Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are associated with increased sensitivity to tyrosine kinase inhibitors (TKIs) and are present in 10-30% of non-small cell lung carcinoma depending on ethnic origin. EGFR protein is also overexpressed in about 90% of squamous cell carcinoma of head and neck (HNSCC), and treatment with TKIs has shown clinical benefit in a subgroup of these patients. Recently, EGFR mutations were described in three Asian patients with larynx cancer. We screened for EGFR tyrosine kinase mutations in tumour DNA of 100 patients of Caucasian origin with HNSCC by direct sequencing of the hotspot regions. Only one patient with larynx cancer displayed a novel, somatic EGFR missense mutation, K745R, affecting a highly conserved residue within the ATP cleft. Similar to reports in lung cancer, EGFR kinase domain mutations in HNSCC patients seem to show a lower incidence in patients of Caucasian origin.
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PMID:Low incidence of mutations in EGFR kinase domain in Caucasian patients with head and neck squamous cell carcinoma. 1632 36

Gefitinib exhibits antitumor activity in patient with non-small cell lung cancer (NSCLC). However, only 10-20% of patients exhibit clinical response to this drug. The molecular mechanisms underlying gefitinib sensitivity remain unknown. Peroxisome proliferators-activated receptor-gamma (PPAR-gamma) plays roles in the regulation of cellular differentiation and growth. This regulation was mediated by increasing Phosphatase and tensin homologue deleted on chromosome Ten (PTEN) levels. PTEN plays a role in the modulation of the phosphatidylinositol 3-kinase pathway (PI3K), which is involved in cell proliferation and survival. This study investigated the effects of PPAR-gamma agonist (rosiglitazone) on the expression of PTEN, as well as EGFR tyrosine kinase inhibitor (gefitinib)'s antitumor activity in A549 cells. The treatment of A549 cells with rosiglitazone reduced the growth of A549 cells in a dose-dependent manner, and facilitated the anti-proliferative effects of gefitinib. PPAR-gamma and PTEN expression were found to have increased in the gefitinib- and rosiglitazone-treated cells. This suggests that PPAR-gamma agonist (rosiglitazone) potentiated gefitinib's anti-proliferative effects by increased of PTEN expression, and suggest that PPAR-gamma ligands may serve as potential therapeutic agents for NSCLC.
Lung Cancer 2006 Mar
PMID:PPAR-gamma agonist increase gefitinib's antitumor activity through PTEN expression. 1638 27

Epidermal growth factor receptor (EGFR) gene mutations are frequently detected in lung cancer, especially in adenocarcinoma, in females, and non-smoking patients. EGFR mutations are closely associated with clinical response to EGFR tyrosine kinase inhibitor. Bronchioloalveolar carcinoma (BAC) appearance is a good predictor of response to this agent. Noguchi et al. subdivided small peripheral adenocarcinoma of the lung into two groups. One group was characterized with tumor cell growth replacing the normal alveolar cells with varying degree of fibrosis (types A-C), and the other shows non-replacing and destructive growth (types D-F). Using probes for the 13 mutations which have been previously described, we have genotyped the EGFR gene status in surgically resected atypical adenomatous hyperplasias (AAH) and small peripheral adenocarcinomas up to 2 cm in diameter using TaqMan PCR assay. In 95 small-sized adenocarcinomas, the EGFR mutations were detected in 37 patients (38.9%), and no mutations were found in five AAHs. In small peripheral adenocarcinomas, EGFR mutations were found 47.1% of types A, B, or C adenocarcinomas; it was less frequent (16%) in Noguchi's types D, E or F adenocarcinomas. These results suggest that type D, F adenocarcinomas are not derived from the less malignant types A-C adenocarcinomas; rather, they have arisen de novo by distinct mechanisms. Although types A and B adenocarcinomas are almost 100% cured by surgery, some type C adenocarcinoma show lymph node metastasis and relapse. EGFR mutation analysis may help identify patients who will respond to treatment with tyrosine kinase inhibitors, e.g., gefitinib.
Lung Cancer 2006 Apr
PMID:Epidermal growth factor receptor gene mutation defines distinct subsets among small adenocarcinomas of the lung. 1715 91

