© 2005 Oxford University Press
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Epidermal Growth Factor Receptor Gene and Protein and Gefitinib Sensitivity in NonSmall-Cell Lung Cancer
Affiliations of authors: University of Colorado Health Sciences Center and University of Colorado Cancer Center, Aurora, CO (FC, FRH, LB, JH, SW, WAF, PAB, MVG); Bellaria Hospital, Bologna, Italy (FC, SB, EM, LC); CINECA Interuniversity Consortium, Bologna, Italy (ER, ID); Scientific Institute University Hospital San Raffaele, Milan, Italy (GLC, VG, CD); Response Genetic, Inc., Los Angeles, CA (KD); Policlinico Monteluce, Perugia, Italy (VL, AS, MT)
Correspondence to: Fred R. Hirsch, MD, PhD, University of Colorado Cancer Center, Department of Medicine and Pathology, 12801 E. 17th Ave., P.O. Box 6511, Mail Stop 8111, Aurora, CO 80010 (e-mail: fred.hirsch{at}uchsc.edu).
Background: Gefitinib is a selective inhibitor of the epidermal growth factor (EGFR) tyrosine kinase, which is overexpressed in many cancers, including nonsmall-cell lung cancer (NSCLC). We carried out a clinical study to compare the relationship between EGFR gene copy number, EGFR protein expression, EGFR mutations, and Akt activation status as predictive markers for gefitinib therapy in advanced NSCLC. Methods: Tumors from 102 NSCLC patients treated daily with 250 mg of gefitinib were evaluated for EGFR status by fluorescence in situ hybridization (FISH), DNA sequencing, and immunohistochemistry and for Akt activation status (phospho-Akt [P-Akt]) by immunohistochemistry. Time to progression, overall survival, and 95% confidence intervals (CIs) were calculated and evaluated by the KaplanMeier method; groups were compared using the log-rank test. Risk factors associated with survival were evaluated using Cox proportional hazards regression modeling and multivariable analysis. All statistical tests were two-sided. Results: Amplification or high polysomy of the EGFR gene (seen in 33 of 102 patients) and high protein expression (seen in 58 of 98 patients) were statistically significantly associated with better response (36% versus 3%, mean difference = 34%, 95% CI = 16.6 to 50.3; P<.001), disease control rate (67% versus 26%, mean difference = 40.6%, 95% CI = 21.5 to 59.7; P<.001), time to progression (9.0 versus 2.5 months, mean difference = 6.5 months, 95% CI = 2.8 to 10.3; P<.001), and survival (18.7 versus 7.0 months, mean difference = 11.7 months, 95% CI = 2.1 to 21.4; P = .03). EGFR mutations (seen in 15 of 89 patients) were also statistically significantly related to response and time to progression, but the association with survival was not statistically significant, and 40% of the patients with mutation had progressive disease. In multivariable analysis, only high EGFR gene copy number remained statistically significantly associated with better survival (hazard ratio = 0.44, 95% CI = 0.23 to 0.82). Independent of EGFR assessment method, EGFR+/P-Akt+ patients had a statistically significantly better outcome than EGFR, P-Akt, or EGFR+/P-Akt patients. Conclusions: High EGFR gene copy number identified by FISH may be an effective molecular predictor for gefitinib efficacy in advanced NSCLC.
Editorial about this Article
- A Curious Link Between Epidermal Growth Factor Receptor Amplification and Survival: Effect of "Allele Dilution" on Gefitinib Sensitivity?
- Frederic J. Kaye
J Natl Cancer Inst 2005 97: 621-623.[Extract] [Full Text] [PDF]
Related Memo to the Media
- Press Release: Study Identifies Possible Marker for Efficacy of Gefitinib in Lung Cancer Patients
- Sarah L. Zielinski
J Natl Cancer Inst 2005 97: 617.[Extract] [Full Text]
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