Epithelial Growth Factor Receptor Mutation Research Articles

Complete response in a lung adenocarcinoma with pleural metastases initially treated with gefitinib and switched to osimertinib after cerebral oligo-progression with unknown T790M mutation: a case report and review of literature

BackgroundFirst- and second-generation anti-epithelial growth factor receptor tyrosine kinase inhibitors have shown great efficacy in the treatment of advanced adenocarcinoma with epithelial growth factor receptor mutations, but this efficacy is limited by certain resistance mechanisms, in particular the T790M mutation, which must be screened before second-line treatment with osimertinib is indicated. The search for this mutation is sometimes difficult, especially in cases of intracranial relapse, through this case report we attempt to discuss the possibility of initiating treatment with osimertinib despite an unknown T790M mutation in such situation.Case reportWe present the case of a 70-year-old Moroccan male patient diagnosed with non-small cell lung carcinoma initially metastatic to the pleura with an epithelial growth factor receptor mutation who received gefitinib in first line with a complete response, he subsequently presented with cerebral oligo-progression with extra cranial stability. The patient was started on osimertinib with unknown T790M status, as it was impossible to perform a cerebral biopsy, the evolution was characterized by a partial response followed by stereotactic radiotherapy then a complete response for 2 years.ConclusionWe can discuss osimertinib as an option for patients with stage IV non-small cell lung cancer with brain oligo-progression on prior tyrosine kinase inhibitors and unknown T790M status, further studies are needed in this area.

Comprehensive Analysis Reveals Epithelial Growth Factor Receptor as a Potential Diagnostic Biomarker in Glioblastoma Multiforme.

Glioblastoma multiforme (GBM), a highly aggressive tumor of the central nervous system, is the most common malignant brain tumor and poses a significant risk to life. GBM patients have a low survival rate owing to their aggressive nature, poor prognosis, genomic variations among patients, and histopathological differences. In this study, we used several bioinformatics platforms, namely Tumor Immune Estimation Resource (TIMER), Gene Expression Profiling Interactive Analysis (GEPIA), University of Alabama at Birmingham Cancer Data Analysis Portal (UALCAN) databases, Kaplan-Meier plotter, and cBioPortal, to conduct a comprehensive analysis to highlight the expression of epithelial growth factor receptor (EGFR) in patients with GBM. Our study highlights EGFR as a potential diagnostic and prognostic marker. According to the TIMER database, EGFR was upregulated in five cancers, including GBM, head and neck squamous cell carcinoma, kidney renal cell carcinoma, kidney renal cell papillary cell carcinoma, and lung squamous cell carcinoma, whereas it was downregulated in breast invasive carcinoma, colon adenocarcinoma, pheochromocytoma and paraganglioma, prostate adenocarcinoma, rectum adenocarcinoma, and uterine corpus endometrial carcinoma. Our investigation highlighted the expression of EGFR in various clinicopathological parameters, which include age, sex, gender, and TP53 mutation status in patients with GBM. We found that EGFR was upregulated in middle-aged and older adults compared to normal tissues, while it was not significantly downregulated in young adults and older adults. EGFR was upregulated in Caucasians compared to normal tissue, whereas it was downregulated in Asian and African American populations, but this was not statistically significant. In terms of gender, EGFR was upregulated in the male population compared to the female population. Furthermore, EGFR was upregulated in patients with TP53 mutations compared to normal tissues. We also examined the correlation between EGFR gene expression and immune cell infiltration in GBM patients and the impact of EGFR mutations on patient prognosis. Our results revealed a significant positive correlation between EGFR, B cells, and macrophages, but this was not significant for other cell types. This study signified that upregulation of EGFR was associated with a poor prognosis in patients with GBM validated by the GEPIA and UALCAN databases.

RETRACTION: Afatinib plus bevacizumab treatment for a patient with EGFR S645C-mutant NSCLC

Epithelial growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) improve the survival outcomes of patients with advanced lung adenocarcinoma with common mutations. However, challenges persist in treating rare, uncommon EGFR mutations, such as EGFR S645C, which accounts for only 0.011% of the EGFR mutations in the Guardant360 database. Despite preclinical studies indicating its resistance to osimertinib, we present a case of using afatinib plus bevacizumab to successfully treat a patient with EGFR S645C mutation, for which an effective treatment had not been previously reported. This case report presents real-world evidence for optimal therapeutic options for patients with EGFR S645C mutation.