Gefitinib--a specific inhibitor of epidermal growth factor receptor (EGFR)-associated tyrosine kinase--has demonstrated efficacy in a subgroup of patients with non-small-cell lung carcinoma (NSCLC) who fail conventional chemotherapy. It is also reported to have an antitumor effect in brain metastases from NSCLC. Additionally, EGFR mutations have shown a strong association with gefitinib sensitivity for NSCLC. Here, we assessed the efficacy of gefitinib in brain metastases from NSCLC and evaluated the association of this efficacy with EGFR mutations. We retrospectively reviewed eight cases in which patients were suffering from brain metastases before the initiation of gefitinib treatment. Brain tumor response could be evaluated by MRI in these patients; EGFR gene analyses were also available. We evaluated whether objective tumor response was observed after gefitinib treatment and assessed the efficacy of gefitinib as effective, noneffective, or not assessable in consideration of the influence of previous radiotherapy. Of the eight patients, the efficacy of gefitinib was assessed as effective in three and as noneffective in three. All three patients demonstrating effective efficacy had EGFR mutations in the tyrosine kinase domain (deletion mutation in two patients and point mutation in one patients), whereas none of the three patients demonstrating noneffective efficacy had EGFR mutations. Gefitinib appears to be effective in treating brain metastases in a subgroup of patients. Our data suggested a possible association between the efficacy of gefitinib in the treatment of brain metastases and EGFR mutations.
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PMID:EGFR mutations in patients with brain metastases from lung cancer: association with the efficacy of gefitinib. 1651 Aug 49

Gefitinib (ZD1839), a small-molecule epidermal growth factor receptor tyrosine kinase inhibitor, is an anticancer agent for patients with non-small cell lung carcinoma. Recently, however, as a result of accumulating evidence, it has been recognized that gefitinib can give rise to lethal lung toxicity. The authors report a case of interstitial lung disease (ILD) induced by gefitinib, which improved promptly following cessation of the administration of the agent. Clinical signs suggesting a good prognosis were noted, namely, findings similar to acute eosinophilic pneumonia on CT and a disassociation in the elevation of specific serum markers of ILD. At the time of onset of ILD, serum concentrations of surfactant protein (SP)-A and SP-D were significantly increased, whereas that of KL-6 was not increased. A previous study of three cases of lethal lung toxicity resulting from gefitinib administration revealed a significant and almost equal increase in KL-6, SP-A and SP-D. These results suggest that SP-A and SP-D may be indicators of gefitinib-induced ILD and that KL-6 is a predictor of outcome. Using a combination of these markers may help to establish a differential prognosis in patients with gefitinib-induced ILD.
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PMID:Gefitinib-induced interstitial lung disease showing improvement after cessation: disassociation of serum markers. 1654 9

Our objective was to evaluate gefitinib (IRESSA), an epidermal growth factor receptor tyrosine kinase inhibitor, versus docetaxel as second-line monotherapy for advanced non-small-cell lung cancer (NSCLC). SIGN (Second-line Indication of Gefitinib in NSCLC; code 1839IL/0503) was a multicenter, randomized, parallel-group, open-label, phase II trial that investigated oral gefitinib (250 mg/day) or i.v. docetaxel (75 mg/m2 every 3 weeks) in patients with advanced NSCLC who had previously received one chemotherapy regimen. The primary objective was assessment of symptom improvement (using the FACT-L Lung Cancer Subscale). Secondary objectives included quality of life (FACT-L total score), response rate (using RECIST), overall survival and safety. This trial recruited 141 patients (68 to gefitinib and 73 to docetaxel) who received treatment for a median duration of 3.0 (gefitinib) and 2.8 (docetaxel) months. Similar efficacy was observed with gefitinib and docetaxel, 36.8 and 26.0% symptom improvement rates, 33.8 and 26.0% quality-of-life improvement rates, 13.2 and 13.7% objective response rates, and 7.5 and 7.1 months median overall survival, respectively. Fewer drug-related adverse events were observed with gefitinib compared with docetaxel (all grades: 51.5 versus 78.9%; Common Toxicity Criteria grade 3/4: 8.8 versus 25.4%). There were no withdrawals or deaths due to drug-related adverse events with gefitinib, while three patients withdrew and three died due to adverse events in the docetaxel group that were possibly drug related. We conclude efficacy with gefitinib was similar to docetaxel, but with a more favorable tolerability profile, in the second-line treatment of advanced NSCLC. These results support further investigation of gefitinib in this disease setting.
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PMID:Phase II, open-label, randomized study (SIGN) of single-agent gefitinib (IRESSA) or docetaxel as second-line therapy in patients with advanced (stage IIIb or IV) non-small-cell lung cancer. 1654 97

Gefitinib, a tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), produces radiographic regression and symptom relief in patients with refractory advanced non-small cell lung cancer. However, it remains controversial whether gefitinib improves patient survival. We report three cases of refractory metastatic non-small cell lung cancer who have survived approximately 3 years since they first started gefitinib. These long-term survivors were Japanese female non-smokers with adenocarcinoma, who often had multiple lung metastases and were effectively re-treated with gefitinib. One patient had a surgical specimen available for DNA extraction and showed deletions in exon 19 of EGFR. Our experience suggests that gefitinib may improve long-term survival in selected patients. Further studies are required to identify biomarkers downstream of the EGFR mutations that are involved in multiple lung metastases and which could identify those patients who may benefit from gefitinib re-treatment.
Lung Cancer 2006 May
PMID:Long-term survival in three patients with metastatic non-small cell lung cancer treated with gefitinib. 1672 71

