CI: 0.61-0.95), P = 0.002; exon 20: HR = 1.56 (95% CI: 1.02-2.38), P = 0.004}. EGFR mutation type was prognostic of progression-free survival versus wild-type [exon 19: HR = 0.62 (95% CI: 0.49-0.78), P < 0.0001; exon 20: HR = 1.46 (95% CI: 0.96-2.21), P = 0.07]. First-line treatment choice did not influence OS in multivariate analysis. First-line TKI predicted improved progression-free survival versus chemotherapy [HR = 0.67 (95% CI: 0.53-0.85), P = 0.001]. OS was longer for del19 versus L858R, which was associated with better OS compared with other exon 21 mutations, including L861Q. TKI improved survival in patients with exon 18 mutations, while chemotherapy was more beneficial for exon 20-mutated patients.

UNASSIGNED

EGFR mutation type can inform the most appropriate treatment. Therapeutic schedule had no impact on OS in our study, although TKI should be prescribed in first-line considering the risk of missing the opportunity to use this treatment.

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Pubmed
Survival but not brain metastasis response relates to lung cancer mutation status after radiosurgery.
Journal: Journal of neuro-oncology
October/31/2016
Description

We prospectively addressed whether EGFR and KRAS mutations, EML4-ALK, ROS1 and RET rearrangements, or wild-type (WT), affects radiosurgery outcomes and overall survival (OS) in non-small cell lung cancer (NSCLC) patients with brain metastases (BM). Of 326 patients with BM treated in 2012-2014 with Gamma Knife radiosurgery (GKRS), 112 NSCLC patients received GKRS as their initial intracranial treatment. OS, intracranial progression-free survival, and time to intracranial failure were determined. Univariate and multivariate analysis were performed to determine factors affecting OS. Toxicity of treatment was evaluated. Median follow-up was 9 months. Patients with EGFR mutant BM had improved survival compared to WT. Median time to development of BM was higher in EGFR mutant patients, but this difference was not significant (2.2 vs 0.9 months; p = 0.2). Median time to distant brain failure was independent of EGFR mutation status. Karnofsky performance status (KPS), non-squamous histopathology, targeted therapy, systemic disease control, EGFR mutation, and low tumor volume were predictive of increased OS on univariate analysis. KPS (p = 0.001) and non-squamous histopathology (p = 0.03) continued to be significant on multivariate analysis. Patients with EGFR mutant BM underwent salvage treatment more often than those without (p = 0.04). Treatment-related toxicity was no different in patients treated with GKRS combined with targeted therapies versus GKRS alone (5 vs 7%, p = 0.7). Patients with EGFR mutant BM had improved survival compared to a WT cohort. Intracranial disease control following radiosurgery was similar for all tumor subtypes. Radiosurgery is effective for BM and concurrent treatment with targeted therapy appears to be safe.

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Pubmed
The activating role of phospho-(Tyr)-calmodulin on the epidermal growth factor receptor.
Journal: The Biochemical journal
February/28/2016
Description

The activity of calmodulin (CaM) is modulated not only by oscillations in the cytosolic concentration of free Ca(2+), but also by its phosphorylation status. In the present study, the role of tyrosine-phosphorylated CaM [P-(Tyr)-CaM] on the regulation of the epidermal growth factor receptor (EGFR) has been examined using in vitro assay systems. We show that phosphorylation of CaM by rat liver solubilized EGFR leads to a dramatic increase in the subsequent phosphorylation of poly-L-(Glu:Tyr) (PGT) by the receptor in the presence of ligand, both in the absence and in the presence of Ca(2+). This occurred in contrast with assays where P-(Tyr)-CaM accumulation was prevented by the presence of Ca(2+), absence of a basic cofactor required for CaM phosphorylation and/or absence of CaM itself. Moreover, an antibody against CaM, which inhibits its phosphorylation, prevented the extra ligand-dependent EGFR activation. Addition of purified P-(Tyr)-CaM, phosphorylated by recombinant c-Src (cellular sarcoma kinase) and free of non-phosphorylated CaM, obtained by affinity-chromatography using an immobilized anti-phospho-(Tyr)-antibody, also increased the ligand-dependent tyrosine kinase activity of the isolated EGFR toward PGT. Also a CaM(Y99D/Y138D) mutant mimicked the effect of P-(Tyr)-CaM on ligand-dependent EGFR activation. Finally, we demonstrate that P-(Tyr)-CaM binds to the same site ((645)R-R-R-H-I-V-R-K-R-T-L-R-R-L-L-Q(660)) as non-phosphorylated CaM, located at the cytosolic juxtamembrane region of the EGFR. These results show that P-(Tyr)-CaM is an activator of the EGFR and suggest that it could contribute to the CaM-mediated ligand-dependent activation of the receptor that we previously reported in living cells.