EGFR Mutation and FHIT Methylation: Inverse Relationship in Patients with Lung Adenocarcinoma and Tuberculosis

Objective: To investigate the genetic correlations between epithelial growth factor receptor (EGFR) mutation and FHIT methylation in patients diagnosed with lung adenocarcinoma (AC) and pulmonary tuberculosis (TB). Methods: The presence of EGFR mutations and the methylation status of the FHIT gene in patients presenting with AC and TB were analyzed. The correlation between TB status and the observed genetic and epigenetic variations was also examined. Results: Among the 90 patients included in the study, 38 exhibited EGFR mutations (14 among those with TB and 24 among those without TB), while 29 exhibited FHIT myelination (19 among those with TB and 10 among those without TB). Furthermore, the protein expression levels of EGFR and FHIT were significantly higher in patients diagnosed solely with AC compared to those presenting with both AC and TB. A robust inverse correlation was identified between TB status and the frequency of EGFR mutation (P < 0.001). Moreover, significant associations were observed between TB status and FHIT methylation (P < 0.01). Conclusion: The findings suggest a correlation between TB and the prevalence of EGFR mutation and FHIT methylation in the pathogenesis of AC.

Detection of EGFR T790M mutation using liquid biopsy for non-small cell lung cancer: Utility of droplet digital polymerase chain reaction vs. cobas real-time polymerase chain reaction

BackgroundDigital platforms for mutation detection yield higher sensitivity than non-digital platforms but lack universal positive cut-off values that correlate with the outcome of osimertinib treatment. This study determined compared droplet digital polymerase chain reaction (ddPCR) to the standard cobas assay for epithelial growth factor receptor (EGFR) T790M mutation detection in patients with non-small cell lung cancer. MethodsStudy patients had EGFR-mutant tumours with disease progression on first/second generation EGFR tyrosine kinase inhibitors, and osimertinib treatment after T790M mutation detection. T790M status was tested by cobas assay using liquid biopsy, and only by ddPCR if an EGFR mutation was identified but T790M was negative. Clinical efficacy of osimertinib was compared between patients with T790M detected by cobas vs. only by ddPCR. A positive cut-off value for ddPCR was determined by assessing efficacy with osimertinib. Results61 patients had tumors with an acquired T790M mutation, 38 detected by cobas and an additional 23 only by ddPCR. The median progression-free survival (PFS) for the cobas- and ddPCR-positive groups was 9.5 and 7.8 months, respectively (p=0.43). For ddPCR, a fractional abundance (FA) of 0.1% was used as a cut-off value. The median PFS of patients with FA ≥0.1% and <0.1% was 8.3 and 4.6 months, respectively (p=0.08). FA ≥0.1% was independently associated with a longer PFS. ConclusionUsing ddPCR to follow up the cobas assay yielded more cases (38% of total) with a T790M mutation. A cut-off value of FA ≥0.1% identified patients who responded as well to osimertinib as those identified by cobas assay. This sequential approach should detect additional patients who might benefit from osimertinib treatment.

Profiling the molecular and clinical landscape of glioblastoma utilizing the Oncology Research Information Exchange Network brain cancer database.

Glioblastoma exhibits aggressive growth and poor outcomes despite treatment, and its marked variability renders therapeutic design and prognostication challenging. The Oncology Research Information Exchange Network (ORIEN) database contains complementary clinical, genomic, and transcriptomic profiling of 206 glioblastoma patients, providing opportunities to identify novel associations between molecular features and clinical outcomes. Survival analyses were performed using the Logrank test, and clinical features were evaluated using Wilcoxon and chi-squared tests with q-values derived via Benjamini-Hochberg correction. Mutational analyses utilized sample-level enrichments from whole exome sequencing data, and statistical tests were performed using the one-sided Fisher Exact test with Benjamini-Hochberg correction. Transcriptomic analyses utilized a student's t-test with Benjamini-Hochberg correction. Expression fold changes were processed with Ingenuity Pathway Analysis to determine pathway-level alterations between groups. Key findings include an association of MUC17, SYNE1, and TENM1 mutations with prolonged overall survival (OS); decreased OS associated with higher epithelial growth factor receptor (EGFR) mRNA expression, but not with EGFR amplification or mutation; a 14-transcript signature associated with OS > 2 years; and 2 transcripts associated with OS < 1 year. Herein, we report the first clinical, genomic, and transcriptomic analysis of ORIEN glioblastoma cases, incorporating sample reclassification under updated 2021 diagnostic criteria. These findings create multiple avenues for further investigation and reinforce the value of multi-institutional consortia such as ORIEN in deepening our knowledge of intractable diseases such as glioblastoma.

