Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0001418 (adenocarcinoma)
68,496 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gefitinib is a small molecule that specifically inhibits the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) type 1 by interfering with the adenosine triphosphate (ATP) binding site. At doses that maximally inhibit EGFR tyrosine kinase activity chosen for phase II trials, the most common side effects of gefitinib are low-grade rash or diarrhea. An infrequent but serious side effect of gefitinib is interstitial lung disease (ILD). The Iressa dose evaluation for advanced lung cancer phase II trials (IDEAL 1 and IDEAL 2) of single agent gefitinib, 250 or 500 mg orally per day in pretreated patients with non-small cell lung cancer (NSCLC), found about 20% of patients on IDEAL-1 and 10% of patients on IDEAL-2 had major objective responses and improvement of symptoms. The data from the IDEAL trials and the extensive experience from the 21,000 patients treated on the expanded access program, suggests that the patients who have a major objective response probably have a significant survival benefit in addition to palliative benefit. In addition, approximately 40% of patients on the IDEAL trials experienced improvement in symptoms. Gefitinib was approved for third line treatment of NSCLC. Gefitinib is effective, safe, and well-tolerated single-agent therapy in previously treated NSCLC. Although there have been no direct comparisons, the small molecule inhibitors of EGFR gefitinib and erlotinib appear to have similar efficacy. Erlotinib has been shown to produce a survival advantage compared to best supportive care in an unselected group of previously treated patients with NSCLC. Until similar trials are completed comparing gefitinib to best supportive care, there is a similar survival advantage for gefitinib. Nonsmokers, women, and patients with adenocarcinoma, are more likely to have major objective responses than other patients. Bronchioalveolar lung cancer is a subtype of NSCLC that is more likely to respond to gefitinib. Several groups have now reported that most, but not all, tumors experiencing a major objective response to gefitinib have mutations associated with the ATP-binding site of EGFR. It is reasonable to move gefitinib in to second-line therapy for patients who are known to have a tumor that is more likely to respond to gefitinib. Also, I would treat such patients with gefitinib as first-line therapy on an appropriate clinical trial approved by the Institutional Review Board (IRB). Outside of a clinical trial, patients with advanced disease should initially be treated with a combination of doublet chemotherapy. There is strong evidence that there is no benefit to concurrent chemotherapy and gefitinib. Gefitinib should not be given concurrently with cytotoxic chemotherapy as initial treatment for NSCLC. Sequential therapy combining chemotherapy and gefitinib in advanced disease or as adjuvant therapy should only be done in the context of a clinical trial approved by the IRB. There is preclinical evidence suggesting that gefitinib is a radiosensitizer. Early results from trials combining radiation, or chemoradiotherapy with gefitinib have shown that these combinations are without excessive additive toxicity. There is no proven clinical benefit for concurrent Gefitinib and radiation. Gefitinib should only be given with radiation as part of an appropriate clinical trial approved by the IRB.
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PMID:Gefitinib therapy for non-small cell lung cancer. 1561 Jul 17

The epidermal growth factor receptor (EGFR) is a promising target in the treatment of advanced stage non-small-cell lung cancer (NSCLC). Currently erlotinib and gefitinib are approved by the US Food and Drug Administration, whereas cetuximab is being studied for use in NSCLC. Erlotinib has shown a survival advantage in patients with advanced NSCLC. Further studies have identified female sex, nonsmokers, Asian race, good performance status, and adenocarcinoma histology as predictors of patient response to these agents. A genetic mutation in EGFR has also been correlated with an increase in response.
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PMID:Epidermal growth factor receptor inhibitors and their role in non-small-cell lung cancer. 1594 81

Over the past few years, two epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), gefitinib (Iressa) and erlotinib (Tarceva), have been developed for the treatment of patients with cancer. In patients with non-small cell lung cancer (NSCLC), these therapies occasionally demonstrate remarkable and durable activity. However, EGFR TKIs are active in only a small subset of patients. Responders are more often nonsmokers, of East Asian descent, and female, and have tumors with adenocarcinoma histology. In April 2004, two groups reported that a cluster of somatic mutations in the kinase domain of the EGFR are observed in the majority of NSCLCs that demonstrate remarkable responses to EGFR TKIs. These findings have been validated by other investigators and have revolutionized the manner in which clinicians are thinking about their utilization for the treatment of NSCLC. This review focuses on the clinical experience with EGFR TKIs, the present knowledge regarding the biology of EGFR mutations, the limitations of using EGFR mutational status to predict who will respond to EGFR TKIs, and the implications of this information on the use of these agents for the treatment of advanced NSCLC.
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PMID:Factors predicting response to EGFR tyrosine kinase inhibitors. 1605 33