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Pubmed
Molecular subclassification determined by human papillomavirus and epidermal growth factor receptor status is associated with the prognosis of oropharyngeal squamous cell carcinoma.
Journal: Human pathology
July/31/2016
Description

Human papillomavirus (HPV) infection is an indicator of good response to chemoradiotherapy in oropharyngeal squamous cell carcinoma (OPSCC), and epidermal growth factor receptor (EGFR) is a molecular-therapeutic target in head and neck squamous cell carcinoma. Here we investigated the prevalence and prognostic significance of HPV infection and EGFR alteration in OPSCC. We analyzed the presence of high-risk HPV using in situ hybridization, protein expressions of p16 and EGFR using immunohistochemistry, and the EGFR gene copy number gain using chromogenic in situ hybridization (CISH) in 105 cases of OPSCC. The biopsy specimens before chemoradiotherapy were used for these analyses. HPV infection and p16 protein overexpression were detected in 53.3% and 52.4% of the OPSCCs, and each factor was associated with better overall survival (P = .0026 and P = .0026) and nonkeratinizing histology (P = .0002 and P = .0004), respectively. EGFR gene copy number gain (high polysomy or amplification) was detected in 12.4% of the OPSCCs and was correlated with EGFR protein overexpression (P = .0667) and worse overall survival (P < .0001). HPV infection and EGFR gene copy number gain (EGFR CISH positive) were mutually exclusive. The HPV-negative/EGFR CISH-positive OPSCCs had significantly worse overall survival than did the HPV-positive/EGFR CISH-negative OPSCCs and HPV-negative/EGFR CISH-negative OPSCCs (P < .0001 and P < .0001, respectively). The EGFR CISH-negative OPSCCs had favorable prognosis irrespective of HPV infection. Our results suggest that EGFR gene copy number gain-positive tumors represent an HPV-negative, aggressive subgroup of OPSCCs. The molecular subclassification of OPSCCs based on HPV infection and EGFR status may serve as important information for appropriate therapeutic strategy.

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Pubmed
[Correlation of epidermal growth factor receptor mutations and HER2/3 protein expression with clinical outcome in advanced non-small cell lung cancer patients treated with gefitinib].
Journal: Chinese journal of cancer
December/4/2011
Description

OBJECTIVE

The effect of gefitinib on advanced non-small cell lung cancer (NSCLC) was various. How to choose the sensitive patients and improve the effect was difficulty in clinic. This study was to assess the correlation of epidermal growth factor receptor (EGFR) mutations and HER2/3 protein expression with the effect of gefitinib on Chinese patients with advanced NSCLC.

METHODS

From May 2002 to February 2005, a total of 106 Chinese NSCLC patients who had failed at least one chemotherapy regimen were treated with gefitinib 250 mg once a day. The mutations in the exons 18-24 of EGFR gene were detected in the tumor tissues from 106 patients before the treatment of gefitinib, and HER2/3 expression in 84 tumor samples were detected by immunohistochemistry.

RESULTS

Mutation was identified in 32 (30.2%) tumor tissues. Overall remission rate was significantly higher in the HER2 high expression patients than in the HER2 low expression patients (36.8% vs 17.4%, P=0.044). HER2 and HER3 expression levels were not associated with time to progression (TTP) and overall survival (OS). The patients with HER2/3 single high expression had relatively longer TTP and OS than those with HER2/3 single low expression (6.1 vs 9.1 months, P=0.725; 6.1 vs 9.0 months, P=0.862), while those with concomitant HER2/3 high expression had significant longer TTP and OS. EGFR-mutated patients with HER2 expression or high HER2 and HER3 expressions were more sensitive to gefitinib.

CONCLUSIONS

EGFR mutations combined with HER2/3 expressions is a significant predictor for gefitinib efficacy on Chinese patients with advanced NSCLC.

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Pubmed
Pemetrexed-based chemotherapy in advanced lung adenocarcinoma patients with different EGFR genotypes.
Journal: Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine
June/11/2015
Description

