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Background: EGFR over-expression plays a key role in the development and progression of lung cancer. However, its status as a prognostic biomarker for survival outcomes is unclear. Objectives: To evaluate the prognostic utility of serum EGFR mRNA expression in Non-Small cell lung cancer (NSCLC) for treatment response and survival. Methods: EGFR mRNA levels were determined in serum using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Based on ROC curve, a cut off value of 16.0-fold increase was selected to categorize patients into low EGFR (≤ 16.0) and high EGFR (> 16.0) groups. Results: A total of 350 subjects were included (78.3% males), with mean (± SD) age of 57.1 (± 11.2) years, and including 247 (70.6%) adenocarcinoma (ADC). Majority (73.1%) had metastatic (stage IV) disease. Patients had higher pre-treatment serum EGFR mRNA levels than controls [median fold-increase (min, max), 16.2 (1.9, 66.7). Serum EGFR mRNA levels significantly reduced in those who achieved objective response and disease control. Significantly longer OS and PFS was observed in subjects having baseline EGFR mRNA expression ≤ 16.0 fold- increase compared to those with > 16.0 fold- increase [median (95% CI) OS: 25.0 (14.9, NR) versus 7.7 (6.3, 8.9) months; HR (95% CI) 2.9 (2.3, 4.0), p < 0.001; and PFS: 9.9 (7.1, 11.5) versus 6.0 (4.1, 7.5) months; HR (95% CI) 1.8 (1.3, 2.4), p < 0.001]. Conclusion: Serum EGFR mRNA expression is a useful parameter for predicting treatment response and survival outcomes in NSCLC.

Introduction:Squamous cell carcinoma of the oral cavity is one of the most common head and neck cancers with an aggressive course and high mortality rates.The aimof the study was to determine the EGFR expression levels in tumor tissues in patients with squamous cell carcinoma of the tongue and oral mucosa depending on the efficacy of the therapy.Material and methods:The study included 60 patients with squamous cell carcinoma of the tongue and oral mucosa T3-4N0-1M0. The main group included 30 patients receiving chemotherapy (cisplatin/fluorouracil) in combination with targeted therapy with cetuximab. The control group included 30 patients receiving chemotherapy without cetuximab. Both groups were divided into two subgroups: sensitive and resistant.Results:In treatment-resistant patients of the main group with cetuximab, the average EGFR expression was twice lower than the initial levels (p = 0.0080) and 1.7 times higher than in treatment-resistant patients of the control group (p = 0.0157). In treatment-sensitive patients, the average EGFR expression was 19.8 times lower (p = 0.0020) than initial values and 14.9 times higher (p = 0.0067) than in treatment-sensitive controls.Conclusions:A natural decrease in the EGFR expression in tumor tissues due to the targeted therapy was revealed. However, some patients were resistant to cetuximab, which dictates the need to search for predictors of targeted therapy efficacy in patients with locally advanced squamous cell carcinoma of the tongue and oral mucosa.

Background and Aim: Glioblastoma multiforme (GBM) is the most common malignant and invasive tumor of the brain. The relation between prognosis and survival of GBM patients with Epidermal Growth Factor Receptor (EGFR) expression is challenging. Thus, we aimed to evaluate the prognosis and survival of patients with GBM and its relationship with EGFR expression. Materials and Methods: This single-arm cohort study was conducted on 70 patients with GBM during 2012-2018 in Shahid Rahnemoon and Mortaz hospitals. The immunohistochemistry technique was applied to paraffin blocks of brain tumors for examining EGFR expression. Other data were extracted from medical records. To determine the survival rate, the Kaplan–Meier curves were used. A chi-square test was used for the analysis of data. Statistically, p-value 0.05). Conclusion: Based on our study, it seems that the GBM tumor was associated with poor prognosis and a low survival rate. It was also found that the expression of the EGFR gene did not affect the survival rate of patients with GBM. Therefore, its use as a predictor factor for survival and prognosis is questionable.

Purpose Gd-encapsulated carbonaceous dots (Gd@C-dots) have excellent stability and magnetic properties without free Gd leakage, therefore they can be considered as a safe alternative T1 contrast agent to commonly used Gd complexes. To improve their potential for cancer diagnosis and treatment, affibody-modified Gd@C-dots targeting non-small-cell lung cancer (NSCLC) EGFR-positive tumors with enhanced renal clearance were developed and synthesized. Materials and methods Gd@C-dots were developed and modified with Ac-Cys-ZEGFR:1907 through EDC/NHS. The size, morphology, and optical properties of the Gd@C-dots and Gd@C-dots-Cys-ZEGFR:1907 were characterized. Targeting ability was evaluated by in vitro and in vivo experiments, respectively. Residual gadolinium concentration in major organs was detected with confocal imaging and inductively coupled plasma mass spectrometry (ICP-MS) ex vivo. H&E staining was used to assess the morphology of these organs. Results Gd@C-dots with nearly 20 nm in diameter were developed and modified with Ac-Cys-ZEGFR:1907. EGFR expression in HCC827 cells was higher than NCI-H520. In cell uptake assays, EGFR-expressing HCC827 cells exhibited significant MR T1WI signal enhancement when compared to NCI-H520 cells. Cellular uptake of Gd@C-dots-Cys-ZEGFR:1907 was reduced, when Ac-Cys-ZEGFR:1907 was added. In vivo targeting experiments showed that the probe signal was significantly higher in HCC827 than NCI-H520 xenografts at 1 h after injection. In contrast to Gd@C-dots, Gd@C-dots-Cys-ZEGFR:1907 nanoparticles can be efficiently excreted through renal clearance. No morphological changes were observed by H&E staining in the major organs after injection of Gd@C-dots-Cys-ZEGFR:1907. Conclusion Gd@C-dots-Cys-ZEGFR:1907 is a high-affinity EGFR-targeting probe with efficient renal clearance and is therefore a promising contrast agent for clinical applications such as diagnosis and treatment of NSCLC EGFR-positive malignant tumors.

