Biological and clinical implications of EGFR mutations in lung cancer.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
It would be possible to individualize EGFR-TKI treatment of lung cancer by selecting patients according to EGFR mutational status and other biomarkers.
Mitsudomi
Tetsuya
T
Department of Thoracic Surgery, Aichi Cancer Center Hospital, Nagoya, 464-8681, Japan. mitsudom@aichi-cc.jp
Kosaka
Takayuki
T
Yatabe
Yasushi
Y
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000077156:Gefitinib; D018773:Genes, erbB-1 / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000494:pharmacology
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib