Studies have found that the epidermal growth factor receptor (EGFR) gene is mutated in many non–small-cell lung cancers and that these mutations are associated with increased sensitivity to gefitinib (Iressa) or erlotinib (Tarceva), tyrosine kinase (TK) inhibitors that target EGFR. Recent studies have found that EGFR gene mutations are more common among females, patients from Japan, never smokers, and patients with adenocarcinomas, which are the same groups that have the highest response rates to TK inhibitors. However, little is known about how EGFR gene mutations affect lung cancer development.
To examine the role of EGFR gene mutations in the development of lung cancer, Adi F. Gazdar, M.D., of the University of Texas Southwestern Medical Center in Dallas, and colleagues searched for these mutations in primary lung tumors from patients in Japan, Taiwan, the United States, and Australia. They also examined these mutations in DNA from nonmalignant lung tissue from many of the lung cancer patients and from other epithelial cancer tissues.
In lung cancer patients, mutations in the TK domain of the EGFR gene were more common in never smokers than in smokers (51% versus 10%), adenocarcinomas versus other types of lung cancer (40% versus 3%), in patients of East Asian ancestry than in other ethnicities (30% versus 8%), and in females versus males (42% versus 14%). Mutation status was not associated with age at diagnosis, clinical stage, the presence of certain histologic features, or overall survival, and they were not found in any normal tissue or tissue from other cancer types. EGFR TK domain mutations are the first known mutation to occur in never smokers. In addition, the researchers found mutations in the KRAS gene--an EGFR signaling pathway gene--in 8% of lung cancers but not in any that had an EGFR gene mutation.
These findings "support the hypothesis that at least two distinct molecular pathways are involved in the pathogenesis of lung adenocarcinomas, one involving EGFR TK domain mutations and the other involving KRAS gene mutations," the authors write. These results also "suggest that exposure to carcinogens in environmental tobacco smoke may not be the major pathogenic factor involved in the origin of lung cancers in never smokers but that an as-yet-unidentified carcinogen(s) plays an important role."
In an editorial, William R. Sellers, M.D., and Matthew Meyerson, M.D., Ph.D., of the Dana-Farber Cancer Institute, Boston, and the Broad Institute of Harvard and the Massachusetts Institute of Technology, Cambridge, Mass., discuss how these latest findings fit in with previous research on EGFR gene mutations and lung cancer. "The discovery of EGFR gene mutations in lung cancer points out the need for a comprehensive and global view of the genomes of human cancers," they write. "While we work toward such 'global × global' views of cancer, it will be important to conduct clinical trials with broad representation across different ethnic groups. … Although ethnic variation in the incidence of somatic mutations complicates the task of defining the cancer genome, these differences provide unique opportunities to discover the predisposition factors linked to the development of cancer."
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JNCI Journal of the National Cancer Institute