Biological and clinical implications of EGFR mutations in lung cancer
- 847 Downloads
Patients with non-small-cell lung cancer sometimes show a dramatic clinical response to gefitinib or erlotinib, small-molecule tyrosine kinase inhibitors (TKI) specific for the epidermal growth factor receptor (EGFR). However, until April 2004, it was unclear how to identify patients who would benefit from these drugs. Then, two groups from Boston reported that EGFR gene mutations in the kinase domain are strongly associated with gefitinib sensitivity. EGFR mutations are more frequent in Asians, females, nonsmokers, and adenocarcinomas than in their counterparts. These populations precisely coincide with those populations with higher response rates to TKIs. We and others subsequently confirmed and extended these findings.
We reviewed recent literatures on EGFR mutations and EGFR-TKIs. We discuss topics including the molecular epidemiology and biology of EGFR mutations in relation to EGFR-TKIs, the controversy about whether EGFR mutations account for all the clinical activity of EGFR-TKIs, and the mechanisms of acquired resistance to gefitinib or erlotinib.
The discovery of EGFR mutations has great biologic and clinical implications in lung cancer. However, all but one phase III trials have so far failed to show a survival advantage of the treatment arm involving EGFR-TKIs.
It would be possible to individualize EGFR-TKI treatment of lung cancer by selecting patients according to EGFR mutational status and other biomarkers.
Key wordsMolecular targeted therapy Tyrosine kinase inhibitor Gefitinib Individualized therapy Predictive factor
Unable to display preview. Download preview PDF.
- 20.Marchetti, A, Martella, C, Felicioni, L, et al. 2005EGFR mutations in non-small-cell lung cancer: analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatmentJ Clin Oncol23857865PubMedCrossRefGoogle Scholar
- 45.Thatcher N, Chang A, Parikh P (2005) Results of a Phase III placebo-controlled study (ISEL) of gefitinib (IRESSA) plus best supportive care (BSC) in patients with advanced non-cmall-cell lung cancer (NSCLC) who had received 1 or 2 prior chemotherapy regimens. Proc Am Assoc Cancer Res 46 (suppl): Abstract# LB-6Google Scholar
- 48.Hirsch, FR, Varella-Garcia, M, McCoy, J, et al. 2005Increased epidermal growth factor receptor gene copy number detected by fluorescence in situ hybridization associates with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes: a Southwest Oncology Group StudyJ Clin Oncol2368386845PubMedCrossRefGoogle Scholar
- 51.Thatcher, N, Chang, A, Parikh, P, et al. 2005Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer)Lancet36615271537PubMedCrossRefGoogle Scholar
- 55.Kris MG, Sandler A, Miller V, et al. (2004) Cigarette smoking history predicts sensitivity to erlotinib: results of a phase II trial in patients with bronchioloalveolar carcinoma (BAC). J Clin Oncol 22:Abstract# 7062Google Scholar