Evaluate Epidermal Growth Factor Receptor Expression Research Articles

EGFR expression and relapse in patients with melanoma receiving adjuvant PD-1-based immunotherapy.

e21566 Background: Since 2018, adjuvant immune checkpoint inhibitors (ICI) have been available for patients with resected stage III/IV melanoma. The Checkmate 238 and Keynote 054 studies showed a survival benefit in patients receiving adjuvant ICI. However, there is no validated biomarker to identify patients at high risk of relapse, despite receiving adjuvant therapy. Here we investigated resistance patterns to immune checkpoint inhibition in the adjuvant setting. Methods: In this cohort study, a discovery cohort of 30 patients from the Department of Dermatology, University Hospital Zürich, was used to evaluate resistance patterns to adjuvant ICI. A second cohort of 107 patients from the Department of Dermatology, University Hospital Tuebingen, was used to validate the findings. We measured epidermal growth factor receptor (EGFR) expression in primary tumor and metastatic tissue by immunohistochemistry and digital pathology using QuPath. The primary endpoint was relapse-free survival. Results: We included 137 patients with melanoma receiving adjuvant ICI: 63 (46%) were females, and 52 (38%) patients harbored a BRAFV600 mutation. The median follow-up was 45 and 39 months in the Zürich and Tuebingen cohorts, respectively (95% confidence interval (CI) 41.8-48.2 and 36.8-41.2, respectively). The two cohorts were homogenous in terms of patients' and tumor characteristics, except for the relapse rate, which was significantly higher in the Tuebingen cohort ( p< 0.002). 71 (52%) therapy naïve in transit or lymph node metastasis and 23 (17%) primary tumors were available to evaluate EGFR expression by immunohistochemistry and digital pathology using QuPath. Surprisingly, in both cohorts, patients with high EGFR expression in metastatic tissue had a significantly higher relapse rate than patients with low EGFR expression ( p= 0.0004 and p= 0.0168 for the Zürich and Tuebingen cohorts, respectively). EGFR expression in primary tumors did not correlate with relapse-free survival ( p= 0.7286). Next-generation sequencing revealed that EGFR expression assessed by immunohistochemistry was not associated with the presence of EGFR mutations and/or amplifications. Conclusions: Currently, there are no validated biomarkers to identify patients with melanoma at high risk of recurrence, despite receiving adjuvant ICI. We found in two independent cohorts that EGFR expression in therapy naive metastatic tissue is positively associated with relapse in patients receiving adjuvant ICI. Our data identified EGFR as a prognostic biomarker that can easily be assessed by immunohistochemistry, allowing us to stratify patients for adjuvant ICI therapy according to their risk of relapse. Stratification according to EGFR expression should be considered in future clinical trials in the adjuvant setting.

Abstract P1-13-18: EGFR signaling contributes to acquired resistance to CDK4/6 inhibitors in ER+ breast cancer cells in vitro and in vivo