Background Despite advanced treatments could inhibit progression of colorectal carcinoma (CRC), the recurrence and metastasis remain challenging issues. Accumulating evidences implicated that AVL9 played a vital role in human cancers, but it’s biological function and mechanism in CRC remain unclear. Aim To investigate the biological role and mechanism of AVL9 in colorectal carcinoma. Results AVL9 expression was significantly upregulated in tumor tissues than that in matched normal tissues both at mRNA and protein levels. High expression of AVL9 was closely correlated with M status, stages and poor prognosis of colorectal carcinoma (CRC) patients. Functionally, AVL9 overexpression promoted cell migration rather than cell proliferation in vitro, whereas AVL9 knockdown exhibited the contrary results. Mechanistically, AVL9 regulated EGFR expression, and knockdown of EGFR restrained AVL9-induced cell migration. Conclusion These findings demonstrated that AVL9 contributed to CRC cell migration by regulating EGFR expression, suggesting a potential biomarker and treatment target for CRC.

Introduction: Nasopharyngeal carcinoma (NPC) is a lymphoepithelial malignancy of the nasopharynx, one of the etiologies is the infection of Epstein–Barr virus in undifferentiated type of nasopharyngeal carcinoma. The Epstein-Barr virus Nucleus Antigen-1 (EBNA-1) is Epstein–Barr virus-encoded proteins as regulatory virus transcription. Epithelial Growth Factor Receptor (EGFR) consist of a single polypeptide chain of amino acid, ErbB members, tyrosine kinase receptor, a transmembrane glycoprotein encoded by gen location in the short arms of a chromosome and overexpression in epithelial tumors. EGFR plays a central role in signal transduction pathways which regulate key cellular functions in epithelial malignancies. and may also present in NPC. Objective: To investigate this relation of expression patterns of EBNA-1 and EGFR in a histological type of undifferentiated nasopharyngeal carcinoma. Method: Observational, analytical study with a cross-sectional method of 34 formalin-fixed within inclusion criteria are EBNA-1 and positive staining of EGFR expression (30 patients) and exclusion criteria of negative staining of EGFR (4 patients). All biopsy samples work with paraffin embedded and resulted in hematoxylin-eosin undifferentiated histological types of the advanced stage in nasopharyngeal carcinoma. EBNA-1 and EGFR expression used immunohistochemistry staining. Result: EBNA-1 and EGFR expression level were detection and correlated with the advanced stadium of nasopharyngeal undifferentiated carcinoma. Conclusion: EBNA-1 is significantly related to EGFR expression in the advanced stadium of undifferentiated nasopharyngeal carcinoma. Overexpression of EGFR is mostly found in advanced NPC but not in all ages. Male is dominated and overall age below 55 years old. Screening of EGFR with immunohistochemistry is highly considered before anti-EGFR treatment

There are few studies investigating the biomarker signatures and their relations with prognosis of pulmonary artery sarcoma patients. In the present study, we performed a cohort study on 16 cases of pulmonary artery sarcoma in an attempt to identify the potential diagnostic markers and molecular therapeutic targets of that vascular sarcoma. Patients who had undergone pulmonary artery sarcoma tumorectomy over 7 ½ years in our hospital were enrolled in this retrospective study. The resected tumors were analyzed by histopathology, the expression and mutation of Murine Double Minute 2 (MDM2), Epidermal Growth Factor Receptor (EGFR), and Platelet-Derived Growth Factor Alpha (PDGFRA) by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). The correlations between patients’ outcomes and tumor histological, IHC and FISH features were statistically analyzed. MDM2 immunostaining was seen mainly in intimal sarcoma. At univariate analysis, MDM2 expression had a positive correlation with shorter progression free survival (PFS). MDM2 and EGFR co-expression also had a positive correlation with shorter PFS and tumor metastasis. This study investigated MDM2, EGFR, and PDGFRA as potential biomarkers for diagnosis of pulmonary artery sarcoma and therapeutic targets.

Cancer patients contracting SARS-CoV-2 encounter additional challenges due to inflammatory bursts and lymphopenia, which may aggravate breast cancer prognosis. In this in silico analysis, we identified the potential of miRNAs as new therapeutic targets to treat breast cancer patients infected with COVID-19 via the regulation of ADAM17 and EGFR expression microRNAs.

Introduction. Head and neck tumors (HNT) are tumors that normally occur at the head and neck region of the body. Epidermal growth factor receptor (EGFR) has been found to be highly expressed in breast and other tumors; therefore, there is the need to investigate the level of EGFR expression among patients with head and neck tumors in Ghana. Method. The level of EGFR expression was determined in head and neck tumor and control head and neck tissues with quantitative real-time PCR and immunohistochemistry analysis. Results. The level of EGFR expressions was high in tumor tissues than in the control tissues. There was a significant difference of p value 0.025 among the ages >40 and ≤ 40 when the high and low level of EGFR was compared in the head and neck malignant tumor. The area under the curve for the high expression of EGFR among the malignant head and neck tumors was 0.901 with a specificity of 86.4%. Conclusion. EGFR can serve as a prognostic marker in monitoring patients with HNT as well as a molecular therapeutic target.

Treatment options for triple negative breast cancer (TNBC) are generally limited to cytotoxic chemotherapy. Recently, antiepidermalgrowth factor receptor (EGFR) therapy has been introduced for TNBC patients. We engineered a novelnanobioconjugate based on a poly(b-L-malic acid) (PMLA) nanoplatform for TNBC treatment. The nanobioconjugate carriesanti-tumor nucleosome-specific monoclonal antibody (mAb) 2C5 to target breast cancer cells, anti-mouse transferrinreceptor (TfR) antibody for drug delivery through the host endothelial system, and Morpholino antisense oligonucleotide(AON) to inhibit EGFR synthesis. The nanobioconjugates variants were: (1) P (BioPolymer) with AON, 2C5 and anti-TfR fortumor endothelial and cancer cell targeting, and EGFR suppression (P/AON/2C5/TfR), and (2) P with AON and 2C5 (P/AON/2C5). Controls included (3) P with 2C5 but without AON (P/2C5), (4) PBS, and (5) P with PEG and leucine ester (LOEt) forendosomal escape (P/mPEG/LOEt). Drugs were injected intravenously to MDA-MB-468 TNBC bearing mice. Tissueaccumulation of injected nanobioconjugates labeled with Alexa Fluor 680 was examined by Xenogen IVIS 200 (live imaging)and confocal microscopy of tissue sections. Levels of EGFR, phosphorylated and total Akt in tumor samples were detectedby western blotting. In vitro western blot showed that the leading nanobioconjugate P/AON/2C5/TfR inhibited EGFRsynthesis significantly better than naked AON. In vivo imaging revealed that 2C5 increased drug-tumor accumulation.Significant tumor growth inhibition was observed in mice treated with the lead nanobioconjugate (1) [P = 0.03 vs. controls;P,0.05 vs. nanobioconjugate variant (2)]. Lead nanobioconjugate (1) also showed stronger inhibition of EGFR expressionand Akt phosphorylation than other treatments. Treatment of TNBC with the new nanobioconjugate results in tumorgrowth arrest by inhibiting EGFR and its downstream signaling intermediate, phosphorylated Akt. The nanobioconjugaterepresents a new generation of nanodrugs for treatment of TNBC.

Purpose One-third of patients with RAS wild-type mCRC do not benefit from anti-EGFR monoclonal antibodies. This might be a result of variable pharmacokinetics and insufficient tumor targeting. We evaluated cetuximab tumor accumulation on [89Zr]Zr-cetuximab PET/CT as a potential predictive biomarker and determinant for an escalating dosing strategy. Patients and methods PET/CT imaging of [89Zr]Zr-cetuximab (37 MBq/10 mg) after a therapeutic pre-dose (500 mg/m2 ≤ 2 h) cetuximab was performed at the start of treatment. Patients without visual tumor uptake underwent dose escalation and a subsequent [89Zr]Zr-cetuximab PET/CT. Treatment benefit was defined as stable disease or response on CT scan evaluation after 8 weeks. Results Visual tumor uptake on [89Zr]Zr-cetuximab PET/CT was observed in 66% of 35 patients. There was no relationship between PET positivity and treatment benefit (52% versus 80% for PET-negative, P = 0.16), progression-free survival (3.6 versus 5.7 months, P = 0.15), or overall survival (7.1 versus 9.4 months, P = 0.29). However, in 67% of PET-negative patients, cetuximab dose escalation (750–1250 mg/m2) was applied, potentially influencing outcome in this group. None of the second [89Zr]Zr-cetuximab PET/CT was positive. Eighty percent of patients without visual tumor uptake had treatment benefit, making [89Zr]Zr-cetuximab PET/CT unsuitable as a predictive biomarker. Tumor SUVpeak did not correlate to changes in tumor size on CT (P = 0.23), treatment benefit, nor progression-free survival. Cetuximab pharmacokinetics were not related to treatment benefit. BRAF mutations, right-sidedness, and low sEGFR were correlated with intrinsic resistance to cetuximab. Conclusion Tumor uptake on [89Zr]Zr-cetuximab PET/CT failed to predict treatment benefit in patients with RAS wild-type mCRC receiving cetuximab monotherapy. BRAF mutations, right-sidedness, and low sEGFR correlated with intrinsic resistance to cetuximab.

Background Human epidermal growth factor receptor (EGFR) is an oncogenic gene and one of top targets of precision therapy in lung cancer with EGFR mutations. Although there are many reports for some individual cancers, comprehensive profiling of EGFR mutations, overexpression, amplification, DNA methylation, and their clinical associations across many different cancers simultaneously was not available. This study aimed to fill the gap and provide insights to the alteration spectrum of EGFR and its therapeutic and prognostic implications. Methods The Cancer Genome Atlas (TCGA) datasets for 32 cancer types involving 11,314 patients were analyzed for alterations (mutations and amplification/deletion), abnormal expression and DNA methylation in EGFR gene. Mutation frequency, genomic location distribution, functional impact, and clinical targeted therapy implication were compared among different cancer types, and their associations with patient survival were analyzed. Results EGFR alteration frequency, mutation sites across functional domains, amplification, overexpression, and DNA methylation patterns differed greatly among different cancer types. The overall mutation frequency in all cancers combined was relatively low. Targetable mutations, mainly in lung cancer, were primarily found in the Pkinase_Tyr domain. Glioblastoma multiforme had the highest rate of alterations, but it was dominated by gene amplification and most mutations were in the Furin‐like domain where targeted therapy was less effective. Low‐grade glioma often had gene amplification and increased EGFR expression which was associated with poor outcome. Colon and pancreatic adenocarcinoma had very few EGFR mutations; however, high EGFR expression was significantly associated with short patient survival. Squamous cell carcinoma regardless of their sites (the head and neck, lung, or esophagus) exhibited similar characteristics with an alteration frequency of about 5.0%, was dominated by gene amplification, and had increased EGFR expression generally associated with short patient survival. DNA methylation was highly associated with EGFR expression and patient outcomes in some cancers. Conclusions EGFR aberration type, frequency, distribution in functional domains, and expression vary from cancer to cancer. While mutations in the Pkinase_Tyr domain are more important for treatment selection, increased expression from amplification or deregulation affects more tumor types and leads to worse outcome, which calls for new treatment strategies for these EGFR‐driven tumors.