Clinical characteristics and their influences on the survival of leptomeningeal metastasis derived from lung adenocarcinoma harboring epithelial growth factor receptor mutation

Objective: To analyze the clinical characteristics of leptomeningeal metastasis (LM) patients from epithelial growth factor receptor (EGFR)-mutated lung adenocarcinoma, and their impacts on the survival of the patients. Methods: From July 2018 to July 2022, the clinicopathological data of 81 patients diagnosed as EGFR-mutated lung adenocarcinoma LM by cytopathology who admitted to the Department of Oncology of Xiangya Hospital of Central South University were retrospectively analyzed, including 33 males and 48 females. The age ranged from 31 to 76 years, with a median age of 54 years. All the 81 patients were followed up, with a median follow-up of 21.0 months (95%CI: 12.5 to 29.5 months). The Kaplan Meier method was used to draw survival curve. Cox proportional hazards regression model was used to analyze the impact of the factors on the survival of patients. Results: Among the 81 patients, the interval between the initial diagnosis of lung cancer and the pathological diagnosis of LM in cerebrospinal fluid (CSF) was 0-108 months, with a median interval of 14 months. Fifty-two patients (64.2%) used the third-generation epithelial growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs), while 17 patients (21.0%) used EGFR-TKIs in combination with other drugs, and 12 patients (14.8%) were treated with best supportive care (BSC). Sixty patients (74.1%) had a Kanofsky performance status (KPS) score of less than 60 points, and 71 patients (87.7%) had brain parenchymal metastasis and/or spinal metastasis. Twenty-two patients (27.2%) used pemetrexed through intrathecal CSF, and 17 patients (21.0%) used pemetrexed through the Ommaya sac to the CSF of the ventricle. The incidence of adverse event related to the administration of pemetrexed through CSF was 64.1% (25/39), mainly manifested as myelosuppression, including 22 patients of leukocyte reduction, 25 patients of hemoglobin reduction, and 14 patients of platelet reduction. The median post-leptomeningeal metastasis overall survival (pLM-OS) in 81 patients was 11.0 (95%CI: 7.7-14.3) months. KPS score≥60 points (HR=0.407, 95%CI: 0.170-0.973, P=0.043), CSF cytology negative after treatment (vs persistent positive, HR=0.351, 95%CI: 0.155-0.792, P=0.012), intraventricular administration of pemetrexed (vs non intraventricular administration of pemetrexed, HR=0.319, 95%CI: 0.137-0.745, P=0.008) and the treatment with third-generation EGFR-TKIs after LM (vs EGFR-TKIs in combination with other drugs, HR=0.486, 95%CI: 0.237-0.998, P=0.049) were a factor affecting pLM-OS of patients. Conclusions: Brain parenchyma, or/and spine are the most sites where the LM patients concurrently metastasize. KPS score≥60 points and CSF cytology negative after treatment, intraventricular administration of pemetrexed and the treatment with third-generation EGFR-TKIs are indictors affecting pLM-OS of the patients.

Osimertinib resistance prognostic gene signature: STRIP2 is associated with immune infiltration and tumor progression in lung adenocarcinoma.

Although the use of osimertinib can significantly improve the survival time of lung adenocarcinoma (LUAD) patients with epithelial growth factor receptor mutation, eventually drug resistance will limit the survival benefit of most patients. This study aimed to develop a novel prognostic predictive signature based on genes associated with osimertinib resistance. The differentially expressed genes (DEGs) associated with osimertinib resistance in LUAD were screened from Gene Expression Omnibus datasets and The Cancer Genome Atlas datasets. Multivariate cox regression was used to establish a prognostic signature, and then a nomogram was developed to predict the survival probability of LUAD patients. We used ROC curve and DCA curve to evaluate its clinical prediction accuracy and net benefit.In addition, the differentially expressed genes significantly associated with prognosis were selected for immune infiltration analysis and drug sensitivity analysis, and their roles in the progression of lung adenocarcinoma were verified by in vitro experiments. Our evaluation results indicated that the new nomogram had higher clinical prediction accuracy and net benefit value than the TN nomogram. Further analysis showed that patients with low STRIP2 expression had a higher level of immune response, and may be more likely to benefit from immune checkpoint inhibitors and conventional antitumor drugs. This may help to select more precise and appropriate therapy for LUAD patients with osimertinib resistance. Furthermore, in vitro experiments showed that STRIP2 promoted the LUAD cells proliferation, migration and invasion. This further demonstrates the importance of this gene signature for prognostic prediction. We developed a reliable prognostic model based on DEGs associated with osimertinib resistance and screened for biomarker that can predict the immune response in LUAD patients, which may help in the selection of treatment regimens after osimertinib resistance.