Abstract Breast cancer driven by different hormone receptors, including estrogen receptor (ER+), is responsible for approximately 70-80% of cases among women. While endocrine therapy (ET) of ER+ primary tumors with antiestrogens or aromatase inhibitors is an effective first-line therapy, its success is limited by intrinsic and acquired resistance. Response to ET can be limited due to overexpression of cyclin D1, which promotes the activation of cyclin-dependent kinases 4 and 6 (CDK4/6). Selective inhibition of CDK4/6 and ER signaling is now standard-of-care therapy for ER+ metastatic breast cancer. CDK4/6 inhibitors (CDK4/6i), including palbociclib (PD), ribociclib, and abemaciclib, used in combination with ET, have shown improvement in progression-free survival compared to ET alone in the metastatic setting. However, the inevitable development of acquired resistance significantly limits the efficacy of this targeted therapy. Rewired signaling driven by different oncogenes, including the epidermal growth factor receptor (EGFR), overcomes the targeted inhibition of CDK4/6, which, in turn, allows cell cycle progression contributing to acquired resistance. We evaluated the expression and activity of EGFR in the panel of different matching pairs of ER- and ER+ CDK4/6i-sensitive (pS) and CDK4/6i-resistant (pR) breast cancer cell lines in vitro. Increased EGFR expression in ER+ MCF7/pR cells correlated with elevated ER phosphorylation, suggesting a direct cross-talk between EGFR and ER signaling in PD-resistant cells. Stimulation with EGF promoted ER activation, whereas estrogen stimulation promoted EGFR activation in ER+ pS and pR cell lines, indicating a direct cross-regulation between these molecular targets. Treatment of MCF7/pR cells with CDK4/6i resulted in elevated EGFR mRNA expression, confirming the dependency of resistant cells on EGFR signaling. Moreover, exposure to the EGFR inhibitors dramatically inhibited the proliferation of MCF7/pR cells compared to the parental cells, suggesting that EGFR could be an essential bypass signaling regulator contributing to resistance to CDK4/6i. We found that combined treatment with EGFRi and CDK4/6i significantly inhibited Rb phosphorylation in pR cells improving the effect of CDK4/6i on cell cycle arrest. We evaluated EGFR expression in MCF7/pS and pR mouse xenograft models in vivo. We observed a significant elevation in EGFR expression and phosphorylation in response to PD treatment, confirming the importance of EGFR signaling in maintaining the acquired resistance to CDK4/6i in ER+ breast cancer cells. Taken together, our findings suggest that EGFR signaling plays an important role in acquired resistance to CDK4/6i in ER+ breast cancer cells in vitro and in vivo and targeting EGFR with small-molecule inhibitors (like erlotinib or gefitinib) or chimeric monoclonal antibodies (i.e. cetuximab) can be a promising approach to improve CDK4/6i efficacy in breast cancer patients. Citation Format: Nadiia Lypova, Lilibeth Lanceta, Susan Daugherty, Jason Chesney, Yoannis Imbert-Fernandez. EGFR signaling contributes to acquired resistance to CDK4/6 inhibitors in ER+ breast cancer cells in vitro and in vivo. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-13-18.

Role of Epidermal Growth Factor Receptor in Gallbladder Carcinoma and its Association with Various Clinicopathological Parameters: A Cross-sectional Study

Introduction: Carcinoma of gallbladder is an aggressive disease with poor outcome. The Epidermal Growth Factor Receptor (EGFR) is a transmembrane receptor that regulate growth, proliferation and differentiation in cells. Increased EGFR receptor expression has been studied in various cancers like lung, colorectal, breast and pancreatic tumours and antiEGFR antibody has been used successfully for therapeutic and diagnostic purposes. Aim: To evaluate EGFR expression in gallbladder carcinoma and its association with clinicopathological factors to reveal its relation to prognosis. Methods and Methods: The present study was a crosssectional study in which 64 samples were collected of resected specimen of Gallbladder Carcinoma (GBC), from the Department of Pathology, King George’s Medical University, Lucknow, Uttar Pradesh, India, for a period of one year and six months. Haematoxylin-eosin-stained sections were evaluated for tumour type and histopathological grading and TNM staging was done. Immunohistochemistry (IHC) was performed and analysed prospectively using ready to use anti-EGFR as per manufacturer’s protocols. Association between EGFR expression and clinicopathological factors were statistically analysed using Statistical Package for the Social Sciences (SPSS) software version 21.0. Results: EGFR expression was positive in 81.25% (52/64) cases of GBC which showed a highly significant association between tumour grade and stage. About 60% of poorly differentiated GBC displayed strong (3+) staining intensity as compared to 30% of moderately differentiated (3+) and 10% of well differentiated tumours (3+). It suggests that with decreasing differentiation of tumour EGFR staining intensity increases (p<0.001). Positivity rate of EGFR expression were also increased with increase of tumour TNM stage (stage I to stage IV). Strong EGFR expression was associated with decreased overall survival with significant p value (p=0.031, log rank test). Conclusion: EGFR expression is inversely related with tumour differentiation, and overall survival. EGFR expression increases with high TNM staging. So, it can be used as prognostic marker for gallbladder carcinoma and opening a hope towards the new therapeutic options

EGFR Overexpression and Sequence Analysis of KRAS, BRAF, and EGFR Mutation Hot Spots in Canine Intestinal Adenocarcinoma.

Epidermal growth factor receptor (EGFR) is overexpressed in many human colorectal cancers and anti-EGFR agents are employed as immunotherapies. However, KRAS, EGFR, and BRAF gene mutations can influence the activity of the anti-EGFR agents. We evaluated EGFR expression at protein and mRNA levels in canine intestinal adenocarcinomas using immunohistochemistry (IHC) and RNA in situ hybridization (RNA-ISH). We also investigated the mutation status of EGFR, KRAS, and BRAF to aid the development of anti-EGFR agents for canine intestinal adenocarcinoma. EGFR expression was highest in adenocarcinoma, followed by intramucosal neoplasia (adenoma and in situ carcinoma), and nonneoplastic canine intestinal tissue, at both protein (P = .000) and mRNA (P = .005) levels. The EGFR, KRAS, and BRAF genes showed wild-type sequences at the mutation hot spots in all 13 specimens. Thus, EGFR might serve as a promising diagnostic marker in canine intestinal adenocarcinoma, and further studies would be needed to develop EGFR-targeted anticancer therapies.

Prognostic Significance of Epidermal Growth Factor Receptor Expression in Distant Metastatic Melanoma from Primary Cutaneous Melanoma.

BackgroundEpidermal growth factor receptor (EGFR) is overexpressed in many cancers. However, EGFR expression in melanoma and its role are conflicting.ObjectiveThis study aimed to evaluate EGFR expression in distant metastatic melanoma and analyze its relationship with histologic and clinical characteristics and survival.MethodsDiagnostic tissues from 55 cases of distant metastatic melanoma was evaluated by immunohistochemistry for EGFR expression. Clinicopathologic features and survival outcomes were analyzed according to EGFR expression.ResultsThe positive EGFR expression in distant metastatic melanoma was significantly correlated with the absence of ulceration. The EGFR expression in distant metastatic melanoma was significantly associated with poor survival, under the conditions of male sex and primary cutaneous melanoma without ulceration or Breslow thickness ≤4.0 mm. This study bears limitations of a retrospective study in a single institution.ConclusionEGFR immunostaining had predictive values for survival outcome. The EGFR expression in distant metastatic melanoma in male, no ulcer, or Breslow thickness ≤4.0 mm appeared to be involved in disease progression.

Expression, intracellular localization, and mutation of EGFR in conjunctival squamous cell carcinoma and the association with prognosis and treatment

Conjunctival squamous cell carcinoma (SCC) is primarily treated with surgical resection. SCC has various stages, and local recurrence is common. The purpose of this study was to determine molecular localization of epidermal growth factor receptor (EGFR) and the possibility of EGFR as a biomarker for the management of conjunctival SCC. In this retrospective study, we performed immunohistochemistry to evaluate EGFR expression and localization in tumor cells, EGFR mutation-specific expression (E746-A750del and L858R), and human papillomavirus expression in a series of 29 conjunctival SCCs. All 29 tumors in our cohort were EGFR positive (100%). Twenty-one of 29 tumors (72%) showed focal EGFR staining, and seven (28%) showed diffuse EGFR staining. In addition, we calculated the percentages of the two most important mutations in EGFR (exon 19 746-A750del (8/29, 27.5%), exon 21 (L858R mutant (2/29, 6.8%)) in conjunctival SCCs. We observed that the translocation of EGFR from the membrane into the cytoplasm was related to clinical prognosis, as we detected correlations between EGFR cytoplasmic staining and final orbital exenteration and between decreased EGFR membrane staining and progression-free survival. EGFR is important in the pathology of ocular surface squamous neoplasia including SCC and is a prognostic factor. Increased understanding of EGFR mutations may have important implications for future treatment options.

Patient-Derived Head and Neck Cancer Organoids Recapitulate EGFR Expression Levels of Respective Tissues and Are Responsive to EGFR-Targeted Photodynamic Therapy.

Patients diagnosed with head and neck squamous cell carcinoma (HNSCC) are currently treated with surgery and/or radio- and chemotherapy. Despite these therapeutic interventions, 40% of patients relapse, urging the need for more effective therapies. In photodynamic therapy (PDT), a light-activated photosensitizer produces reactive oxygen species that ultimately lead to cell death. Targeted PDT, using a photosensitizer conjugated to tumor-targeting molecules, has been explored as a more selective cancer therapy. Organoids are self-organizing three-dimensional structures that can be grown from both normal and tumor patient-material and have recently shown translational potential. Here, we explore the potential of a recently described HNSCC–organoid model to evaluate Epidermal Growth Factor Receptor (EGFR)-targeted PDT, through either antibody- or nanobody-photosensitizer conjugates. We find that EGFR expression levels differ between organoids derived from different donors, and recapitulate EGFR expression levels of patient material. EGFR expression levels were found to correlate with the response to EGFR-targeted PDT. Importantly, organoids grown from surrounding normal tissues showed lower EGFR expression levels than their tumor counterparts, and were not affected by the treatment. In general, nanobody-targeted PDT was more effective than antibody-targeted PDT. Taken together, patient-derived HNSCC organoids are a useful 3D model for testing in vitro targeted PDT.

Expression of epidermal growth factor receptor in squamous cell carcinoma of uterine cervix

Context: Cervical cancer is one of the most important cancer deaths among females. Epidermal growth factor receptor (EGFR) plays a role in cell differentiation, cell motility, neovascularization, invasion, metastasis, and resistance of cancer cells to chemotherapeutic agents and radiation. Tyrosine kinase inhibitors and anti-EGFR monoclonal antibodies have shown better response in various invasive tumors. Aims: The aim of the study is to evaluate EGFR expression in squamous cell carcinoma (SCC) of the cervix and to assess its relation to tumor characteristics. Settings and Design: This was a retrospective, case–control study. Subjects and Methods: Formalin-fixed paraffin-embedded tissues from 30 cases with SCC along with 20 age-matched cases with normal cervix as controls were obtained from the archives. EGFR expression was analyzed in both cases and controls. Statistical Analysis Used: The Chi-square test was used to compare and find the association between the variables. Statistical analysis was done using the IBM SPSS (IBM, Armonk, NY, USA) software and P 4 cm size. There was no association of EGFR expression with tumor grade, tumor stage, and lymph node metastasis. Conclusions: The present study showed that a significantly higher number of cases of invasive SCC of uterine cervix show increased EGFR expression. The EGFR expression is associated with tumor size.

Development and characterization of 89Zr-labeled panitumumab for immuno-positron emission tomographic imaging of the epidermal growth factor receptor.

The epidermal growth factor receptor (EGFR) is overexpressed in the majority of malignancies and has been associated with poor outcomes. Panitumumab, an anti-EGFR monoclonal antibody that binds to the extracellular binding domain of EGFR, is increasingly used with radiotherapy and chemotherapy but has associated toxicities. The purpose of this study was to develop and characterize a novel targeted imaging agent for the EGFR using radiolabeled panitumumab. Flow cytometry studies were performed to evaluate EGFR expression in several cell lines. Desferrioxamine-Bz-NCS (DFO) was conjugated to panitumumab and labeled with (89)Zr. Cell uptake studies were performed in four cell lines. For biodistribution studies and micro-positron emission tomography/computed tomography (PET/CT), mouse xenograft models were generated using the same cell lines. PET was performed, and tumors and select organs were harvested for biodistribution studies. Panitumumab was radiolabeled with (89)Zr with high radiochemical purity and specific activity and was found to be stable in serum. Cell binding studies demonstrated that radiotracer uptake in cells correlated with the degree of EGFR expression. MicroPET/CT imaging studies demonstrated a high intensity of (89)Zr-panitumumab in A431 and HCT 116 tumors in comparison with the EGFR-negative tumors. Biodistribution studies confirmed the results from the imaging studies. (89)Zr-panitumumab imaging of EGFR-positive tumors demonstrated levels of radiotracer uptake associated with EGFR expression.

Epidermal growth factor receptor expression and gene copy number analysis in gastric carcinoma samples from Chinese patients.

Epidermal growth factor receptor (EGFR) expression and gene copy number have been observed to be associated with a positive clinical response to EGFR inhibitors. The present study aimed to evaluate EGFR expression and gene copy number in samples of gastric carcinoma (GC) from Chinese patients. EGFR expression and gene copy number were detected using immunohistochemistry and fluorescence in situ hybridization, in tissue array slides containing 150 individual samples of GC tissue. The association between EGFR status, clinicopathological features and overall patient survival was analyzed. Out of the 150 cases of GC evaluated, 63 (42.00%) demonstrated weak EGFR expression and 20 (13.33%) demonstrated EGFR overexpression. EGFR expression was observed to be associated with tumor location (P<0.05). Out of 104 cases of GC, which produced a clear FISH signal, 6 (5.77%) exhibited EGFR gene amplification and 5 (4.80%) exhibited balanced polysomy. Patients exhibiting GC, who demonstrated weak EGFR expression, EGFR overexpression or increased EGFR gene copy number, possessed an unfavorable prognosis. Multivariate analysis revealed that EGFR expression, tumor/node/metastasis stage and tumor location were potential independent unfavorable prognostic factors for GC patients. In conclusion, EGFR overexpression, gene amplification and polysomy were observed in GC patients and were associated with an unfavorable prognosis. Evaluation of EGFR status may therefore facilitate the identification of a subset of GC patients sensitive to treatment with EGFR-targeted therapies.

A sensitive electrochemiluminescence cytosensor for quantitative evaluation of epidermal growth factor receptor expressed on cell surfaces

A sensitive electrochemiluminescence (ECL) strategy for evaluating the epidermal growth factor receptor (EGFR) expression level on cell surfaces was designed by integrating the specific recognition of EGFR expressed on MCF-7 cell surfaces with an epidermal growth factor (EGF)-funtionalized CdS quantum dots (CdSQDs)-capped magnetic bead (MB) probe. The high sensitivity of ECL probe of EGF-funtionalized CdSQD-capped-MB was used for competitive recognition with EGFR expressed on cell surfaces with recombinant EGFR protein. The changes of ECL intensity depended on both the cell number and the expression level of EGFR receptor on cell surfaces. A wide linear response to cells ranging from 80 to 4×106cellsmL−1 with a detection limit of 40cellsmL−1 was obtained. The EGF-cytosensor was used to evaluate EGFR expression levels on MCF-7 cells, and the average number of EGFR receptor on single MCF-7 cells was 1.35×105 with the relative standard deviation of 4.3%. This strategy was further used for in-situ and real-time evaluating EGFR receptor expressed on cell surfaces in response to drugs stimulation at different concentration and incubation time. The proposed method provided potential applications in the detection of receptors on cancer cells and anticancer drugs screening.

Epidermal Growth Factor Receptor Expression in Spindle Cell Carcinomas of the Head and Neck.

Spindle cell carcinoma (SpCC) is an uncommon head and neck squamous cell carcinoma (SCC) variant consisting of spindled and/or pleomorphic cells with epithelial differentiation. Epidermal growth factor receptor (EGFR) is expressed by >90 % of conventional SCC, and high level expression is associated with a poorer prognosis. Anti-EGFR therapies are commonly used to treat head and neck SCC. However, no studies have evaluated EGFR expression in SpCC. Cases of SpCC were retrieved from department files. The diagnosis required either a biphasic lesion with a squamous neoplastic component, or a purely spindle cell or pleomorphic tumor with immunohistochemical positivity for epithelial markers. EGFR immunohistochemistry was performed and was quantified in quartiles. Medical records were reviewed for clinical follow up information. EGFR was expressed in 21/30 (70 %) cases, including in the squamous component in 18/19 (95 %) and the spindle cell component in only 12/30 (40 %). Where the spindle cell component was positive, the intensity and distribution were lower than for the squamous component. Recurrent tumors were predominantly (80-90 %) of the spindle cell component, and had low (or absent) EGFR expression. Kaplan-Meier survival analysis showed no statistically significant differences in overall or disease free survival between the EGFR expressing and non-expressing groups (p = 0.414 and 0.19, respectively). SpCCs of the head and neck have a poor prognosis, and markedly reduced EGFR expression. EGFR-specific therapies may not be ideal for SpCC patients, which may lack EGFR expression, but further studies are needed.

Epidermal Growth Factor Receptor Is a Prognosis Predictor in Patients With Esophageal Squamous Cell Carcinoma