Background: Oral cancer is a leading cause of cancer in India and contributes to 12% deaths worldwide. The identification of high-risk oral premalignant lesions such as leukoplakia and intervention at premalignant stages could result in significant loss of mortality and morbidity among these patients. The most frequently observed genetic aberrations in these lesions are of mutations in p53, c-erbB2, and epidermal growth factor receptor (EGFR). No specific tumor markers have been identified consistently in oral leukoplakias and the available studies show wide variations in their expression. Materials and Methods: A total of eighty cases were taken up for study which included forty cases of leukoplakia and forty cases of squamous cell carcinomas (SCCs). Results: There was a significant correlation between the expression of markers p53 and EGFR in leukoplakia and SCC. The expression of p53 was correlated between leukoplakia, SCC, and control and was found to be significant (P ≤ 0.001). Similarly, EGFR expression was significant (P ≤ 0.001) between cases of leukoplakia, SCCs, and controls. c-erbB2 was found to be negative though cytoplasmic positivity was observed in a few cases. Similarly, in SCCs, it was observed that lesser the differentiation, more is the expression of both p53 and EGFR. Similarly, a definite correlation was observed between p53 and EGFR (P ≤ 0.001) but not with c-erbB2 (P ≤ 1.000). Conclusion: Thus, the author concludes that p53 and EGFR are useful biomarkers for the diagnosis of leukoplakia and their risk of malignant transformation.

// Fei Miao 1 , Mengmeng Zhang 1 , Yuechao Zhao 1 , Xiaolu Li 1 , Rongyan Yao 1 , Fan Wu 1 , Rong Huang 1 , Kai Li 1 , Shiying Miao 1 , Changwu Ma 4 , Hongge Ju 2, 3 , Wei Song 1 , Linfang Wang 1 1 Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100005, China 2 Department of Pathology, Baotou Medical College, Baotou 014040, China 3 Department of Pathology, The First Affiliated Hospital of Baotou Medical College, Baotou 014010, China 4 Department of Medical Oncology, Chifeng Municipal Hospital, Chifeng 024000, China Correspondence to: Changwu Ma, email: docmachangwu@126.com Hongge Ju, email: juhongge1088@163.com Wei Song, email: songwei@ibms.pumc.edu.cn Keywords: colorectal cancer, EGFR, RHBDD1, AP-1, c-Jun Received: September 02, 2016 Accepted: January 24, 2017 Published: February 25, 2017 ABSTRACT Our previous study showed that RHBDD1 can activate the EGFR signaling pathway to promote colorectal cancer growth. In the present study, EGFR was decreased when RHBDD1 was knocked down or inactivated. Further analysis found that c-Jun and EGFR protein expression was decreased in RHBDD1 knockdown and inactivated cells. c-Jun overexpression in RHBDD1-inactivated cells rescued EGFR expression in a dose-dependent manner. RHBDD1 overexpression in RHBDD1-inactivated cells restored EGFR expression, but this effect was counteracted by c-Jun knockdown. Furthermore, EGFR and c-Jun were attenuated in the RHBDD1 knockdown and inactivated groups in animal tumor models. Tissue microarray assays demonstrated a correlation between RHBDD1 and EGFR in colorectal cancer patients. Therefore, our findings indicate that RHBDD1 stimulates EGFR expression by promoting the AP-1 pathway.

The epidermal growth factor receptor (EGFR) located in dorsal root ganglion has been found as a new target for chronic pain treatment. However, it is not clear whether the change of EGFR expression in the dorsal root ganglion contributes to neuropathic pain development. In this study, we used a chronic compression of unilateral lumbar dorsal root ganglions (CCD)-induced rat neuropathic pain model and found that CCD caused the upregulation of both phosphorylated EGFR and total EGFR expression in compressed lumbar 4/5 (L4/L5) dorsal root ganglions by western blotting and immunohistochemistry methods. Either inhibition of EGFR activation by EGFR inhibitor or knockdown of EGFR expression by EGFR small interference RNA (siRNA) relieved CCD-induced pain hypersensitivities to mechanical, thermal, and cold stimuli in rats. Moreover, EGFR knockdown reversed CCD-induced the increase of intracellular mammalian target of rapamycin (mTOR) expression as well as the activation of the satellite glial cells in the ipsilateral compressed L4/L5 dorsal root ganglions. These findings suggest that not only activated EGFR but also total EGFR contribute to CCD-induced neuropathic pain by enhancing intracellular mTOR signaling.

The majority of borderline ovarian tumours (BOTs) behave in a benign fashion, but some may show aggressive behavior. The reason behind this has not been elucidated. The epidermal growth factor receptor (EGFR) is known to contribute to cell survival signals as well as metastatic potential of some tumours. EGFR expression and gene status have not been thoroughly investigated in BOTs as it has in ovarian carcinomas. In this study we explore protein expression as well as gene mutations and amplifications of EGFR in BOTs in comparison to a subset of other epithelial ovarian tumours. We studied 85 tumours, including 61 BOTs, 10 low grade serous carcinomas (LGSCs), 9 high grade serous carcinomas (HGSCs) and 5 benign epithelial tumours. EGFR protein expression was studied using immunohistochemistry. Mutations were investigated by Sanger sequencing exons 18-21 of the tyrosine kinase domain of EGFR. Cases with comparatively higher protein expression were examined for gene amplification by chromogenic in situ hybridization. We also studied the tumours for KRAS and BRAF mutations. Immunohistochemistry results revealed both cytoplasmic and nuclear EGFR expression with variable degrees between tumours. The level of nuclear localization was relatively higher in BOTs and LGSCs as compared to HGSCs or benign tumours. The degree of nuclear expression of BOTs showed no significant difference from that in LGSCs (mean ranks 36.48, 33.05, respectively, p=0.625), but was significantly higher than in HGSCs (mean ranks: 38.88, 12.61 respectively, p< 0.001) and benign tumours (mean ranks: 35.18, 13.00 respectively, p= 0.010). Cytoplasmic expression level was higher in LGSCs. No EGFR gene mutations or amplification were identified, yet different polymorphisms were detected. Five different types of point mutations in the KRAS gene and the V600E BRAF mutation were detected exclusively in BOTs and LGSCs. Our study reports for the first time nuclear localization of EGFR in BOTs. The nuclear localization similarities between BOTs and LGSCs and not HGSCs support the hypothesis suggesting evolution of LGSCs from BOTs. We also confirm that EGFR mutations and amplifications are not molecular events in the pathogenesis of BOTs.

