Study identifies possible marker for efficacy of gefitinib in lung cancer patients

Patients with advanced non–small-cell lung cancer (NSCLC) whose tumor cells contain extra copies of the epidermal growth factor receptor (EGFR) gene may be more likely to respond to the drug gefitinib (Iressa), and this high gene copy number may be an effective predictor of gefitinib efficacy, according to a new study in the May 4 issue of the Journal of the National Cancer Institute.

NSCLC is the leading cause of cancer death worldwide. In patients with advanced disease, chemotherapy produces only modest survival benefits. However, about 12% to 27% of advanced NSCLC patients respond to tyrosine kinase inhibitors, such as gefitinib and erlotinib (Tarceva). Methods to predict which patients are most likely to respond to these drugs are under development.

To investigate possible predictive markers for gefitinib efficacy, Fred R. Hirsch, M.D., Ph.D., of the University of Colorado Cancer Center in Aurora, and colleagues evaluated EGFR status, gene copy number, and protein expression and Akt activation status in 102 patients with advanced NSCLC.

Amplification or high copy number of the EGFR gene (33 of 102 patients) was associated with a better response rate (36% versus 3%), disease control rate (67% versus 26%), time to progression (9.0 versus 2.5 months), and survival (18.7 versus 7.0 months) compared with patients with a low number or no extra copies of the EGFR gene. A similar association was found for patients with high protein expression (58 of 98 patients) compared with patients with low protein expression. EGFR mutations (15 of 89 patients) were also associated with a better response rate and time to progression. However, further statistical analysis revealed that only high EGFR gene copy number is associated with better survival.

"In conclusion, results from this study demonstrate that gefitinib is most effective in advanced NSCLC patients with high EGFR gene copy number, protein expression, or EGFR mutations. Because only high EGFR gene copy number was associated with prolonged survival … and because [fluorescence in situ hybridization (FISH)] is a readily available clinical test, the EGFR FISH analysis represents an ideal test for selecting candidate NSCLC patients for gefitinib therapy," the authors write.

In an editorial, Frederic J. Kaye, M.D., of the National Cancer Institute and National Naval Medical Center, discusses this new research in the context of other recent studies that have examined the factors that may influence the effectiveness of tyrosine kinase inhibitors. "Unfortunately, it appears that it may be easier to accurately predict drug resistance than drug efficacy," he writes. "Until reliable prognostic tools can be prospectively validated in clinical trials, clinicians will need to balance the desire to minimize false hope while maximizing the ability to offer clinically meaningful benefit to their patients."

Contacts:

Article: Fred R. Hirsch, University of Colorado Cancer Center, 303-724-3858 or 303-724-3155 (assistant), fred.hirsch@uchsc.edu

Editorial: National Cancer Institute Press Office, 301-496-6641, NCIPressOfficers@mail.nih.gov

Citations:

Article: Cappuzzo F, Hirsch FR, Rossi E, Bartolini S, Ceresoli GL, Bemis L, et al. Epidermal Growth Factor Receptor Gene and Protein and Gefitinib Sensitivity in Non–Small-Cell Lung Cancer. J Natl Cancer Inst 2005;97:643–55.

Editorial: Kaye FJ. A Curious Link Between Epidermal Growth Factor Receptor Amplification and Survival: Effect of "Allele Dilution" on Gefitinib Sensitivity? J Natl Cancer Inst 2005;97:621–3.

Note: The Journal of the National Cancer Institute is published by Oxford University Press and is not affiliated with the National Cancer Institute. Attribution to the Journal of the National Cancer Institute is requested in all news coverage. Visit the Journal online at http://jncicancerspectrum.oupjournals.org/.

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Journal

JNCI Journal of the National Cancer Institute