NEW YORK (Reuters Health) - About 10% of patients with non-small-cell lung cancer (NSCLC) respond to the drug gefitinib (Iressa), which targets the epidermal growth factor receptor (EGFR). Mutations in the tumor EGFR gene are responsible for this sensitivity, according to two papers published Thursday.
If verified with further research, future treatment protocols could include testing for EGFR mutations and considering gefitinib therapy before using standard chemotherapeutic agents.
The findings stem from studies reported this week in online issues of The New England Journal of Medicine (NEJM) and Science.
In the NEJM study, Dr. Daniel A. Haber, from Massachusetts General Hospital in Boston, and colleagues tested for EGFR mutations in tumors obtained from 9 patients with gefitinib-responsive NSCLC, 7 patients with gefitinib-unresponsive NSCLC, and 25 patients who had not been exposed to the drug.
Eight of the patients with responsive tumors had mutations in the tyrosine kinase domain of the EGFR gene compared with none of the patients with unresponsive tumors (p < 0.001). Two patients in the unexposed cohort had EGFR mutations, yielding a rate of 8% -- close to the 10% sensitivity rate seen clinically.
The mutations involved amino acid changes around the ATP-binding pocket of the tyrosine kinase domain. Moreover, in vitro testing of the EGFR mutants revealed increased tyrosine kinase activity in response to the natural ligand and increased sensitivity to gefitinib inhibition.
The results indicate that certain “EGFR mutations confer sensitivity to gefitinib,” Dr. Haber told Reuters Health. However, the finding that one patient with responsive NSCLC did not have such mutations suggests that other mechanisms may be involved, he added. “Still, the great majority seems to have such mutations.”
“We are now interested in conducting multicenter trials that will involve testing for EGFR mutations and then upfront treatment with gefitinib,” Dr. Haber said. “In the lab, we want to see if other tumors might also carry these mutations -- there’s no particular reason why they should be limited to lung cancer.”
In the Science study, Dr. Matthew Meyerson, from the Dana-Farber Cancer Institute in Boston, and colleagues sequenced the EGFR gene in tumor samples obtained from NSCLC patients in Japan and in the US.
Previous reports have shown that gefitinib response rates are much higher in Japanese than in US populations. Consistent with this observation, the researchers found EGFR mutations in 15 of 58 tumors tested from Japan compared with just 1 of 61 tumors tested from the US.
Similar to the other study, several EGFR mutations were identified that were present in gefitinib-sensitive tumors but not in resistant tumors.
Source: N Engl J Med 2004;350.Science 2004. [ Google search on this article ]
MeSH Headings:Behavioral Sciences: Carcinoma, Non-Small-Cell Lung: Cytological Techniques: Behavioral Disciplines and Activities: Drug and Narcotic Control: Drug Screening: Drug Screening Assays, Antitumor: Health Care Economics and Organizations: Evaluation Studies: Health Occupations: Health Services Administration: Legislation: Legislation, Drug: Membrane Proteins: Investigative Techniques: Organization and Administration: Pharmacy Administration: Quality of Health Care: Receptors, Cell Surface: Receptor, Epidermal Growth Factor: Receptors, Gastrointestinal Hormone: Social Control, Formal: Social Sciences: Sociology: Technology: Technology, Industry, and Agriculture: Technology, Medical: Allied Health Occupations: Drug Approval: Health Care Quality, Access, and Evaluation: Health Care Evaluation Mechanisms: Receptors, Growth Factor: Receptors, Peptide: Receptor Protein-Tyrosine Kinases: Analytical, Diagnostic and Therapeutic Techniques and Equipment: Anthropology, Education, Sociology and Social Phenomena: Biological Sciences: Health Care: Psychiatry and Psychology: Technology, Food and BeveragesCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