Purpose: Although controversial, assessment of epidermal growth factor receptor (EGFR) expression is required for the approved indications of Cetuximab in metastatic colorectal cancer (mCRC). With the objective of improving patient selection, “ERBITUX-OUEST” study aimed at analyzing EGFR status in a large cohort of mCRC patients who received cetuximab without preliminary EGFR screening, and assessing the correlation between EGFR status and response to treatment retrospectively. Patients and methods: 332 patients treated with Irinotecan Cetuximab based regimen after progression on irinotecan or oxaliplatin therapy were included. EGFR status was assessed using three available immunohistochemistry (IHC) tests and in situ hybridization in case of negativity. Clinical outcomes of EGFR-positive and EGFR-non-detected (or considered as negative with at least one test) patients were compared. Results: Of the 332 samples centrally screened, 194 were classified as full-positive (i.e., EGFR-positive for all three tests), 86 as full-negative, and 52 as discordant. One third of the 131 negative samples with FDA approved test should be reclassified as positive with at least one of the two others tests. Regarding results from FDA approved test only, neither objective response rate (ORR), progression-free survival (PFS) nor overall survival (OS) differed significantly between EGFR-negative and EGFR-positive patients (P = 0.788, 0.326 and 0.888, respectively). Similarly, comparison of full-negative to other groups did not show any significant difference in terms of ORR (P = 0.507), PFS (P = 0.222) or OS (P = 0.686). Conclusion: These data strongly argue against mCRC patients selection for Cetuximab treatment based on EGFR expression as measured by currently available IHC technics.

The digestive system is an important energy supply system in human body. It can transform the nutrients in food into the energy of human life activities. In special cases, it can convert nutrients into body fat for storage. The appearance of digestive system tumor is a bad disease. It can lead to the loss of tongue coating cells and various complications[1]. According to the experimental theory of medicine, by observing the expression of EGFR in the exfoliated cells of tongue coating and the content of EGF in saliva of patients with tumor of digestive system, we can find the relationship between EGF and the changes of tongue coating cells of patients. Through the way of experiment, we can draw the corresponding conclusion. I think this conclusion will also provide theoretical help for the treatment of cancer-related diseases of digestive system in medicine.

The epidermal growth factor receptor (EGFR) gene is frequently altered in a variety of cancer types, with mutation and/or amplification occurring in approximately 57% of glioblastoma (GBM), 47% of non-small-cell lung cancer (NSCLC) and 31% of cancers of the head and neck (HNSCC). In these cancers EGFR protein overexpression is detectable in as much as 45%, 89% and 84% of these tumors respectively. This data suggests that transcriptional control of EGFR expression contributes to high EGFR protein levels in NSCLC and HNSCC, and may be a novel target to control EGFR expression in other dependent malignancies. In GBM, in which there is a stronger correlation between EGFR copy number and expression, targeting EGFR transcription may also be a viable approach for targeting tumors with high EGFR irrespective of copy number. Epigenetic mechanisms are critical for transcriptional regulation, however studies investigating the mechanisms regulating EGFR transcription are limited. Here we identify two novel super enhancers present in the first intron of the EGFR gene that we have termed EGFR super enhancers 1 and 2 (SE1, SE2). SE1 and SE2 span 37kb and 33kb respectively, contain H3K27Ac enhancer histone marks in NSCLC, GBM and HNSCC cells that functionally enhance transcription in reporter assays, and negatively impact EGFR transcript levels when perturbed by CRISPR/Cas9 guided deletion. Using locally-generated ATAC-seq and transcription factor ChIP-seq from the ENCODE consortium we have identified putative binding sites for AP-1 transcription factor subunits in critical constituent enhancers within SE1 and SE2. Disrupting the binding of these transcription factors through site directed mutagenesis negatively impacts the enhancer function in reporter assays. Our results identify and characterize these novel enhancers, shedding light on the role that epigenetic mechanisms play in regulating EGFR transcription in EGFR-dependent cancer types and presents a novel angle by which these malignancies can be treated.

Objective: to evaluate the expression of the epithelial growth factor receptor (EGFR) by immunohistochemistry, and to verify its association with prognostic factors and survival of patients operated by cholangiocarcinoma. Methods: we verified the immunohistochemical expression of EGFR in 35 surgical specimens of cholangiocarcinoma (CCA). We obtained survival curves with the Kaplan-Meier method. Results: we found significant EGFR expression in ten (28.6%) of the 35 CCAs, eight with score 3 and two with score 2. Advanced stages (III and IV) presented higher EGFR expression (p=0.07). The clinical characteristics that were most associated with positive EGFR expression were female gender (p=0.06) and absence of comorbidities (p=0.06). Overall survival at 12, 24, 36 and 48 months was 100%, 82.5%, 59% and 44.2%, respectively. The survival of EGFR positive patients at 12, 24, 36 and 48 months was 100%, 75%, 50% and 0%, whereas for negative EGFR patients it was 100%, 87.5%, 65.6% and 65.6%, respectively. Conclusion: EGFR expression occurred in 28.6% of the cases studied and was associated with lower survival. RESUMO Objetivo: avaliar a expressão do receptor do fator de crescimento epitelial (EGFR) por meio de imuno-histoquímica, e verificar sua associação com fatores prognósticos e com a sobrevida dos pacientes operados por colangiocarcinoma. Métodos: a expressão imuno-histoquímica de EGFR foi verificada em 35 peças cirúrgicas de colangiocarcinomas (CCA). Curvas de sobrevida foram obtidas pelo método de Kaplan-Meier. Resultados: expressão significativa de EGFR foi encontrada em dez (28,6%) de 35 CCA, oito com escore 3 e dois com escore 2. Estágios avançados (III e IV) apresentaram maior expressão de EGFR (p=0,07). As características clínicas que mais estiveram associadas com a expressão positiva de EGFR foram o sexo feminino (p=0,06) e ausência de comorbidades (p=0,06). A sobrevida global aos 12, 24, 36 e 48 meses foi de 100%, 82,5%, 59% e 44,2%, respectivamente. A sobrevida de pacientes EGFR positivos aos 12, 24, 36 e 48 meses foi de 100%, 75%, 50% e 0%, enquanto que para EGFR negativos foi de 100%, 87,5%, 65,6% e 65,6%, respectivamente. Conclusão: a expressão do EGFR ocorreu em 28,6% dos casos estudados e esteve associada a menor sobrevida.

