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At least 37 records · Page 2Linked to original sources
PubMed2006

Frequent EGFR mutations in brain metastases of lung adenocarcinoma.

Lung adenocarcinomas often metastasize to the brain, and the prognosis of patients with brain metastases is still very poor. The epidermal growth factor receptor (EGFR) gene is mutated in a considerable fraction of primary lung adenocarcinomas, in particular those with drastic response to EGFR tyrosine kinase inhibitors. The present study was designed to elucidate the prevalence of EGFR mutations in brain metastases and the timing of their occurrence during cancer progression. EGFR mutations were detected in 12 of 19 metastatic lung adenocarcinomas to the brain (63%). This frequency was higher than those in previous studies for EGFR mutations at various stages of lung adenocarcinoma in East Asia, including Japan (i.e., 20-55%). In 6 cases with EGFR mutations, the corresponding primary lung tumors were also examined for the mutations, and in all of them, the same types of EGFR mutations were detected also in the primary tumors. In 2 of them, second metastatic brain tumors in addition to the first ones were also available for analysis, and the same types of EGFR mutations were detected in both the first and second ones in both cases. These results indicate that EGFR mutations are present frequently in brain metastases and occur preceding brain metastasis. These findings will be highly informative for treatment of metastatic lung adenocarcinoma to the brain.

Adenocarcinoma↗
PubMed2006

Non-responsiveness to gefitinib in a patient with lung adenocarcinoma having rare EGFR mutations S768I and V769L.

Mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) are associated with clinical responsiveness to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) in patients with non-small cell lung cancers (NSCLCs). However, certain rare EGFR mutations including S768I are reported to confer less in vitro sensitivity to gefitinib, an EGFR-TKI, than major mutations such as exon 19 deletions and L858R and even the wild-type counterpart. Here, we report the first case of adenocarcinoma of the lung in which the patient had rare mutations S768I and V769L and was treated with gefitinib. Disease progressed during 6 weeks of treatment. This case suggests that in vitro sensitivity to gefitinib correlates with distinct clinical responsiveness to gefitinib in various types of EGFR mutations.

Adenocarcinoma↗
PubMed2006

A rapid, sensitive assay to detect EGFR mutation in small biopsy specimens from lung cancer.

It has been demonstrated that lung cancers, specifically a subset of pulmonary adenocarcinomas, with epidermal growth factor receptor (EGFR) mutation are highly sensitive to EGFR-targeted drugs. Therefore, a rapid, sensitive assay for mutation detection using routine pathological specimens is demanded in clinical practice to predict the response. We therefore developed a new assay for detecting EGFR mutation using only a paraffin section of a small biopsy specimen. The method was very sensitive, detecting as few as 5% cancer cells in a background of normal cells, the results usually being obtained within 4 hours. Furthermore, it was accurate, as shown by the high concordance with reverse transcriptase-polymerase chain reaction-coupled direct sequencing (186 of 195, 95%). The practical application of this assay to 29 cases treated with gefitinib resulted in a high prediction rate: 10 of the 11 responders were shown to be positive for the mutation, and all patients with progressive disease were negative. In addition, a mutation at codon 790, conferring gefitinib resistance, was successfully analyzed in a similar manner. In conclusion, the assay is a rapid, sensitive method using paraffin sections of biopsy specimens without a tumor cell-enrichment procedure and is quite useful to select a treatment of choice in clinical practice.

Biopsy↗
PubMed2005

Variability in organ-specific EGFR mutational spectra in tumour epithelium and stroma may be the biological basis for differential responses to tyrosine kinase inhibitors.

Organ-specific differences in epidermal growth factor receptor (EGFR) mutational spectra and frequencies were found in lung cancer and sporadic and BRCA1/2-related breast cancers. Additionally, we found a high frequency of EGFR mutations in the tumour stroma of these invasive breast carcinomas. Those organ-specific mutational spectra and potential targets in the cancer-associated stroma might influence the efficacy of TKI therapy.

Antineoplastic Agents↗
PubMed2006

Detection of EGFR mutations in archived cytologic specimens of non-small cell lung cancer using high-resolution melting analysis.