Somatic tyrosine kinase (TK) domain mutations of the epidermal growth factor receptor (EGFR) gene are associated with sensitivity of non-small cell lung cancer (NSCLC) to tyrosine kinase inhibitors (TKI's), however their incidence in distinct populations is not clarified. We sequenced exons 18-21 of the EGFR TK domain from 60 Greek and Czech patients, enrolled in an adjuvant chemotherapy trial following total resection for stages I-IIIa disease. Somatic mutations were found in 9/60 patients (15.0%), several being novel. EGFR mutations were more common in Stage I tumors (p = 0.023), they were also more common in women and never smokers; however, no other significant association of clinicopathological features with mutations was found. Median TTP and OS of patients with and without mutations were 13.2 and 40 months compared to 22.9 and 43.2 months, respectively. These differences were not statistically significant. K-ras (5/60, 8%) and EGFR mutations were found to be mutually exclusive. We identified a wide spectrum of somatic EGFR TK mutations reporting a relatively high incidence (15%) in NSCLC patients of Greek and Czech origin. As ethnicity seems to be a factor for the origin of these mutations, further studies in distinct populations are warranted.
Lung Cancer 2006 May
PMID:Mutations of the epidermal growth factor receptor tyrosine kinase domain and associations with clinicopathological features in non-small cell lung cancer patients. 1656 21

c-kit, a growth factor receptor with tyrosine kinase activity, plays an important role in the biology of cancer. Its expression has been documented in several malignancies. We performed a retrospective study in 85 patients diagnosed with small cell lung cancer (SCLC) to determine the prevalence and role of c-kit as a possible prognostic marker in this lung cancer malignancy. Demographic and clinical data were obtained from patient charts. c-kit, analyzed as immunohistochemical expression in paraffin-embedded tumour tissues, was observed in 60% of patients. All patients were former or present smokers. At diagnosis, 46% of the patients had limited disease (LD) and 54% extended disease (ED). c-kit expression was observed in 59% of LD and 61% of ED patients (p=0.4). Patients received a median of 4 cycles first-line combination chemotherapy (platinum and etoposide). In LD patients, time to progression (TTP) was 11.5 months in c-kit (+) versus 5.9 in c-kit (-) patients (p=0.14), and median survival 15.4 and 12.8 months, respectively (p=0.33). In the ED group, TTP was 5.5 months in c-kit (+) versus 3.8 in c-kit (-) patients (p=0.34), whereas median survival was 6.3 and 7.9 months, respectively (p=0.45). With the limited number of patients in mind, our findings tended towards an association between c-kit expression and survival in the LD group.
Lung Cancer 2006 Jun
PMID:Analysis of c-kit expression in small cell lung cancer: prevalence and prognostic implications. 1657 70

Gefitinib (Iressatrade mark) is an epidermal growth factor receptor tyrosine kinase inhibitor that has been approved for the treatment of lung cancer in Japan, however, after marketing several cases of severe pulmonary toxicity were reported. The West Japan Thoracic Oncology Group conducted an independent survey of acute pulmonary toxicity and interstitial lung disease (ILD) caused by gefitinib in its member's institutions. The purpose of this study was to clarify the image characteristics of ILD caused by the molecular-targeting drug gefitinib. A total of 1976 patients had been treated with gefitinib between August and December 2002, and 102 of them were suspected of having acute pulmonary toxicity and ILD. A final definite diagnosis of gefitinib-induced ILD was made by at least three radiologists based on a review and analysis of the chest radiography and CT findings plus the clinical data in the medical records. The imaging findings were classified into four patterns: (A) a nonspecific area with ground-glass attenuation, (B) a multifocal area of airspace consolidations, (C) patchy distribution of ground-glass attenuation accompanied by interlobar septal thickening, and (D) extensive bilateral ground-glass attenuation or airspace consolidations with traction bronchiectasis. CT as well as chest radiography had been performed in 65 of the 102 patients at the onset of ILD, and chest radiography alone had been performed in 26. After excluding 11 cases with insufficient data and 21 cases concluded to be other pulmonary diseases, 70 patients were diagnosed with gefitinib-induced ILD. Finally, the diagnostic image findings were classified as pattern A in 29 cases, pattern B in 7 cases, pattern C in 3 cases, pattern D in 20 cases and others in 11 cases. The CT images were classified as pattern A, B, C, and D in 24, 7, 1, and 12 cases, respectively. The mortality rate was significantly higher in the patients with pattern D than the other patterns. Pattern D were thought to represent the features of diffuse alveolar damage. In conclusion, the molecular-targeting drug gefitinib induces pulmonary toxicity at a certain rate and the imaging findings of ILD induced by gefitinib are similar to those of pulmonary toxicity induced by conventional antineoplastic agents.
Lung Cancer 2006 May
PMID:Imaging of gefitinib-related interstitial lung disease: multi-institutional analysis by the West Japan Thoracic Oncology Group. 1657 71


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