To investigate the ability of CT texture analysis to assess and predict the expression statuses of E-cadherin, Ki67, VEGFR2 and EGFR in gastric cancers, the enhanced CT images of 139 patients with gastric cancer were retrospectively reviewed. The region of interest was manually drawn along the margin of the lesion on the largest slice in the arterial and venous phases, which yielded a series of texture parameters. Our results showed that the standard deviation, width, entropy, entropy (H), correlation and contrast from the arterial and venous phases were significantly correlated with the E-cadherin expression level in gastric cancers (all P

Aim: Zirconium-89 has gained great interest for PET, when imaging at late time points is required. Desferrioxamine B (DFO), is mostly used for this radionuclide as bifunctional chelator (BFC) and w ...

Background Aspirin intake reduces the risk of colorectal cancer (CRC), but the molecular underpinnings remain elusive. Epidermal growth factor receptor (EGFR), which is overexpressed in about 80% of CRC cases, is implicated in the etiology of CRC. Here, we investigated whether aspirin can prevent CRC by normalizing EGFR expression. Methods Immunohistochemistry staining was performed on paraffin-embedded tissue sections from normal colon mucosa, adenomatous polyps from FAP patients who were classified as regular aspirin users or nonusers. The interplay between cyclooxygenase-2 (COX-2) and EGFR was studied in primary intestinal epithelial cells isolated from ApcMin mice, immortalized normal human colon epithelial cells (HCECs) as well as murine embryonic fibroblasts (MEFs). Results Immunohistochemistry staining results established that EGFR overexpression is an early event in colorectal tumorigenesis, which can be greatly attenuated by regular use of aspirin. Importantly, EGFR and COX-2 were co-overexpressed and co-localized with each other in FAP patients. Further mechanistic studies revealed that COX-2 overexpression triggers the activation of the c-Jun-dependent transcription factor, activator protein-1 (AP-1), which binds to the Egfr promoter. Binding facilitates the cellular accumulation of EGFR and lowers the threshold required for pre-neoplastic cells to undergo transformation. Conclusion Aspirin might exert its chemopreventive activity against CRC, at least partially, by normalizing EGFR expression in gastrointestinal precancerous lesions., Highlights • CRC progression is accompanied by an elevation in EGFR levels, which can be attenuated by aspirin intake. • The widespread overexpression of EGFR occurs as a consequence of COX-2 activation in FAP patients. • This study revealed a functional association between COX-2 and EGFR expression during colorectal carcinogenesis.

Biomarkers predicting treatment response to the monoclonal antibody cetuximab in locally advanced head and neck squamous cell carcinomas (LAHNSCC) are lacking. We hypothesize that tumor accessibility is an important factor in treatment success of the EGFR targeting drug. We quantified uptake of cetuximab labeled with Zirconium-89 (89Zr) using PET/CT imaging. Seventeen patients with stage III-IV LAHNSCC received a loading dose unlabeled cetuximab, followed by 10 mg 54.5±9.6 MBq 89Zr-cetuximab. PET/CT images were acquired either 3 and 6 or 4 and 7 days post-injection. 89Zr-cetuximab uptake was quantified using standardized uptake value (SUV) and tumor-to-background ratio (TBR), and correlated to EGFR immunohistochemistry. TBR was compared between scan days to determine optimal timing. Uptake of 89Zr-cetuximab varied between patients (day 6-7: SUVpeak range 2.5-6.2). TBR increased significantly (49±28%, p < 0.01) between first (1.1±0.3) and second scan (1.7±0.6). Between groups with a low and high EGFR expression a significant difference in SUVmean (2.1 versus 3.0) and SUVpeak (3.2 versus 4.7) was found, however, not in TBR. Data is available at www.cancerdata.org (DOI: 10.17195/candat.2016.11.1). In conclusion, 89Zr-cetuximab PET imaging shows large inter-patient variety in LAHNSCC and provides additional information over FDG-PET and EGFR expression. Validation of the predictive value is recommended with scans acquired 6-7 days post-injection.

The epidermal growth factor receptor (EGFR) serves as an attractive target for cancer molecular imaging and therapy. Our previous positron emission tomography (PET) studies showed that the EGFR-targeting affibody molecules (64)Cu-DOTA-ZEGFR:1907 and (18)F-FBEM-ZEGFR:1907 can discriminate between high and low EGFR-expression tumors and have the potential for patient selection for EGFR-targeted therapy. Compared with (64)Cu, (18)F may improve imaging of EGFR-expression and is more suitable for clinical application, but the labeling reaction of (18)F-FBEM-ZEGFR:1907 requires a long synthesis time. The aim of the present study is to develop a new generation of (18)F labeled affibody probes (Al(18)F-NOTA-ZEGFR:1907 and (18)F-CBT-ZEGFR:1907) and to determine whether they are suitable agents for imaging of EGFR expression. The first approach consisted of conjugating ZEGFR:1907 with NOTA and radiolabeling with Al(18)F to produce Al(18)F-NOTA-ZEGFR:1907. In a second approach the prosthetic group (18)F-labeled-2-cyanobenzothiazole ((18)F-CBT) was conjugated to Cys-ZEGFR:1907 to produce (18)F-CBT-ZEGFR:1907. Binding affinity and specificity of Al(18)F-NOTA-ZEGFR:1907 and (18)F-CBT-ZEGFR:1907 to EGFR were evaluated using A431 cells. Biodistribution and PET studies were conducted on mice bearing A431 xenografts after injection of Al(18)F-NOTA-ZEGFR:1907 or (18)F-CBT-ZEGFR:1907 with or without coinjection of unlabeled affibody proteins. The radiosyntheses of Al(18)F-NOTA-ZEGFR:1907 and (18)F-CBT-ZEGFR:1907 were completed successfully within 40 and 120 min with a decay-corrected yield of 15% and 41% using a 2-step, 1-pot reaction and 2-step, 2-pot reaction, respectively. Both probes bound to EGFR with low nanomolar affinity in A431 cells. Although (18)F-CBT-ZEGFR:1907 showed instability in vivo, biodistribution studies revealed rapid and high tumor accumulation and quick clearance from normal tissues except the bones. In contrast, Al(18)F-NOTA-ZEGFR:1907 demonstrated high in vitro and in vivo stability, high tumor uptake, and relative low uptake in most of the normal organs except the liver and kidneys at 3 h after injection. The specificity of both probes for A431 tumors was confirmed by their lower uptake on coinjection of unlabeled affibody. PET studies showed that Al(18)F-NOTA-ZEGFR:1907 and (18)F-CBT-ZEGFR:1907 could clearly identify EGFR positive tumors with good contrast. Two strategies for (18)F-labeling of affibody molecules were successfully developed as two model platforms using NOTA or CBT coupling to affibody molecules that contain an N-terminal cysteine. Al(18)F-NOTA-ZEGFR:1907 and (18)F-CBT-ZEGFR:1907 can be reliably obtained in a relatively short time. Biodistribution and PET studies demonstrated that Al(18)F-NOTA-ZEGFR:1907 is a promising PET probe for imaging EGFR expression in living mice.