Our previous study indicated the survival rate for esophageal squamous cell cancer (ESCC) patients in stage III and positive lymph node groups with postoperative radiation therapy was significantly increased compared with surgery alone. But a predictive biomarker was needed to identify the patients who would benefit from postoperative radiotherapy. This study aims to evaluate epidermal growth factor receptor (EGFR) as an indicator to predict the prognosis of ESCC and to identify the patients who would benefit from postoperative radiotherapy. Tissue samples were collected from our previous randomized study: 243 in the surgery alone group and 198 in the surgery plus radiotherapy group. Expression of EGFR was analyzed by immunohistochemical staining. The expression of EGFR is correlated with depth of tumor invasion (p=0.005), lymph node metastasis (p<0.001), and pathologic stage (p<0.001). The survival rate of patients with high EGFR expression is significantly lower than that of patients with low EGFR expression (p=0.000). Notably, in stage IIA cases, the 5-year survival rate is 57.6% in the low EGFR expression group and 36.6% in the high expression group (p=0.020). EGFR is one of the independent variants that influence the prognosis. Moreover, for high EGFR expression patients the survival rate of the surgery plus radiotherapy group is higher than that of the surgery alone group (p=0.034). Expression of EGFR can be a prognostic predictor for ESCC. Patients with high expression of EGFR may benefit from postoperative radiation therapy.

Clinicopathological and immunohistochemical profile of non-small cell lung carcinoma in a tertiary care medical centre in South India

Background:Lung cancer is a highly aggressive malignancy causing high morbidity and mortality. An increasing incidence of lung cancer has been observed in India. Currently, the classification of lung carcinoma has gone beyond small cell lung carcinoma and non-small cell lung carcinoma (NSCLC). Precise subtyping of poorly differentiated NSCLC into adenocarcinoma and squamous cell carcinoma has a direct impact on patient management and prognosis. With this background, many molecules are under study for developing targeted therapies. Epidermal growth factor receptor (EGFR) is one such biomarker considered to be useful in targeted therapy for adenocarcinoma.Objective:The aim of this study was to subtype poorly differentiated NSCLC based on the expression of thyroid transcription factor-1 (TTF-1) and p-63 and to evaluate EGFR expression in adenocarcinomas.Materials and Methods:A retrospective analysis of 84 cases of poorly differentiated carcinomas of the lung was performed. Paraffin sections were immunostained with TTF-1 and p-63 and the tumors were subtyped. EGFR expression was assessed in adenocarcinomas by immunohistochemistry.Results:Fifty-five percent of the NSCLC were adenocarcinoma, with a peak incidence between 61 and 70 years of age and a male predominance. EGFR was expressed in 89% of the adenocarcinomas.Conclusions:Poorly differentiated non-small cell carcinoma can be subtyped by immunohistochemical markers and hence has a direct impact on the current therapeutic strategies.

Role of EGFR as a prognostic factor for survival in head and neck cancer: a meta-analysis

The prognostic role of epidermal growth factor receptor (EGFR) in head and neck squamous cell carcinoma (HNSCC) remains controversial. The goal of this study was to summarize existing evidence regarding whether EGFR overexpression is a prognostic factor in HNSCC. Relevant studies were identified using Pubmed, Ovid, and Web of Science databases. A meta-analysis was conducted on the prognostic value of EGFR expression for overall survival (OS) and disease-free survival (DFS). Thirty-seven studies were included. Primary analysis indicated that EGFR overexpression was associated with reduced OS (hazard ratio [HR]: 1.694, 95% confidence interval [CI]: 1.432–2.004). DFS, on the other hand, was not associated with EGFR expression after adjusting for publication bias (HR: 1.084, 95% CI: 0.910–1.290). Subgroup analysis gave a statistically significant pooled HR for OS in laryngeal carcinoma (HR: 2.519, 95% CI: 1.615–3.928) and in oropharyngeal carcinoma (HR: 2.078, 95% CI: 1.605–2.690). The pooled HR was statistically significant for DFS with respect to oropharyngeal carcinoma (HR: 1.055, 95% CI: 1.020–1.092), but not laryngeal carcinoma (HR: 1.750, 95% CI: 0.911–3.360). When dividing studies based on the immunohistochemistry (IHC) scoring system, only the group that evaluated EGFR expression according to the intensity and extent of staining showed no between-study heterogeneity for both OS and DFS. Overall, EGFR overexpression was associated with shortened OS, but not DFS. Future studies are needed that stratify patients by specific tumor sites. Furthermore, when estimating protein level by the IHC method, it is advisable to consider both intensity and extent of staining.