Patient-derived cell-based pharmacogenomic assessment to unveil underlying resistance mechanisms and novel therapeutics for advanced lung cancer

BackgroundA pharmacogenomic platform using patient-derived cells (PDCs) was established to identify the underlying resistance mechanisms and tailored treatment for patients with advanced or refractory lung cancer.MethodsDrug sensitivity screening and multi-omics datasets were acquired from lung cancer PDCs (n = 102). Integrative analysis was performed to explore drug candidates according to genetic variants, gene expression, and clinical profiles.ResultsPDCs had genomic characteristics resembled with those of solid lung cancer tissues. PDC molecular subtyping classified patients into four groups: (1) inflammatory, (2) epithelial-to-mesenchymal transition (EMT)-like, (3) stemness, and (4) epithelial growth factor receptor (EGFR)-dominant. EGFR mutations of the EMT-like subtype were associated with a reduced response to EGFR-tyrosine kinase inhibitor therapy. Moreover, although RB1/TP53 mutations were significantly enriched in small-cell lung cancer (SCLC) PDCs, they were also present in non-SCLC PDCs. In contrast to its effect in the cell lines, alpelisib (a PI3K-AKT inhibitor) significantly inhibited both RB1/TP53 expression and SCLC cell growth in our PDC model. Furthermore, cell cycle inhibitors could effectively target SCLC cells. Finally, the upregulation of transforming growth factor-β expression and the YAP/TAZ pathway was observed in osimertinib-resistant PDCs, predisposing them to the EMT-like subtype. Our platform selected XAV939 (a WNT-TNKS-β-catenin inhibitor) for the treatment of osimertinib-resistant PDCs. Using an in vitro model, we further demonstrated that acquisition of osimertinib resistance enhances invasive characteristics and EMT, upregulates the YAP/TAZ-AXL axis, and increases the sensitivity of cancer cells to XAV939.ConclusionsOur PDC models recapitulated the molecular characteristics of lung cancer, and pharmacogenomics analysis provided plausible therapeutic candidates.

PD-L1 expression, tumor mutational burden, and immune cell infiltration in non-small cell lung cancer patients with epithelial growth factor receptor mutations.

BackgroundImmunotherapy using programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors seems less effective in non-small cell lung cancer (NSCLC) patients with epithelial growth factor receptor (EGFR) mutations. Varied responses to PD-1/PD-L1 inhibitors have recently been observed in NSCLC patients harboring different types of EGFR mutations. Some EGFR-mutated NSCLC patients may benefit from PD-1/PD-L1 inhibitors. At present, PD-L1 expression, tumor mutational burden (TMB), and tumor immune microenvironment (TIME) are biomarkers for predicting the efficacy of PD-1/PD-L1 inhibitors in NSCLC patients. We retrospectively evaluated PD-L1 expression, TMB, and immune cell infiltration in NSCLC patients with EGFR mutation subtypes.MethodsPD-L1 expression, TMB, and the abundance of immune cell infiltration in NSCLC patients were evaluated in public databases and clinical samples. TMB was detected using the NGS technique, PD-L1 was detected using immunohistochemistry, and the abundance of immune cell infiltration in NSCLC samples was detected using multiple immunohistochemistry.ResultsPD-L1 expression and TMB were lower in EGFR-mutated NSCLCs than in wild-type patients. Differences in the abundance of immune cell infiltration were also observed between EGFR-mutated and wild-type NSCLC. The expression of PD-L1, TMB, and abundance of immune cell infiltration were different in patients harboring different subtypes of EGFR mutations. Patients with uncommon EGFR mutations, especially the G719X mutation, showed higher TMB and expressions of PD-L1 than classical EGFR mutations. M1 macrophages were higher in uncommon EGFR mutations than classical EGFR mutations.ConclusionsThe expression of PD-L1 and TMB in uncommon EGFR-mutated NSCLCs, especially the G719X mutation, were higher than those for classical EGFR-mutated NSCLCs and similar to EGFR wild-type. The abundance of immune cell infiltration in uncommon EGFR-mutated NSCLCs was similar to that in EGFR wild-type. Our findings suggest that uncommon EGFR-mutated NSCLCs may benefit from PD-1/PD-L1 inhibitors.

WX-0593 combined with an epithelial growth factor receptor (EGFR) monoclonal antibody in the treatment of xenograft tumors carrying triple EGFR mutations.