Mutations of the epidermal growth factor receptor (EGFR), particularly deletional mutations (DEL) in exon 19 and L858R in exon 21, are reportedly correlated with clinical outcome in patients with non-small cell lung cancer (NSCLC) receiving the EGFR tyrosine kinase inhibitors gefitinib and erlotinib, suggesting that detection of EGFR mutations would have an important role in clinical decision making. We established and validated an easy, inexpensive, and rapid method for detecting DEL and L858R from cytologic material by high-resolution melting analysis (HRMA). Dilution for sensitivity studies revealed that DEL and L858R were detectable in the presence of at least 10% and 0.1% EGFR-mutant cells, respectively. We analyzed 37 archived cytological slides of specimens from 29 patients with advanced NSCLC and compared the results with direct sequencing data obtained previously. Of 37 samples, 34 (92%) yielded consistent results with direct sequencing, 2 were false negative, and 1 was indeterminate. The sensitivity of this analysis was 90% (19/21) and specificity, 100% (15/15). These results suggest that HRMA of archived cytologic specimens of advanced NSCLC is useful for detecting EGFR mutations in clinical practice.

Archives↗
PubMed2026

Distinct spatial immune microenvironment features of different EGFR mutation subtypes in early-stage lung adenocarcinoma.

Epidermal growth factor receptor (EGFR) mutations are common in lung adenocarcinoma (LUAD), yet their influence on the spatial tumor immune microenvironment (TIME) in early-stage disease remains unclear. We characterized the spatial TIME in 144 treatment-naïve, early-stage LUADs using integrated genomic sequencing and multiplex immunohistochemistry (mIHC). Although EGFR-mutant tumors overall displayed reduced CD8 + T-cell infiltration compared with EGFR-wild-type tumors, substantial heterogeneity was observed among EGFR subtypes. Specifically, L858R and rare-variant subtypes exhibited higher tumor mutational burden, greater CD8 + T-cell density, and enrichment of T-cell-dominant cellular neighborhoods relative to 19del subtype, consistent with a comparatively immune-infiltrated phenotype. In contrast, 19del tumors showed lower T-cell infiltration. TP53 co-mutation was also associated with enhanced CD8 + T-cell infiltration. These cross-sectional findings identify hypothesis-generating spatial immune phenotypes across EGFR-mutant LUAD subtypes; their potential relevance to perioperative treatment selection requires prospective validation in outcome-annotated treatment cohorts.

Humans↗
PubMed2006

Frequent EGFR mutations in noninvasive bronchioloalveolar carcinoma.

Mutations of the epidermal growth factor receptor gene (EGFR) have been reported to be present in a considerable fraction of lung adenocarcinomas showing dramatic response to EGFR tyrosine kinase inhibitors. To clarify pathogenic significance of the mutations for the development of lung adenocarcinoma, we investigated stage I lung adenocarcinomas for the mutations. First, 107 cases of macrodissected stage I adenocarcinomas were examined for mutations in exons 18-21 of the EGFR gene. EGFR mutations were detected in 36 of the 107 cases (34%). In particular, among the stage I cases, the mutations were detected in 17 of 42 small-sized adenocarcinomas (<or=2 cm in diameter) (40%), including 7 of 11 noninvasive bronchioloalveolar carcinomas (BACs) (64%) and 7 of 25 invasive adenocarcinomas with BAC components (28%). Second, 26 cases of laser capture microdissected small-sized adenocarcinomas, including 9 cases in the first analysis, were examined for the mutations. Reanalysis of microdissected materials in the 9 cases identified the mutations in 2 more adenocarcinomas with BAC components. Moreover, in the analysis of the other 17 microdissected materials, EGFR mutations were detected in 7 of 12 BACs (58%) and in 3 of 5 adenocarcinomas with BAC components (60%). EGFR mutations are present frequently in BACs, and are thus likely to be a critical genetic alteration for the formation of noninvasive lung adenocarcinoma.

Adenocarcinoma↗
PubMed2006

L858R EGFR mutation status correlated with clinico-pathological features of Japanese lung cancer.

