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1、1Clinical Implications of EGFR Expression in the Development and Progression of Solid Tumors: Focus on Non-Small Cell Lung Cancer【关键词】 EGFR,Cancer,therapy,Lung,cancer,Anti-EGFR,agentsLEARNING OBJECTIVES After completing this course, the reader will be able to: Describe the EGFR signaling pathway as
2、a target for new anticancer agents. Characterize the various EGFR agents developed for the treatment of NSCLC. 2Identify the appropriate indications for the use of these new agents. ABSTRACT Dysregulation of the epidermal growth factor receptor (EGFR) signaling pathway is associated with the develop
3、ment and progression of malignancy, and EGFR-targeted therapies offer the promise of better treatment for many types of solid tumors, including non-small cell lung cancer. Anti-EGFR agents include monoclonal antibodies (mAbs) targeting the EGFR extracellular receptor domain and small-molecule tyrosi
4、ne kinase inhibitors (TKIs) targeting the EGFR intracellular kinase domain. Both mAbs and TKIs have demonstrated encouraging results as monotherapies and in combination with chemotherapy and radiotherapy. This review provides a critical update on the status of these novel therapeutics. INTRODUCTION
5、Lung cancer is a major cause of morbidity and 3mortality worldwide. In the U.S., 172,570 new cases and 163,510 related deaths were predicted for 2005, with lung cancer comprising 29% of all cancer deaths 1, 2. Between 80% and 87% of newly diagnosed lung cancers are non-small cell lung cancer (NSCLC)
6、. Advanced presentation and lack of effective treatment options afford poor prognoses 3, 4, and despite notable technological progress, improvements in NSCLC survival over the past two decades have been modest 5. This review focuses on new approaches in NSCLC therapy using monoclonal antibodies (mAb
7、s) and tyrosine kinase inhibitors (TKIs) targeting molecules involved in tumor growth and angiogenesis, including the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF). CURRENT CONCEPTS IN ADVANCED NSCLC CHEMOTHERAPY Chemotherapy for advanced, inoperable NSCLC is
8、generally palliative. The potential benefits of improved tumor 4size, symptoms, and quality of life are mitigated by the disadvantages of increased hospitalization, inconvenience, cost, and serious adverse events 6. The advent of paclitaxel, gemcitabine, vinorelbine, irinotecan, and topotecan and th
9、eir combination with platinum drugs has modestly improved response rates (RRs) and survival (Table 1) 3, 6. Although cisplatin combinations with any of the newer agents produce longer survival times than carboplatin combinations 7, no particular platinum-based regimen has demonstrated superior effic
10、acy over any other. A randomized, controlled study comparing paclitaxel plus carboplatin with vinorelbine plus cisplatin in 202 patients with advanced NSCLC demonstrated fewer life-threatening toxicities and greater convenience and tolerability for paclitaxel plus carboplatin but a similar overall R
11、R and median survival time 8. A randomized, controlled study evaluating four platinum-containing regimens in 1,155 patients found that the overall RR and survival time did not differ significantly for paclitaxel plus cisplatin, gemcitabine plus cisplatin, docetaxel plus cisplatin, and paclitaxel plu
12、s carboplatin, although paclitaxel plus carboplatin had lower toxicity 9. Other randomized, controlled studies showed that the gemcitabine plus cisplatin 5and gemcitabine plus paclitaxel did not produce a longer overall survival time compared with paclitaxel plus cisplatin 10 and that docetaxel plus
13、 cisplatin produced more favorable overall response and survival rates than vinorelbine plus cisplatin 11. Median survival times for patients receiving these standard chemotherapy regimens have generally been 811 months. A triweekly docetaxel regimen is the current standard for second-line chemother
14、apy in NSCLC, with an approximately 12% RR and 68 months median survival time 12. Weekly paclitaxel courses have been well received and have resulted in an approximately 9 months median survival time 13. Pemetrexed, compared with docetaxel as second-line treatment for NSCLC in phase III studies, app
15、eared to have similar efficacy but significantly fewer adverse effects 14. Despite these advancements, a plateau of effectiveness appears to have been reached for the treatment of NSCLC with standard chemotherapy 3, and substituting one agent for another in combination chemotherapy regimens does not
16、 necessarily guarantee a significantly better overall RR and 6survival 15. Current research efforts in both first- and second-line treatments for NSCLC focus on a number of promising agents targeted against the EGFR signaling pathway. EGFR BIOLOGY AND EXPRESSION IN NSCLC EGFR, a member of the HER/Erb-B family of receptor tyrosine kinases, mediates cell proliferation, differentiation, survival, angiogenesis, and migration 16. This mole