Esophageal cancer is the sixth most common cause of cancer-related death worldwide. Because of very poor 5-year survival new therapeutic approaches are mandatory. Erlotinib (Tarceva), an inhibitor of epidermal growth factor receptor tyrosine kinase (EGFR-TK), potently suppresses the growth of various tumors but its effect on esophageal carcinoma, known to express EGFR, remains unexplored. We therefore studied the antineoplastic potency of erlotinib in human esophageal cancer cells. Erlotinib induced growth inhibition of the human esophageal squamous cell carcinoma (ESCC) cell lines Kyse-30, Kyse-70 and Kyse-140, and the esophageal adenocarcinoma cell line OE-33, as well as of primary cell cultures of human esophageal cancers. Combining erlotinib with the EGFR-receptor antibody cetuximab, the insulin-like growth factor receptor tyrosine kinase inhibitor tyrphostin AG1024, or the 3-hydroxy-3-methylglutaryl coenzyme. A reductase (HMG-CoAR) inhibitor fluvastatin resulted in additive or even synergistic antiproliferative effects. Erlotinib induced cell cycle arrest at the G1/S checkpoint. The erlotinib-mediated signaling involved the inactivation of EGFR-TK and ERK1/2, the upregulation of the cyclin-dependent kinase inhibitors p21(Waf1/CIP1) and p27(Kip1), and the downregulation of the cell cycle promoter cyclin D1. However, erlotinib did not induce immediate cytotoxicity or apoptosis in esophageal cancer cells. The inhibition of EGFR-TK by erlotinib appears to be a promising novel approach for innovative treatment strategies of esophageal cancer, as it powerfully induced growth inhibition and cell cycle arrest in human esophageal cancer cells and enhanced the antineoplastic effects of other targeted agents.
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PMID:Targeting the epidermal growth factor receptor by erlotinib (Tarceva) for the treatment of esophageal cancer. 1621 53

Cisplatin (Platinol; Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com) and carboplatin (Paraplatin; Bristol-Myers Squibb), together with newer chemotherapies, such as docetaxel (Taxotere; Aventis Pharmaceuticals Inc., Bridgewater, NJ, http://www.aventispharma-us.com), paclitaxel (Taxol; Bristol-Myers Squibb), vinorelbine (Navelbine; GlaxoSmith-Kline, Philadelphia, http://www.gsk.com), pemetrexed (Alimta; Eli Lilly and Company, Indianapolis, http://www.lilly.com), and gemcitabine (Gemzar; Eli Lilly and Company), have improved treatment outcomes in both advanced non-small cell lung cancer (NSCLC) and in the adjuvant/neoadjuvant setting. Newer systemic treatments for NSCLC, used in advanced stage IV management, are beginning to be studied in earlier stages of the disease, when treatment is better tolerated and potentially curative. Hopefully, newer agents with proven efficacies in advanced disease will enhance curability. Following the successful addition of bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA, http://www.gene.com) to carboplatin/paclitaxel in advanced disease, bevacizumab is now being incorporated into adjuvant and neoadjuvant trials. Trials in stage IB-IIIA patients will study neoadjuvant docetaxel/cisplatin/bevacizumab. The discovery that patients with exon 19 and 21 mutations in the epidermal growth factor receptor gene EGFR have around an 80% response rate to gefitinib (Iressa; AstraZeneca Pharmaceuticals, Wilmington, DE, http:// www.astrazeneca-us.com) and that this response confers survival benefit indicates its potential utility for mutation-positive patients with advanced- and earlier-stage disease. Clinical characteristics, such as never smoking status and adenocarcinoma, and especially bronchioloalveolar carcinoma histological features, can also identify individuals likely to respond to EGFR tyrosine kinase inhibitors. Studies of neoadjuvant erlotinib (Tarceva; OSI Pharmaceuticals, Inc., Melville, NY, http://www.osip.com) in operable NSCLC are planned. One such study includes cisplatin and docetaxel. Effective development of active agents and disease management based on molecular profiling of lung tumors will change tomorrow's standard of care.
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PMID:How today's developments in the treatment of non-small cell lung cancer will change tomorrow's standards of care. 1627 56

The tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva) have shown anti-tumor activity in the treatment of non-small cell lung cancer (NSCLC). Dramatic and durable responses have occurred in NSCLC tumors with mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). In contrast, these inhibitors have shown limited efficacy in glioblastoma, where a distinct EGFR mutation, the variant III (vIII) in-frame deletion of exons 2-7, is commonly found. In this study, we determined that EGFRvIII mutation was present in 5% (3/56) of analyzed human lung squamous cell carcinoma (SCC) but was not present in human lung adenocarcinoma (0/123). We analyzed the role of the EGFRvIII mutation in lung tumorigenesis and its response to tyrosine kinase inhibition. Tissue-specific expression of EGFRvIII in the murine lung led to the development of NSCLC. Most importantly, these lung tumors depend on EGFRvIII expression for maintenance. Treatment with an irreversible EGFR inhibitor, HKI-272, dramatically reduced the size of these EGFRvIII-driven murine tumors in 1 week. Similarly, Ba/F3 cells transformed with the EGFRvIII mutant were relatively resistant to gefitinib and erlotinib in vitro but proved sensitive to HKI-272. These findings suggest a therapeutic strategy for cancers harboring the EGFRvIII mutation.
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PMID:Epidermal growth factor receptor variant III mutations in lung tumorigenesis and sensitivity to tyrosine kinase inhibitors. 1667 72