Somatic mutations of the epidermal growth factor receptor (EGFR) gene were found in about 25-40% of Japanese lung cancer patients. These mutations are associated with clinical and radiographic responses to EGFR tyrosine kinase inhibitors. Most common mutation are arginine for leucine substitution at amino acid 858 (L858R) and exon 19 deletions, especially deletion type 1 mutation. We investigated these EGFR mutation statuses in 575 surgically treated non-small cell lung cancer (NSCLC) cases. Three-hundred and sixty-two adenocarcinoma cases were included. The presence or absence of EGFR mutations of kinase domains was analyzed by genotyping analysis (TaqMan assay; n=386, and LightCycler assay; n=98) and sequences (n=91). EGFR mutations (CTG; CGG; L858R) were found from 63 of 575 lung cancer patients. We also detected the deletion 1a type mutations (2235-2249 del GGAATTAAGAGAAGC) from 39 patients and deletion 1b type mutations (2236-2250 del GAATTAAGAGAAGCA) from 15 patients in exon 19. These mutation statuses were significantly correlated with gender, smoking status (never smoker versus smoker), and pathological subtypes (adenocarcinoma versus non-adenocarcinoma). L858R mutation (p<0.0001), but not deletion 1 type mutation (p=0.0665), was correlated with differentiation status (well versus moderately or poorly) of lung cancers. L858R mutation ratio was significantly higher in non-smoker (p=0.0496) and adenocaicinoma (p=0.0136) when compared to deletion 1 type mutations. The EGFR mutation status, especially L858R mutation might be correlated with the clinico-pathological features related to good response to gefitinib, such as gender, smoking history, and pathological subtypes of Japanese lung cancers.

Adenocarcinoma↗
PubMed2005

The EGFR mutation and its correlation with response of gefitinib in previously treated Chinese patients with advanced non-small-cell lung cancer.

BACKGROUND: The aim of the study was to evaluate the efficacy of gefitinib and the epidermal growth factor receptor (EGFR) mutation to gefitinib response in a series of Chinese patients with pretreated advanced non-small-cell lung cancer (NSCLC). METHODS: A total of 98 patients who had failed at least one platinum-based regimen received gefitinib 250 mg once daily. The mutation analysis of the EGFR kinase domain was performed for 30 patients using paraffin-embedded tumor tissue. RESULTS: The response rate was 31.6% and the disease control rate was 67.3%. Objective response was correlated with adenocarcinoma, female gender and non-smokers. Median progress free survival (PFS) was 7.0 months, median overall survival (OS) was 12.0 months and 1-year survival was 53.1%. The median PFS and OS were improved among patients with adenocarcinoma, gefitinib responders and non-smokers. Active gene mutation was detected in 12 patients. Mutation rates were higher among gefitinib responders, non-smokers, patients with adenocarcinoma and female patients. OS was longer for patients with gene mutation than for patients without mutation. CONCLUSION: Gefitinib demonstrated significant antitumor activity with a favorable toxicity profile for pretreated Chinese patients with advanced NSCLC. The active mutation of the EGFR kinase domain was strongly associated with response to gefitinib and prolonged overall survival.

Adenocarcinoma↗
PubMedDate not supplied

Epidermal growth factor receptor (EGFR): mutational and protein expression analysis in gastric cancer.

BACKGROUND: Since specific epidermal growth factor receptor (EGFR) somatic mutations have been demonstrated to influence the response to anti-EGFR therapy in non-small cell lung cancer, EGFR gene mutational analysis of different types of neoplasm is under investigation. PATIENTS AND METHODS: EGFR protein expression and gene mutations in exons 18, 19 and 21 were investigated in 49 gastric adenocarcinomas. RESULTS: no specific EGFR gene mutations were detected, while EGFR positive staining was detected in 6% of the cases. CONCLUSION: Our findings indicate that in gastric adenocarcinoma, specific EGFR gene mutations are very rare or absent and the rate of EGFR protein expression is low.

Adenocarcinoma↗
PubMed2006

Identification of EGFR mutations in esophageal cancer.

BACKGROUND: It is well known that the prognosis for esophageal cancer is worse than for other digestive cancers in spite of multimodality treatment, and there is an urgent need to improve this situation. The epidermal growth factor receptor (EGFR) inhibitor, gefitinib, was approved in Japan to treat advanced non-small cell lung cancer patients and several papers have since reported that the successfully treated patients had genetic mutations in EGFR. PURPOSE: The aim of this study was to investigate the existence of EGFR mutations in esophageal cancer cell lines and primary lesions, and also to explore the possibility of treating esophageal cancer using gefitinib. MATERIALS AND METHODS: Nineteen esophageal cancer cell lines were cultured and DNA was extracted using an ultracentrifugation method. Fifty cases of primary cancer and corresponding normal tissue samples were obtained and DNA was extracted using the same protocol. Nested PCR and DNA sequencing targeting exons 18, 19, 20 and 21 of EGFR were performed to investigate the presence of mutations in esophageal cancer cell lines and primary tumors. RESULTS: Three of the 19 cell lines had the same silent mutation at nucleotide 2607, a G-to-A substitution in exon 20. One of the 50 patients had an EGFR mutation in codon 719, resulting in an amino acid substitution from glycine to aspartic acid. CONCLUSION: EGFR mutations in esophageal carcinoma are rare but do exist, and thus gefitinib could be included in esophageal cancer treatment regimens by selecting those patients who possess such mutations.