BackgroundTo evaluate the safety and therapeutic efficacy of WX-0593, a newly developed potent anaplastic lymphoma kinase (ALK) inhibitor, in combination with an epithelial growth factor receptor (EGFR) monoclonal antibody (QL1203 or Vectibix) for the treatment of xenograft tumors carrying mutant EGFR and osimertinib-resistant mutations (EGFR/T790M/C797S).MethodsThe inhibition of tumor cell proliferation by WX-0593 and Vectibix alone or combined was evaluated in four EGFR triple-mutant cell lines: PC9 (EGFR Del19/T790M/C797S), NCI-H1975 (EGFR L858R/T790M/C797S), Ba/F3 (EGFR L858R/T790M/C797S and EGFR Del19/T790M/C797S). The in vivo antitumor efficacy of WX-0593 alone or combined with QL1203 or Vectibix was evaluated in xenograft tumor models of BALB/c nude mice developed from H1975 (EGFR-Del19/T790M/C797S) and Ba/F3 (EGFR-L858R/T790M/C797S) cell lines. Mice were randomized into groups and treated with or without WX-0593, QL1203, Vectibix, or their combination. The tumor volume, mouse body weight, and therapeutic side effects were monitored routinely. Blood samples were obtained from all mice at different time points after the last dosage of treatment to evaluate the pharmacokinetic parameters of the drugs.ResultsWX-0593 and Vectibix showed a strong synergistic inhibitory effect on the proliferation of two EGFR triple-mutant Ba/F3 cell lines (EGFR L858R/T790M/C797S and Del19/T790M/C797S), but little synergistic inhibitory effect on the proliferation of NCI-H1975 (EGFR L858R/T790M/C797S) and PC9 (EGFR Del19/T790M/C797S). In vivo, WX-0593 (25 mg/kg) showed a modest therapeutic effect when combined with QL1203 or Vectibix, but had no effect on tumor growth as a monotherapy at this dosage. WX-0593 (75 mg/kg) exhibited modest antitumor efficacy that was further enhanced in combination with QL1203 or Vectibix in both tumor models (H1975 and Ba/F3). No significant body weight alteration, any other side effect, or deaths were observed during treatment. Pharmacokinetic analysis showed that the serum level of QL1203 or Vectibix was significantly increased and lasted longer when combined with WX-0593.ConclusionsWX-0593 exhibited a synergetic effect with an EGFR monoclonal antibody on osimertinib-resistant EGFR-mutant non-small cell lung cancer (NSCLC) both in vitro and in vivo. Their combination showed potent antitumor efficacy and an acceptable safety profile, which may be a promising strategy for the treatment of patients with EGFR triple-mutant NSCLC resistant to osimertinib.

18F-Fluorodeoxyglucose PET/CT for Early Prediction of Outcomes in Patients with Advanced Lung Adenocarcinomas and EGFR Mutations Treated with First-Line EGFR-TKIs.

Simple SummaryEpithelial growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are the first-line therapy for patients with advanced-stage lung adenocarcinoma with EGFR mutations. However, 17–31% of these patients do not respond to therapy, making early evaluation of treatment response crucial. This prospective study investigates the value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) for timely prediction of response and survival of these patients. We evaluated 30 patients with stage IIIB/IV lung adenocarcinomas and EGFR mutations, receiving first-line EGFR-TKI therapy. 18F-FDG PET/CT was performed before and two weeks after initiation of treatment. Positron Emission Tomography Response Criteria in Solid Tumors served as an independent predictor of non-progressive disease; baseline and change of metabolic tumor volume represented independent predictors of progression-free survival and overall survival, respectively. Therefore, 18F-FDG PET/CT is an early predictor of outcomes and individual prognosis of patients with stage IIIB/IV lung adenocarcinomas and EGFR mutations receiving first-line EGFR-TKI therapy.This study aims to investigate the role of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in early prediction of response and survival following epithelial growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI) therapy in patients with advanced lung adenocarcinomas and EGFR mutations. Thirty patients with stage IIIB/IV lung adenocarcinomas and EGFR mutations receiving first-line EGFR-TKIs were prospectively evaluated between November 2012 and May 2015. EGFR mutations were quantified by delta cycle threshold (dCt). 18F-FDG PET/CT was performed before and 2 weeks after treatment initiation. PET response was assessed based on PET Response Criteria in Solid Tumors (PERCIST). Baseline and percentage changes in the summed standardized uptake value, metabolic tumor volume (bsumMTV and ΔsumMTV, respectively), and total lesion glycolysis of ≤5 target lesions/patient were calculated. The association between parameters (clinical and PET) and non-progression disease after 3 months of treatment in CT based on the Response Evaluation Criteria in Solid Tumors Version 1.1 (nPD3mo), progression-free survival (PFS), and overall survival (OS) were tested. The median follow-up time was 19.6 months. The median PFS and OS were 12.0 and 25.3 months, respectively. The PERCIST criteria was an independent predictor of nPD3mo (p = 0.009), dCt (p = 0.014) and bsumMTV (p = 0.014) were independent predictors of PFS, and dCt (p = 0.014) and ΔsumMTV (p = 0.005) were independent predictors of OS. 18F-FDG PET/CT achieved early prediction of outcomes in patients with advanced lung adenocarcinomas and EGFR mutations receiving EGFR-TKIs.

Potential applications of clickable probes in EGFR activity visualization and prediction of EGFR-TKI therapy response for NSCLC patients

The epithelial growth factor receptor (EGFR) is abnormally overexpressed on the cell surface of cancer cells and is strongly associated with cancer cell proliferation, migration, differentiation, apoptosis, and angiogenesis. Tools enabling the visualization of EGFR in a structure-function approach are highly desirable to predict EGFR mutations and guide EGFR tyrosine kinase inhibitor (TKI) treatment making. Here, we describe the design, synthesis, and application of new, potent and selective clickable probes 13 (HX03), 20 (HX04) and 24 (HX05) by introducing an alkyne ligation handle to visualize EGFR activity in living cancer cells and tissue slices. These clickable probes are versatile chemical tools based on the key pharmacophore (4-anilinoquinazoline) of EGFR-TKIs (e.g., canertinib, dacomitinib and afatinib) and are able to irreversibly target the kinase domain of EGFR. Among them, 13 exhibits the highest reactivity towards EGFR kinase, particularly to EGFR kinase with primary mutations. Using activity-based protein profiling strategy, 13 showed high sensitivity and selectivity in labeling of endogenous EGFR in a native cellular context. Moreover, 13 was applied to visualize EGFR mutant activity in tumour tissues from non-small-cell lung cancer (NSCLC) xenograft mouse models, and patients with NSCLC for the prediction of EGFR-TKI sensitivity. These results demonstrate that strategically designed EGFR-TKI-based probes allow discriminating EGFR mutations in human tissues and hold promise as useful diagnostic tools in predicting EGFR-TKI therapy response.

Epithelial Growth Factor Receptor Mutations Predict Hepatocellular Carcinoma Patient’s Prognosis

Objective: Hepatocellular Carcinoma (HCC) is an aggressive malignancy and the second leading cause of cancer-related death in the world. Epithelial Growth Factor Receptor (EGFR) overexpression has been demonstrated in HCC patients frequently and is a poor prognostic factor. EGFR is a promising target for cancer treatment, but its variety in response by mutation status. Patients and Methods: We retrospective analyzed 28 Hepatocellular Carcinoma (HCC) patients with good quality DNA samples, 5 hepatic dysplasia tissues, and 5 cholangiocarcinoma samples from 1996 to 2002. EGFR mutation status was detected by ARMS and Scorpions real-time PCR, using therascreen® EGFR RGQ PCR Kit. T790M, exon 19 deletions, L858R, L861Q, G719X, S786I, and exon 20 insertions can be detected. Clinical data of 28 HCC patients were collected for the longest period of 17 years. Results: All patients received liver segmentectomy. No one received tyrosine kinase inhibitor treatment during the following period. All liver samples had T790M mutation detected. Based on overall survival, we calculated cut-off points, by ROC curve. In HCC patients with a higher percentage of T790M or G719X mutations had better overall survival (P=0.001, and 0.036). Patients with exon 19 deletion showed a trend of better overall survival. HCC patients with exon 19 deletions, L858R and G719X mutations showed trends of longer Disease Free Survival (DFS) and HCC patients with higher S768I mutation had a trend of shorter DFS. HCC samples from chronic hepatitis B carriers had a higher T790M mutation rate and the ones from chronic hepatitis C carriers showed the opposite in T790M mutation with statistics significant (P=0.013). No EGFR mutations contribute to HCC recurrence. Conclusion: EGFR mutation status can predict HCC patient’s prognosis post liver segmentectomy.

Use of the Idylla EGFR Mutation Test for Variant Detection in Non-Small Cell Lung Cancer Samples.

Stratified management of patients with non-small cell lung carcinoma (NSCLC) through epithelial growth factor receptor (EGFR) variant analysis has become standard clinical practice. The Idylla system is a fully compliant European in vitro diagnostics device, a fully automated platform designed to rapidly genotype formalin-fixed paraffin-embedded tissue samples. This retrospective study aims to validate the Idylla EGFR Mutation Test for use with extracted DNA from known NSCLC samples. In this study, 20 µL of archival extracted DNA was placed directly inside the Idylla EGFR assay single-use cartridge. Idylla results were compared with the original Sanger sequencing reference method. The Idylla EGFR Mutation Test yielded valid results for all samples tested, confirming the variants identified by the reference method that lay within the Idylla target range. No false-positive cases were noted with the Idylla assay. Variant genotype reports were obtained within 150 minutes. The Idylla EGFR assay is sensitive for extracted DNA and can be reliably applied to cytologic specimens, enabling its implementation as an ancillary first-line test for patients with NSCLC.