Advanced lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) activating mutations usually are highly sensitive to EGFR tyrosine kinase inhibitors (TKIs), but whether EGFR-mutant lung adenocarcinoma is also responsive to pemetrexed-based chemotherapy remains controversial. We conducted a retrospective study to evaluate the efficacy and outcome of pemetrexed-based chemotherapy in advanced lung adenocarcinoma patients with different EGFR mutation statuses. Sixty-nine EGFR-mutant and 89 wild-type patients with advanced lung adenocarcinoma were enrolled. They all had received pemetrexed-based treatments. Chemotherapy objective response rate (ORR), median progression-free survival (mPFS), and thymidylate synthase (TS) expression levels of EGFR-mutant patients were compared with those of EGFR-wild-type patients. For the EGFR-mutant patients treated with first-line platinum/pemetrexed combinations, the ORR was significantly higher than that of the wild-type patients treated with similar regimens (43 vs. 21%, p = 0.039). Nonetheless, for the patients treated with pemetrexed monotherapy, the difference in ORR was not significant between patients with EGFR mutations and those with wild-type EGFR in any line of treatments (in the first-line setting 20 vs. 13%, p = 0.715; in the second-/third-line setting 13 vs. 8%, p = 0.655). On the other hand, the mPFS for the EGFR-mutant patients treated with first-line combinations was also obviously prolonged (8.3 vs. 6.7 months, p = 0.004). However, among the patients receiving second-line platinum/pemetrexed combinations or any line of single-agent pemetrexed, there was no difference in PFS between EGFR-mutant and wild-type patients. Our results indicated that the efficacies and outcomes of pemetrexed treatment in advanced lung adenocarcinoma patients with EGFR activating mutations were similar to those in patients with EGFR-wild-type genotype, except in the setting of first-line platinum/pemetrexed combination chemotherapy.

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Pubmed
Detection of mutation-specific epidermal growth factor receptor (E746-A750del) and lack of detection of human papillomavirus in oral squamous cell carcinoma.
Journal: International journal of oral and maxillofacial surgery
June/2/2015
Description

The clinical impact of epidermal growth factor receptor (EGFR) (E746-A750del) mutation and human papillomavirus (HPV) in oral squamous cell carcinoma (OSCC) is unclear. EGFR (E746-A750del) expression was analyzed in OSCC specimens (n=161) by immunohistochemistry. The expression results were correlated with clinical characteristics and impact on survival. Using INNO-LiPA Extra, high-risk HPV types were genotyped and analyzed in 211 OSCC specimens. Positive EGFR (E746-A750del) expression (n=40/161, 25%) was not associated with any clinicopathological characteristics, prognostic factors, social habits (smoking, alcohol consumption), or tumour-specific survival. HPV16 DNA was detected in three out of 211 samples (HPV16-positive: n=3/211, 1.4%). This study shows that mutation-specific EGFR (E746-A750del) expression and HPV do not appear to be relevant to the survival of patients with OSCC.

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Pubmed
Prognostic value of EGFR expression in de novo and progressed atypical and anaplastic meningiomas: an immunohistochemical and fluorescence in situ hybridization pilot study.
Journal: Journal of neurosurgical sciences
August/7/2013
Description

OBJECTIVE

The aim of this study was to assess both the epidermal growth factor receptor (EGFR) protein expression by immunohistochemistry and the EGFR gene amplification by fluorescence in situ hybridization in meningiomas of different grade, in order to evaluate their possible role in the development of the disease. EGFR protein belongs to the family of tyrosine kinase growth factor receptors, which also includes HER2, HER3 and HER4. Elevated expression or activity of EGFR has been reported in several cancers, including brain tumours. EGFR activation can enhance the malignant potential of epithelial tissues.

METHODS

We investigated whether there was a difference in the EGFR protein expression and the EGFR gene amplification between the so called de novo malignant meningiomas and recurrent meningiomas with or without malignant progression from a previously lower grade tumor. Our goal was to evaluate if EGFR expression was a useful marker to select patients affected by meningioma with a major risk of recurrences. We also assessed the prognostic value of the EGFR expression on overall survival.

RESULTS

Progression from benign meningiomas to atypical or anaplastic meningiomas correlated with an increase in the expression of EGFR protein. Our study shows that EGFR immunostaining in meningiomas directly correlates to the tumor's grade. The EGFR expression did not correlate with the overall survival and the recurrence-free survival of the patients affected by meningioma (de novo, recurrent and progressed).

CONCLUSIONS

We submit that the EGFR expression is not a useful prognostic element to identify patients with a major risk of meningioma recurrence.

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Pubmed
The expression of c-erbB-1 and c-erbB-2 in Iranian patients with gastric carcinoma.
Journal: Pathology oncology research : POR
September/22/2003
Description

To assess the significance of epidermal growth factor receptor family members, the overexpression of c-erbB-1 and c-erbB-2 was retrospectively investigated in 146 southern Iranian gastric cancer patients. Indirect immunostaining was used to evaluate the expression of these two receptors in formalin-fixed paraffin-embedded tissue samples. c-ErbB-1 expression was observed in 47 (32.2%) and c-erbB-2 expression was observed in 24 (16.4%) of tumors. Significant positive correlations were observed between c-erbB-1 expression and tumor size, local invasion, lymph node involvement and tumor stage. There was also a negative correlation between c-erbB-2 expression and tumor stage. These results may suggest the contribution of c-erbB-1 molecule in progression of gastric carcinomas in southern Iranian patients. Moreover, the relatively high percentage of c-erbB-2 positive tumors may provide a useful target for the immunotherapy of these cancers.

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