Overexpression of epidermal growth factor receptor as a prognostic factor in colorectal cancer on the basis of the Allred scoring system

BackgroundOverexpression of epidermal growth factor receptor (EGFR) is found in many types of neoplasms. The aim of the study was to evaluate EGFR expression in colorectal cancer (CRC) specimens and to determine whether EGFR expression correlates with clinicopathological data and overall survival.Patients and methodsTissue specimens from 181 consecutive CRC patients treated at the Military Institute of Medicine in 2006–2010 were collected and examined for EGFR expression, by immunohistochemistry staining. The staining intensity and percentage of cells with membranous EGFR expression were scored and then grouped according to the parameters of the Allred Scoring system. Cutoff values were subjected to further statistical analysis. Univariate tests and a multivariate Cox proportional hazards model were used in data analysis.ResultsEGFR was overexpressed in 96 of 181 CRC specimens (53%). EGFR expression was not correlated with other clinicopathological variables. On univariate analysis, overexpression of EGFR, determined by PS (percentage score) (>3) and total score (sum of PS and intensity score) (>4), was associated with poor overall survival. On multivariate analysis, EGFR overexpression (PS > 3) was an independent adverse prognostic factor (hazard ratio [HR] 1.62; 95% confidence interval [CI]: 1.03–2.53). Elevated carcinoembryonic antigen (CEA) serum concentration before treatment, performance status (Word Health Organization [WHO]-2), and tumor localized in colon and liver metastases were also independent unfavorable prognostic factors.ConclusionEGFR overexpression (PS > 3) in a CRC patient population was an independent adverse prognostic factor. Implementation of the Allred Scoring system criteria into clinical practice might facilitate treatment decisions in CRC patients.

Abstract 2796: Patient-derived xenograft models reveal a subset of clinically relevant squamous non-small cell lung cancers that respond to targeted EGFR inhibition.

Abstract BACKGROUND: Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer cases, carries a poor prognosis and remains an area of high unmet need. Despite recent advances in treating NSCLC adenocarcinomas with targeted epidermal growth factor receptor (EGFR) kinase inhibitors, few advances have been made in the treatment of squamous cell carcinoma (SCC), which accounts for 25% of NSCLC. Although the incidence of EGFR mutations in SCC is low, a retrospective clinical study of erlotinib in SCC suggested that a proportion of SCC patients would benefit from treatment with an EGFR inhibitor (Tseng et al., 2012). METHODS: NSCLC samples obtained from untreated patients undergoing surgery were collected with ethical consent, disaggregated and implanted subcutaneously in MF-1 nude mice (Harlan UK) admixed with a human stromal cell component to generate patient-derived xenograft (PDX) models (LION PDX models). Tumour material was diagnosed on the basis of operative histology and immunohistochemistry (IHC) used to confirm histological subtype. IHC was also used to evaluate EGFR expression and tumours characterised for mutations in p53, LKB1, EGFR and K-RAS by direct DNA sequencing. Patient-derived xenografts were maintained in vivo and study cohorts of mice dosed when tumours reached 100-200mm3 with either erlotinib or gefitinib or vehicle placebo. Response to treatment was evaluated by tumour growth inhibition and waterfall plots. RESULTS: We have identified a subset of tumours with squamous histology in our LION panel of patient-derived NSCLC xenografts that respond to treatment with a targeted EGFR inhibitor. Four out of 11 SCC models tested (36%) responded to treatment with either erlotinib or gefitinib with greater than 50% growth inhibition and two SCC models responded with ∼30% growth inhibition. Responses correlated well with EGFR expression. Work to characterise a further 8 LION SCC PDX models is also underway. CONCLUSIONS: These data support the proposition that a significant subset of NSCLC patients with squamous histology may benefit from treatment with targeted EGFR inhibitors. Our LION SCC models could be valuable for biomarker studies to identify the basis of the EGFR inhibitor responder subset and for evaluating new agents in a more clinically relevant setting. Citation Format: Aaron Cranston, Andrew Mckenzie, Phil Mallinder, Simon Jiang, Kerry Moakes, Yinfei Yin, Alex Reece-Smith, Anna Grabowska, Martin Page, Rajendra Kumari. Patient-derived xenograft models reveal a subset of clinically relevant squamous non-small cell lung cancers that respond to targeted EGFR inhibition. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2796. doi:10.1158/1538-7445.AM2013-2796

Epidermal Growth Factor Receptor Is Related to Poor Survival in Glioblastomas: Single-Institution Experience

