Key Point

Mutations in the tyrosine kinase domain of the EGFR gene are the first cancer-causing molecular changes found to occur specifically in never-smokers.

NEW YORK CITY—Although smoking is inarguably the cause of most lung cancers, the accumulation of genetic or epigenetic alterations can also be a causative factor. In particular, lung cancers having mutations in the epithelial growth factor receptor (EGFR) gene are of interest because these mutations tend to be present in cancers having a greater sensitivity to therapy with gefitinib. The tyrosine kinase domain EGFR mutations are more frequently found in adenocarcinomas, in females, in patients from Japan versus those from the United States, and in never-smokers compared with current or former smokers—the same patient populations that have a greater response to drugs that target the tyrosine kinase domain.

Researchers from hospitals in Japan, Taiwan, the US, and Australia examined tyrosine kinase domain EGFR mutations in primary lung tumors, in noncancerous lung tissue, and in tissue obtained from patients having other types of epithelial cancer. They found that tyrosine kinase domain EGFR mutations can cause lung cancer and that this type of cancer is common among never-smokers, women, and people of East Asian ethnicity.¹

MUTATION MUCH MORE COMMON IN CERTAIN GROUPS

A total of 617 non–small cell tumors were obtained for analysis. Samples of corresponding nonmalignant lung tissue were obtained from 524 patients. Clinical information was available for all patients. Clinical staging was performed for all lung tumors using the revised International System for Staging Lung Cancer.

Tyrosine kinase EGFR mutations were found only in non–small cell lung cancer tissue samples. The mutation was seen more often in patients of East Asian ethnicity than in those of other ethnicities (30% vs 8%, respectively). It was also more common in women than in men (42% vs 14%), in never-smokers than in ever-smokers (51% vs 10%), and in adenocarcinomas than in cancers of other histologies (40% vs 3%).

When the analyses were confined to the subgroup with the greatest frequency of mutations—never-smokers with adenocarcinomas—the incidence of tyrosine kinase EGFR mutation was significantly greater in patients from Japan and Taiwan than in those from the US or Australia (64% vs 36%, respectively). Of the 160 patients from the US, the EGFR mutation was present in 3% of current smokers, 8% of former smokers, and 20% of never-smokers.

Mutations were absent from adjacent nonmalignant tissue in 95 of 130 patients for whom this tissue was available.

RAPID MUTATION ANALYSIS TESTS UNDER DEVELOPMENT

“Mutational analysis is straightforward—PCR and gene sequencing,” said Adi F. Gazdar, MD, Professor of Pathology and Deputy Director of the Hamon Center for Therapeutic Oncology Research at University of Texas Southwestern Medical Center in Dallas. “It is being done in large university and research centers and is commercially available. High-throughput, rapid, relatively inexpensive methodologies are under development, which will lead to greater availability and applicability.”

The authors noted that identifying patients with the tyrosine kinase domain EGFR mutation is important because these patients respond better to certain cancer drugs than do patients without the mutation. They also pointed out that the presence of this mutation in never-smokers suggests that exposure to the carcinogens in environmental tobacco smoke may not be the major factor in the origins of lung cancer in never-smokers.

“There is a need for greater understanding of the relationship of EGFR mutations and other confounding factors such as gene amplification, relationship to other EGFR family members, and downstream signaling genes,” Dr. Gazdar pointed out.

—Gale Jurasek

Reference
1. Shigematsu H, Lin L, Takahashi T, et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst. 2005;97:339-346.

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