Bevacizumab is a recombinant, humanized monoclonal antibody against vascular endothelial growth factor. Erlotinib HCl is a reversible, highly selective epidermal growth factor receptor tyrosine kinase inhibitor. Additionally, both agents have shown benefit in patients with previously treated non-small cell lung cancer (NSCLC). Preclinical data in xenograft models produced greater growth inhibition with the combination than with either agent alone. A phase I/II study in two centers examined combined erlotinib and bevacizumab treatment in patients with nonsquamous stage IIIB/IV NSCLC with one or more prior chemotherapy. In phase I, 150 mg/d erlotinib orally plus 15 mg/kg bevacizumab i.v. every 21 days was established as the phase II dose. A total of 40 patients were enrolled and treated in this study (34 patients at phase II dose): 21 were female, 30 had adenocarcinoma histology, 9 were never smokers, and 22 had two or more prior regimens. The most common adverse events were mild to moderate rash, diarrhea, and proteinuria. Preliminary data showed no pharmacokinetic interaction between erlotinib and bevacizumab. Eight patients (20.0%) had partial responses and 26 (65.0%) had stable disease as their best response. The median overall survival for the 34 patients treated at the phase II dose was 12.6 months, with progression-free survival of 6.2 months. Encouraging antitumor activity and safety of erlotinib plus bevacizumab support further development of this combination for patients with advanced NSCLC. A randomized phase II trial has been completed, and a phase III trial is ongoing.
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PMID:Combining targeted agents: blocking the epidermal growth factor and vascular endothelial growth factor pathways. 1685 21

Erlotinib, a potent inhibitor of the tyrosine-kinase (TK) activity of human epidermal growth factor receptor (HER1/EGFR), produces significant survival and quality of life benefits in patients with previously treated advanced-stage non-small-cell lung cancer. Although the survival benefit from erlotinib was observed in varied subgroups of patients, the radiographic responses were more common in certain patient subgroups, such as women, never-smokers, patients with adenocarcinoma histology, patients of Asian ethnicity, and patients with presence of HER1/EGFR TK domain mutations. Herein, we describe a white male former smoker with advancedstage squamous cell non-small-cell lung cancer, who responded to first-line erlotinib. A molecular analysis of the tumor did not reveal HER1/EGFR TK mutations. This case study, along with subgroup analyses of the BR.21 phase III study, suggests that patients should not be selected for erlotinib treatment based only on characteristics, such as smoking status, tumor histology, HER1/EGFR TK mutation status, sex, or ethnicity.
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PMID:Response to erlotinib in first-line treatment of non-small-cell lung cancer in a white male smoker with squamous-cell histology. 1723 98

Two cases of erlotinib-associated acute pneumonitis are described. The first patient was started on erlotinib treatment for metastatic non-small cell lung cancer. The second patient was treated with erlotinib for metastatic adenocarcinoma of unknown origin. Both patients developed dyspnea and hypoxemia five to six days after initiation of erlotinib treatment. In both cases, computed tomography scan of the chest showed extensive bilateral ground-glass infiltrates consistent with pneumonitis. In both patients, acute pneumonitis resulted in respiratory failure requiring intubation and mechanical ventilation. Diffuse alveolar hemorrhage was excluded by bronchoscopy in both cases. Bronchoalveolar lavage cultures were negative. Erlotinib treatment was stopped and both patients were treated with corticosteroids. The first patient improved gradually and finally was discharged to a rehabilitation centre, but unfortunately the second patient died of Klebsiella sepsis. Naranjo causality scale in both cases suggested a probable association between erlotinib and pneumonitis. Literature on erlotinib-associated pneumonitis is sparse. The clinical presentation and radiographic findings of erlotinib-associated acute pneumonitis are described.
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PMID:Erlotinib-associated acute pneumonitis: report of two cases. 1746 82

Inoperable pancreatic adenocarcinoma is a dilemma that oncologists frequently encounter. Only 15% to 20% of patients are diagnosed when cancer of the pancreas is still surgically resectable. However, pancreaticoduodenectomy is the only curative option for this disease and should be offered to all patients who meet resection criteria and do not have significant comorbidities. For inoperable pancreatic cancer, the goals of treatment are to palliate symptoms and prolong life. Improved survival in locally advanced disease has been demonstrated with chemoradiation plus fluorouracil or with gemcitabine (Gemzar) alone. In metastatic disease, single-agent gemcitabine has been associated with improvement in symptoms and survival. Trials combining various chemotherapeutic agents with gemcitabine have not had a significant impact on overall survival, although meta-analyses suggest a small benefit. The targeted agent erlotinib (Tarceva) has shown a modest improvement in overall survival in combination with gemcitabine. This combination is another option for first-line therapy in patients with locally advanced or metastatic disease. Despite these recent advances, survival for patients with inoperable pancreatic cancer continues to be poor. Future investigations need to focus on understanding the molecular nature of this malignancy, with the goal of developing interventions based on this knowledge.
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PMID:Inoperable pancreatic cancer: standard of care. 1817 46


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