PurposeThere are conflicting results surrounding the prognostic significance of epidermal growth factor receptor (EGFR) status in glioblastoma (GBM) patients. Accordingly, we attempted to assess the influence of EGFR expression on the survival of GBM patients receiving postoperative radiotherapy.Materials and MethodsThirty three GBM patients who had received surgery and postoperative radiotherapy at our institute, between March 1997 and February 2006, were included. The evaluation of EGFR expression with immunohistochemistry was available for 30 patients. Kaplan-Meier survival analysis and Cox regression were used for statistical analysis.ResultsEGFR was expressed in 23 patients (76.7%), and not expressed in seven (23.3%). Survival in EGFR expressing GBM patients was significantly less than that in non-expressing patients (median survival: 12.5 versus 17.5 months, p=0.013). Patients who received more than 60 Gy showed improved survival over those who received up to 60 Gy (median survival: 17.0 versus 9.0 months, p=0.000). Negative EGFR expression and a higher radiation dose were significantly correlated with improved survival on multivariate analysis. Survival rates showed no differences according to age, sex, and surgical extent.ConclusionThe expression of EGFR demonstrated a significantly deleterious effect on the survival of GBM patients. Therefore, approaches targeting EGFR should be considered in potential treatment methods for GBM patients, in addition to current management strategies.

The prognostic significance of growth factors and growth factor receptors in gastric adenocarcinoma

We evaluated growth factors/receptors expression in gastric adenocarcinoma. Immunohistochemistry was used to evaluate epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), VEGF-D, VEGF receptor (VEGFR)-2, VEGFR-3, transforming growth factor (TGF)-α, TGF-β1, and TGF-β-RII in tissue microarrays of adenocarcinoma, dysplasia, metaplasia, and gastritis. In adenocarcinoma, the expression rates of EGFR, VEGF, VEGF-D, VEGFR-2, VEGFR-3, TGF-α, TGF-β1, and TGF-β-RII were 2.0%, 0%, 10.7%, 4.4%, 11.2%, 26.3%, 9.4%, and 19.5%, respectively. VEGF-D, TGF-α, TGF-β1, and TGF-β-RII expression rate were higher in adenocarcinoma than in other groups. TGF-β-RII expression was correlated with VEGFR-3, VEGF-D, and TGF-α expression in adenocarcinomas. Tumor location, histologic type, stage, lymphatic invasion, perineural invasion, angioinvasion, VEGF-D, and VEGFR-2 expressions were associated with patient survival in a log rank test and advanced stage and positive expression of VEGF-D were poor prognostic factors using Cox analysis. VEGF-D expression may be of prognostic value in gastric adenocarcinoma, whereas EGFR and TGF family expression may only have a minor influence.

Increase of Epidermal Growth Factor Receptor Expression in Progression of GERD, Barrett, and Adenocarcinoma of Esophagus

Gastroesophageal reflux disease (GERD) is a pathology with a wide range of clinical and endoscopic manifestations. Epidermal growth factor receptor (EGFR), found in the epithelium of the digestive tract, plays an important role in epithelial repair and shows increased expression in different neoplasms, including esophageal tumors. The purpose of this study was to evaluate EGFR expression using immunohistochemistry in esophageal biopsies obtained from patients with GERD, Barrett's esophagus, and adenocarcinoma of the esophagus. EGFR expression was immunohistochemically determined in biopsies from 194 patients with symptoms suggestive of GERD or adenocarcinoma of the esophagus, seen at two Brazilian university hospitals between January 2003 and December 2008. Based on histopathological analysis, patients were divided into three groups: GERD, Barrett's esophagus and adenocarcinoma of the esophagus. EGFR expression was considered positive when staining was detected in the membrane. Mean age was 55.25 years (range 30-90). Patients with GERD (n = 127) accounted for 65.5% of the sample, compared with 12.4% (n = 24) of patients with Barrett's esophagus and 22.2% (n = 43) of patients with esophageal adenocarcinoma. Immunohistochemical analysis was positive for EGFR in 19.1% of the patients (37/194), divided as follows: 8.7% (11/127) in the GERD group, 25% (6/24) in the Barrett's esophagus group, and 46.5% (20/43) in the esophageal adenocarcinoma group. Statistical analysis revealed significant differences between the three groups (p = 0.0001). GERD patients showed lower levels of EGFR expression than patients with Barrett's esophagus or patients with adenocarcinoma of the esophagus, suggesting a direct relationship between EGFR expression and disease progression.