Gene Mutations in Lung Cancer: Promising Predictive Factors for the Success of Molecular Therapy

Akira Inoue,Toshihiro Nukiwa

doi:10.1371/journal.pmed.0020013

Abstract

Gefitinib and erlotinib are two new treatments for advanced lung cancer. Gene mutations in the cancer may help predict which patients will respond to these treatments.

Highlights

Lung cancer is the leading cause of cancer death in many countries
Gefitinib is the first “molecular-target agent” for lung cancer that inhibits the tyrosine kinase of the epidermal growth factor receptor (EGFR; known as ERBB1)
Subsequent randomized trials in patients with previously untreated, advanced non-small-cell lung cancer (NSCLC) have not shown a clinical advantage of gefitinib combined with standard chemotherapy over chemotherapy alone [2,3,4,5]

Summary

Molecular Therapy for Lung Cancer

Gefitinib is the first “molecular-target agent” for lung cancer that inhibits the tyrosine kinase of the epidermal growth factor receptor (EGFR; known as ERBB1). In April and May 2004, two new studies published in Science and the New England Journal of Medicine helped to explain at the molecular level the low clinical activity of EGFR inhibitors [7,8] These studies identified somatic mutations in the EGFR gene, especially around the region encoding the ATP-binding pocket of the receptor’s tyrosine kinase domain. A high incidence of mutations was detected in patients with NSCLC that had a durable clinical response to gefitinib, and subsequent studies revealed that these mutations were related to the response to erlotinib Such mutations were more frequently detected in patients with adenocarcinoma, in women, in Japanese patients, and in nonsmokers [9]—results that were compatible with previous clinical data. Another question was raised by these studies: is it only EGFR gene mutations that determine the response to EGFR inhibitors?

RAS Gene Mutations in NSCLC

Findings

Therapeutic Implications