Alisertib inhibits migration and invasion of EGFR-TKI resistant cells by partially reversing the epithelial-mesenchymal transition

Epithelial growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been widely used in the clinical treatment of non-small cell lung cancer (NSCLC) patients with EGFR mutations. Previous studies have shown that Aurora kinase A (AURKA) is overexpressed in a broad spectrum of cancer cells, which can induce epithelial-mesenchymal transition (EMT) and contribute to the occurrence of acquired EGFR-TKI resistance. However, whether the inhibition of AURKA could overcome EGFR-TKI resistance or reverse the EMT in TKI-resistant NSCLC cells remains unclear. In the current study, we established three EGFR-TKI-resistant cell lines and analyzed their expression profiles by RNA sequencing. The results revealed that the EMT pathway is significantly upregulated in the three cell lines with EGFR-TKI resistance. The phosphorylation of AURKA at Thr 288 was also upregulated, suggesting that the activation of AURKA plays an important role in the occurrence of EGFR-TKI resistance. Interestingly, the AURKA inhibitor, alisertib treatment restored the susceptibility of resistant cells to EGFR-TKIs and partially reversed the EMT process, thereby reducing migration and invasion in EGFR-TKI-resistant cells. This study provides evidence that targeting AURKA signaling pathway by alisertib may be a novel approach for overcoming EGFR-TKI resistance and for the treatment of metastatic EGFR-TKIs in NSCLC patients.

Vasculogenic mimicry, a negative indicator for progression free survival of lung adenocarcinoma irrespective of first line treatment and epithelial growth factor receptor mutation status

BackgroundVascular mimicry (VM) was associated with the prognosis of cancers. The aim of the study was to explore the association between VM and anticancer therapy response in patients with lung adenocarcinoma.MethodsThis was a single-center retrospective study of patients with lung adenocarcinoma between March 1st, 2013, to April 1st, 2019, at the Second People’s Hospital of Taizhou City. All included patients were divided into the VM and no-VM groups according to whether VM was observed or not in the specimen. Vessels with positive PAS and negative CD34 staining were confirmed as VM. The main outcome was progression-free survival (PFS).ResultsSixty-six (50.4%) patients were male. Eighty-one patients received chemotherapy as the first-line treatment, and 50 patients received TKIs. Forty-five (34.4%) patients were confirmed with VM. There was no difference regarding the first-line treatment between the VM and no-VM groups (P = 0.285). The 86 patients without VM had a median PFS of 279 (range, 90–1095) days, and 45 patients with VM had a median PFS of 167 (range, 90–369) days (P < 0.001). T stage (hazard ratio (HR) = 1.37, 95% confidence interval (CI): 1.10–1.71), N stage (HR = 1.43, 95%CI: 1.09–1.86), M stage (HR = 2.85, 95%CI: 1.76–4.61), differentiation (HR = 1.85, 95%CI: 1.29–2.65), therapy (HR = 0.32, 95%CI: 0.21–0.49), VM (HR = 2.12, 95%CI: 1.33–3.37), and ECOG (HR = 1.41, 95%CI: 1.09–1.84) were independently associated with PFS.ConclusionThe benefits of first-line TKIs for NSCLC with EGFR mutation are possibly better than those of platinum-based regimens in patients without VM, but there is no difference in the benefit of chemotherapy or target therapy for VM-positive NSCLC harboring EGFR mutations.

Mechanism of intrinsic resistance of lung squamous cell carcinoma to epithelial growth factor receptor-tyrosine kinase inhibitors revealed by high-throughput RNA interference screening.

