Epidermal Growth Factor Receptor Mutations in Non–Small-Cell Lung Cancer: Implications for Treatment and Tumor Biology

The epidermal growth factor receptor (EGFR) has emerged as an attractive therapeutic target for patients with non-small-cell lung cancer (NSCLC). However, despite its almost universal presence in NSCLC tumors, therapeutic inhibition of EGFR has resulted in significant tumor regressions in only 10% to 20% of patients. Several investigations over the last 12 months have uncovered somatic mutations in EGFR that underlie the sensitivity to EGFR inhibitors. NSCLC tumors and cell lines with EGFR mutations are exquisitely sensitive to the EGFR tyrosine kinase inhibitors (TKIs), erlotinib and gefitinib, and are biologically distinct from other forms of NSCLC. Somatic mutations in EGFR are found more frequently in patients with adenocarcinomas, nonsmokers, patients of Asian ethnicity, and in females. EGFR mutation detection is now becoming clinically available and is being incorporated into clinical treatment decisions and into the design of future clinical trials. Mutations in K-ras, a mediator of EGFR signaling, are mutually exclusive with EGFR mutations, and are associated with resistance to EGFR TKIs. In addition, secondary mutations, conferring resistance to EGFR TKIs, in patients with primary EGFR mutations once sensitive to EGFR TKIs, are beginning to be identified. The frequency of EGFR mutations, their impact on NSCLC biology, clinical treatment, and clinical trial design, as well as methods and limitations for mutation detection, will be reviewed.