Biomarkers, Tumor↗
PubMed2006

Molecular context of the EGFR mutations: evidence for the activation of mTOR/S6K signaling.

PURPOSE: Activating somatic mutations in the epidermal growth factor receptor (EGFR) gene are present in a small subset of lung adenocarcinomas. These mutations cluster in specific regions and confer sensitivity to inhibitors of the tyrosine kinase activity of EGFR. To further determine the genetic and molecular characteristics of tumors carrying EGFR gene mutations, we investigated the EGFR gene status in lung adenocarcinomas and evaluated its association with specific characteristics of the patients and tumors, such as mutations at KRAS and p53, EGFR and ErbB2 gene amplification, levels of EGFR and HER2 proteins, and levels of downstream effectors of EGFR, such as phospho-extracellular signal-regulated kinase and phospho-S6 proteins. EXPERIMENTAL DESIGN: The mutational status of EGFR was determined by direct sequencing in 86 primary lung adenocarcinomas and 12 lung cancer cell lines, and was correlated with a number of variables relating to the tumor and patient. A tissue microarray containing 37 lung tumors was constructed to determine, by fluorescence in situ hybridization analysis, the number of copies of EGFR and ErbB2 genes and, by immunohistochemistry, the levels of EGFR, HER2, phospho-ERK, and phospho-S6 proteins. RESULTS: EGFR gene mutations were identified in 13% of the primary tumors. The type and clustering of the mutations were identical to those previously reported. Amplification of the EGFR occurred in 14% of the tumors and could arise in tumors with EGFR mutations. Interestingly, mTOR activation, as measured indirectly by augmented levels of phospho-S6 protein, was more frequent in tumors with gene alterations in either EGFR or KRAS (P = 0.00005; Fisher's exact test) than in their wild-type counterparts. CONCLUSIONS: Our data agree with the accumulation of EGFR mutations in a subset of patients with lung cancer. Moreover, we report EGFR gene amplification in EGFR-mutant tumors and a positive correlation between EGFR or KRAS alterations and activation of mTOR signaling.

Adenocarcinoma↗
PubMed1997

Determination of p53 mutations, EGFR overexpression, and loss of p16 expression in pediatric glioblastomas.

Glioblastoma multiforme is a rare neoplasm in children and is often located infratentorially, particularly in the brainstem: Pediatric glioblastomas arise frequently (here 60%) outside the cerebral hemispheres. We investigated 20 pediatric glioblastomas for mutational inactivation of the p53 tumor suppressor gene, loss of p16 protein expression and overexpression of the epidermal growth factor receptor (EGFR). Mutations in the p53 gene were identified in 5/20 (25%) glioblastomas, 4 of which occurred in primary glioblastomas with a clinical history of less than 4 months and neither clinical nor histologic evidence of a less malignant precursor lesion. Loss of p16 expression was detected in 11/18 (61%) glioblastomas. Overexpression of the EGFR was infrequent (2/19, 11%) and included 1 tumor with a p53 mutation. Of 4 secondary glioblastomas that progressed from histologically diagnosed lower grade tumors, one contained a p53 mutation. Our results are at variance with similar studies in adult patients in which primary and secondary glioblastomas are characterized by EGFR overexpression and p53 mutations, respectively, suggesting that the evolution of pediatric glioblastomas follows different genetic pathways.

Adolescent↗
PubMed2005

Response to gefitinib in bronchioloalveolar carcinoma in the absence of EGFR mutation.

Mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene in non-small cell lung cancers are associated with increased sensitivity of these cancers to drugs that inhibit EGFR kinase activity such as gefitinib and erlotinib. Responses to TK inhibitors in the absence of EGFR gene mutation for BAC patients have not been reported. A case of a patient with BAC refractory to chemotherapy who responded to gefitinib in the absence of EGFR gene mutations is reported. Tyrosine kinase inhibitors may have a role in BAC in the absence of EGFR gene mutations. Additional studies on other molecular alterations of the EGFR family members are needed to better predict response to these agents.

Adenocarcinoma, Bronchiolo-Alveolar↗
PubMed1997

Epidermal growth factor receptor (EGFR) and EGFR mutations, function and possible role in clinical trials.

The epidermal growth factor receptor (EGFR) is a growth factor receptor that induces cell differentiation and proliferation upon activation through the binding of one of its ligands. The receptor is located at the cell surface, where the binding of a ligand activates a tyrosine kinase in the intracellular region of the receptor. This tyrosine kinase phosphorylates a number of intracellular substrates that activates pathways leading to cell growth, DNA synthesis and the expression of oncogenes such as fos and jun. EGFR is thought to be involved the development of cancer, as the EGFR gene is often amplified, and/or mutated in cancer cells. In this review we will focus on: (I) the structure and function of EGFR, (II) implications of receptor/ligand coexpression and EGFR mutations or overexpression, (III) its effect on cancer cells, (IV) the development of the malignant phenotype and (V) the clinical aspects of therapeutic targeting of EGFR.

Clinical Trials as Topic↗
PubMed2006

Detection of epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) using a fully automated system with a nano-scale engineered biomagnetite.

A fully automated system using nano-scale engineered biomagnetite was developed to detect mutations in the epidermal growth factor receptor (EGFR) gene in non-small cell lung cancer (NSCLC). Bacterial magnetic particles (BacMPs) were isolated from the magnetic bacterium Magnetospirillum magneticum AMB-1 and conjugated to streptavidin. Biotin-labeled target PCR products were then captured with the BacMPs, hybridized with the detection probe and detected by fluorescence signaling. The process was performed using a newly designed automated processor equipped with an XYZ mobile arm containing a 96-way automated pipetter, reagent dispenser and fluorescence detector. Two types of somatic mutations (in-frame deletions and point substitutions) in the EGFR gene were successfully identified within 3.5h using this system, suggesting that this system could be used in clinical tests of EGFR gene mutations in lung cancer, and potentially other cancer, patients. Additionally, a very low mutation rate could be detected in these samples.

Carcinoma, Non-Small-Cell Lung↗
PubMed2005

EGFR mutation and resistance of non-small-cell lung cancer to gefitinib.

Mutations of the epidermal growth factor receptor (EGFR) gene have been identified in specimens from patients with non-small-cell lung cancer who have a response to anilinoquinazoline EGFR inhibitors. Despite the dramatic responses to such inhibitors, most patients ultimately have a relapse. The mechanism of the drug resistance is unknown. Here we report the case of a patient with EGFR-mutant, gefitinib-responsive, advanced non-small-cell lung cancer who had a relapse after two years of complete remission during treatment with gefitinib. The DNA sequence of the EGFR gene in his tumor biopsy specimen at relapse revealed the presence of a second point mutation, resulting in threonine-to-methionine amino acid change at position 790 of EGFR. Structural modeling and biochemical studies showed that this second mutation led to gefitinib resistance.

Aged↗
PubMed2004

Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways.

Gefitinib (Iressa, Astra Zeneca Pharmaceuticals) is a tyrosine kinase inhibitor that targets the epidermal growth factor receptor (EGFR) and induces dramatic clinical responses in nonsmall cell lung cancers (NSCLCs) with activating mutations within the EGFR kinase domain. We report that these mutant EGFRs selectively activate Akt and signal transduction and activator of transcription (STAT) signaling pathways, which promote cell survival, but have no effect on extracellular signal-regulated kinase signaling, which induces proliferation. NSCLC cells expressing mutant EGFRs underwent extensive apoptosis after small interfering RNA-mediated knockdown of the mutant EGFR or treatment with pharmacological inhibitors of Akt and STAT signaling and were relatively resistant to apoptosis induced by conventional chemotherapeutic drugs. Thus, mutant EGFRs selectively transduce survival signals on which NSCLCs become dependent; inhibition of those signals by gefitinib may contribute to the drug's efficacy.

Animals↗