Although targeted therapy has achieved a great breakthrough in the treatment of lung adenocarcinoma, there are still no effective targeted drugs for lung squamous cell carcinoma (SqCC). In addition, as immunotherapy can only prolong the overall survival (OS) of lung SqCC by ≤5 months, chemotherapy and radiotherapy are still the main types of therapy for advanced SqCC. The expression level of epithelial growth factor receptor (EGFR) in patients with lung SqCC is higher compared with those with adenocarcinoma, but the former group is intrinsically resistant to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Therefore, if the drug resistance in patients with lung SqCC could be reversed, the majority of patients may benefit from EGFR-TKIs. In the present study, the high-throughput RNA interference technology was used to screen the genes involved in the EGFR-TKI erlotinib resistance of lung SqCCs, and integrin-linked kinase (ILK) was identified to be the most effective. The role of ILK in erlotinib resistance was further studied in cell lines, and the expression of ILK was analyzed in patients with SqCC and adenocarcinoma. Finally, the mechanism of ILK in EGFR-TKIs resistance was analyzed using Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO) and ingenuity pathway analysis (IPA). The results demonstrated that the ILK gene knockdown could overcome erlotinib resistance by inhibiting cell proliferation, inducing apoptosis and blocking the cell cycle at the G2/M phase. The expression of ILK in patients with SqCC was significantly higher compared with those with adenocarcinoma with sensitizing EGFR mutations. In addition, the cell cycle pathway ‘G2/M DNA damage and checkpoint regulation’ was identified to be significantly inhibited by ILK knockdown in IPA, KEGG and GO analysis. The results of the present study may improve the understanding of EGFR-TKI resistance in lung SqCCs, thus promoting the development of potential targeted therapies for lung SqCCs.

Impact of Aurora Kinase A Polymorphism and Epithelial Growth Factor Receptor Mutations on the Clinicopathological Characteristics of Lung Adenocarcinoma.

Lung adenocarcinoma (LADC) is the most common subtype of lung cancer worldwide and the epidermal growth factor receptor (EGFR) has a great influence on its clinical course, mainly due to the influence of different phenotypes. The Aurora kinase A (AURKA) would influence the progression of several solid malignancies. However, whether the interaction between EGFR phenotypes and AURKA would influence the clinical characteristics of LADC remains unknown. Herein, this study aimed to explore the effects of single-nucleotide polymorphisms (SNPs) of AURKA and EGFR phenotypes on the clinicopathological characteristics of LADC. Four loci of AURKA SNPs (rs1047972, rs2273535, rs6024836, and rs2064863) were genotyped using TaqMan allelic discrimination in 105 wild-type EGFR individuals and 167 LADC patients with EGFR mutations. After the statistical analysis, patients with LADC who had CT heterozygotes of AURKA rs1047972 had a lower risk of EGFR mutations than patients with wild-type homozygotes. Moreover, female and nonsmoking patients who carried the CT genotype of AURKA rs1047972 had a lower risk of EGFR mutation (p = 0.008 and p = 0.004, respectively). Moreover, in patients with EGFR mutations, AURKA SNP rs6024836 G allele (AG + GG) carriers had a lower risk of developing advanced-stage LADC (stage III or IV; odds ratio = 0.423, 95% confidence interval: 0.203–0.879, p = 0.019) than patients with AA homozygotes. Our results suggested that AURKA rs1047972 variants are significantly associated with EGFR mutations among patients with LADC, particularly in female and nonsmoking patients. AURKA variants may contribute to the pathological development of LADC.

The Impact of EGFR Mutation Status and Brain Metastasis for Non-Small Cell Lung Cancer Treated with Ramucirumab plus Docetaxel

Objectives: Currently, combination therapy of ramucirumab (RAM) + docetaxel (DOC) must play a more important role as a second-line treatment. Epithelial growth factor receptor (EGFR) mutation accounts for around 50% of oncogenic driver mutations in patients with advanced non-small cell lung cancer (NSCLC) in Asian subsets. The number of brain metastases (BM) is relatively higher in EGFR mutation-positive patients compared to EGFR wild-type patients. The objective of this study is to evaluate the efficacy of RAM + DOC focusing on EGFR mutation and BM. Methods: We retrospectively reviewed consecutive advanced NSCLC patients who received combination therapy of RAM + DOC at three institutions. A total of 112 patients with NSCLC were enrolled for efficacy analyses. We evaluated the efficacy of RAM + DOC for EGFR-mutated NSCLC with endpoints including progression-free survival (PFS), time to treatment failure (TTF) and overall survival. Results: Median PFS was 5.7 months for the EGFR mutant group compared with 3.6 months for the EGFR wild-type group (HR 0.53, 95% CI 0.32–0.87; p = 0.01). Median TTF was 5.1 months for the EGFR mutant group compared with 2.8 months for the EGFR wild-type group (HR 0.53, 95% CI 0.33–0.85; p = 0.007). Median PFS and TTF of the EGFR mutant group was significantly longer than median PFS and TTF of the EGFR wild-type group. The multivariate analysis identified EGFR mutation status as an independent favorable factor of PFS. In subset analyses of BM, median PFS of the EGFR mutant group (2.8 months) was significantly shorter than that of the EGFR wild-type group (5.1 months) (HR 7.27, 95% CI 1.78–29.68; p = 0.002). Conclusion: This study revealed that EGFR mutation status and BM might be predictive or prognostic factors for PFS.