Introduction: The phase III FLEX study (NCT00148798) in advanced non-small-cell lung cancer indicated that the survival benefit associated with the addition of cetuximab to cisplatin and vinorelbine was limited to patients whose tumors expressed high lev- els of epidermal growth factor receptor (EGFR) (immunohistochem- istry score of ≥200; scale 0-300). We assessed whether the treatment effect was also modulated in FLEX study patients by tumor EGFR mutation status. Methods: A tumor mutation screen of EGFR exons 18 to 21 included 971 of 1125 (86%) FLEX study patients. Treatment outcome in low and high EGFR expression groups was analyzed across efficacy end- points according to tumor EGFR mutation status. Results: Mutations in EGFR exons 18 to 21 were detected in 133 of 971 tumors (14%), 970 of which were also evaluable for EGFR expression level. The most common mutations were exon 19 dele- tions and L858R (124 of 133 patients; 93%). In the high EGFR expression group (immunohistochemistry score of ≥200), a survival benefit for the addition of cetuximab to chemotherapy was demon- strated in patients with EGFR wild-type (including T790M mutant) tumors. Although patient numbers were small, those in the high EGFR expression group whose tumors carried EGFR mutations may also have derived a survival benefit from the addition of cetuximab to chemotherapy. Response data suggested a cetuximab benefit in the high EGFR expression group regardless of EGFR mutation status. Conclusions: The survival benefit associated with the addition of cetuximab to first-line chemotherapy for advanced non-small-cell lung cancer expressing high levels of EGFR is not limited by EGFR mutation status.

The humanized monoclonal antibody with high affinity for the human epidermal growth factor receptor (HER) 3, RG7116, is a glycoengineered, IgG1 class antibody. By labeling RG7116 with zirconium-89 (Zr-89) we aimed to visualize in vivo HER 3 expression and study the biodistribution of this antibody in human tumor-bearing mice. Biodistribution of 89Zr-RG7116 was studied in subcutaneously xenografted FaDu tumor cells (HER 3-positive). Dose-dependency of Zr-89-RG7116 organ distribution and specific tumor uptake was assessed by administering doses ranging from 0.05 to 10 mg/kg RG7116 to SCID/Beige mice. Biodistribution was analyzed at 24 and 144 h after injection. MicroPET imaging was performed at 1, 3, and 6 days after injection of 1.0 mg/kg Zr-89-RG7116 in the FaDu, H441, QG-56 and Calu-1 xenografts with varying HER 3 expression. The excised tumors were analyzed for HER 3 expression. Biodistribution analyses showed a dose-and time-dependent Zr-89-RG7116 tumor uptake in FaDu tumors. The highest tumor uptake of Zr-89-RG7116 was observed in the 0.05 mg/kg dose group with 27.5% ID/g at 144 h after tracer injection. MicroPET imaging revealed specific tumor uptake of Zr-89-RG7116 in FaDu and H441 models with an increase in tumor uptake over time. Biodistribution data was consistent with the microPET findings in FaDu, H441, QG56 and Calu-1 xenografts, which correlated with HER 3 expression levels. In conclusion, Zr-89-RG7116 specifically accumulates in HER 3 expressing tumors. PET imaging with this tracer provides realtime non-invasive information about RG7116 distribution, tumor targeting and tumor HER 3 expression levels.

Background JFCM, an open-label, multicenter, phase 1b/2 study (n = 181), demonstrated that addition of necitumumab (N) to gemcitabine and cisplatin (GC) resulted in significant improvement in overall survival (OS; hazard ratio [HR] = 0.66) in the first-line treatment of advanced squamous non-small cell lung cancer (NSCLC) patients in Japan. Previous studies have suggested that rash, EGFR expression, and EGFR copy number gain might be associated with the efficacy of EGFR-targeting drugs in the treatment of squamous NSCLC. Methods Our analysis assessed: development of acne-like rash in the first cycle; EGFR expression (evaluated by H-score of immunohistochemistry, H ≥ 200 vs H Results Of the 90 patients in the GC+N arm, 80 (88.9%) had first-cycle rash. Median OS was 14.52 vs 15.93 months (HR = 1.39) in patients experiencing first-cycle rash vs those without rash in the GC+N arm. For EGFR expression, the majority of patients had H Conclusion Our analysis did not identify first-cycle rash, EGFR expression, and EGFR copy number gain as predictive markers of survival in JFCM study. (Trial Registration Number: NCT01763788)

The original version of this article contained a mistake in the first paragraph of "Cell uptake and internalization of 18F-FB-ME07" section. The text "The specific activity was 7.4-14.8 kBq/nmol" should have been "The specific activity was 7.4-14.8 Mbq/nmol".

Die Therapieerfolge bei metastasierten Plattenepithelkarzinomen sind schlecht. Bei vermehrt nachgewiesener EGF-Rezeptorexpression setzte man bei Kopf-Hals-Tumoren und dem nicht kleinzelligen Bronchialkarzinom bereits gegen den EGF-Rezeptor gerichtete Targets in Kombination mit einer Chemotherapie oder Radiatio ein und konnte teilweise eine deutliche Verbesserung des Tumoransprechens wie auch eine Verlangerung des Uberlebens erzielen. Beim Peniskarzinom gibt es bisher keine Untersuchung zum Rezeptorstatus. Retrospektiv untersuchten wir daher unser Patientengut der letzten 14 Jahren hinsichtlich der EGFR-Expression und stellten dieser den klinischen Verlauf der Patienten gegenuber. In die klinische Auswertung gingen 45 Patienten ein, die im Zeitraum von 1990–2004 primar oder sekundar an der Urologischen Universitatsklinik Essen behandelt wurden. Von 44 Patienten standen histologische Blocke des Primartumors, von Metastasen oder beidem zur Verfugung. Mittels immunhistochemischer EGFR-Farbung erfolgte der Nachweis der Antigenexpression. Primar ohne lymphogene Metastasierung waren 25 Patienten (6-mal cN0 und 19-mal pN0), wahrend 20 Patienten primar pathologisch gesicherte Lymphknotenmetastasen aufwiesen, 3 zudem hamatogene Filiae. Von 42 Patienten mit Verlauf leben 18, davon hatten nur 3 primar einen Lymphknotenbefall. Sie erhielten nach der Resektion eine adjuvante Chemotherapie. Von den restlichen 15 primaren N0-Patienten entwickelten 4 im Verlauf ein lymphogenes Rezidiv, das ebenfalls operiert wurde und in 3 Fallen adjuvant chemotherapiert wurde. 24 Patienten sind verstorben, 22 davon am Peniskarzinom; 16 der 22 Patienten hatten primar einen Lymphknotenbefall, 5 zudem einen ausgedehnten Lokalbefund. Auch hier bestand die Behandlung primar in operativen Masnahmen, 10 Patienten erhielten zudem eine Chemotherapie. Trotzdem kam es bei 15 Patienten wiederholt zu Lokalrezidiven. Bei der Unterteilung in primar lymphknotennegative und -positive Patienten zeigte die Kaplan-Meier-Uberlebenskurve einen signifikanten Unterschied (p

Aldosterone plays a key role in cardiovascular and renal injury. The underlying mechanisms are not completely understood. Because the epidermal growth factor receptor (EGFR) is involved in the development of fibrosis and vascular dysfunction, upregulation of EGFR expression by aldosterone-bound mineralocorticoid receptor (MR) is an attractive hypothesis. We investigated the effect of aldosterone on EGFR expression in the aorta of adrenalectomized rats and in human aorta smooth muscle cells (HAoSMC) in primary culture. Aldosterone, but not dexamethasone, stimulated EGFR expression in vivo in the aorta as well as in HAoSMC. EGFR degradation was not affected. Aldosterone-induced EGFR expression in HAoSMC was dose dependent and prevented by spironolactone. Furthermore, incubation of HAoSMC with aldosterone led to enhanced EGF-induced ERK1/2 phosphorylation and an EGFR-dependent increase in media fibronectin. EGFR promoter reporter gene assay as well as chromatin immunoprecipitation data indicate that MR interacts with the EGFR promoter. With deletion constructs we gained evidence that this interaction takes place between the hMR and the EGFR promoter regions 316–163 (stronger activation site, EC50∼1.0 nM) and 163–1 (weaker activation site, EC50∼0.7 nM), which do not comprise canonical glucocorticoid response elements and are not activated by the human glucocorticoid receptor. The interactions require in part the NH2-terminal domains of MR. ELISA-based transcription factor DNA binding assay with in vitro synthesized hMR suggest direct binding to region 163–1. Our results indicate that aldosterone leads to enhanced EGFR expression via an interaction with the EGFR promoter, which is MR specific and could contribute to the aldosterone-induced increase in fibronectin abundance.

Background: In the growing field of tumor targeting, there is an urgent need to profile suitable molecular targets. In this study, CD44v6 and EGFR expression was quantified in samples of patients with head and neck squamous cell carcinoma (HNSCC) using a single-dose (SD) radioimmunoassay. Methods: The SD radioimmunoassay using 125I-chimeric monoclonal antibody (cMAb) U36 and 125I-cMAb cetuximab was first validated and then applied to quantify the expression of their target antigen molecules, CD44v6 and EGFR, in patient samples. Results were compared to immunohistochemical staining. Results: The SD assay provided sensitive quantitative values of the molecular targets studied, generally agreeing with the immunohistochemistry (IHC) results. The results indicated that expression of CD44v6 (0.2-20 nmol/μg membrane) was generally higher than that of EGFR (0.6-2.3 nmol/μg membrane) in the tumor samples analyzed, which corresponded to an average of 700,000 and 90,000 antigen molecules per cell, respectively. Conclusions: The SD radioimmunoassay is simple, reliable, and can be performed on a small amount (50 mg) of tissue. This assay could be a useful tool in the growing field of personalized cancer therapy, and can be used as a complement to IHC. In the tumors studied, CD44v6 was generally expressed at a higher level than EGFR, which might suggest that it could be more readily targeted by MAbs.

Meeting abstracts We generated a novel fully human anti-EGFR antibody showed lower toxicity and higher efficacy in the preclinical, toxicological and pharmacological studies when compared to a commercial drug Cetuximab. In this research, we aimed to understand the probably mechanism. Firstly, the

Objective: The present study aimed to investigate the pattern of expression of transforming growth factor & (TGF-&) and epidermal growth factor receptor (EGFR) in oral squamous cell carcinoma (OSCC) and to correlate their expression with tumor grading.Conclusion: This study showed that OSCC express both EGFR and TGF-& and their expression indicated that these markers may have a potential diagnostic value in histologic examination. In addition their increased expression in high tumour grades suggest that they may be used as indicators of tumor aggressiveness.