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Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer
Federico Cappuzzo1, Fred R Hirsch, Elisa Rossi
1University of Colorado Health Sciences Center and University of Colorado Cancer Center, Aurora, CO 80010, USA.
Background:
Gefitinib is a selective inhibitor of the epidermal growth factor (EGFR) tyrosine kinase, which is overexpressed in many cancers, including non-small-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 Kaplan-Meier 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.
Insights
High epidermal growth factor receptor (EGFR) gene copy number is a strong predictor of positive response to gefitinib therapy in advanced non-small-cell lung cancer (NSCLC). This finding supports EGFR gene copy number as a key biomarker for personalized treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Gefitinib targets the epidermal growth factor receptor (EGFR) tyrosine kinase, often overexpressed in cancers like non-small-cell lung cancer (NSCLC).
- Predictive markers are crucial for optimizing gefitinib therapy in advanced NSCLC.
Purpose of the Study:
- To evaluate EGFR gene copy number, protein expression, mutations, and Akt activation as predictive markers for gefitinib efficacy in advanced NSCLC patients.
- To correlate these molecular markers with treatment response, disease progression, and overall survival.
Main Methods:
- Tumors from 102 NSCLC patients receiving gefitinib were analyzed for EGFR status (gene copy number, protein expression, mutations) and phospho-Akt (P-Akt) levels using FISH, DNA sequencing, and immunohistochemistry.
- Kaplan-Meier analysis, log-rank tests, and Cox regression modeling were used to assess survival outcomes and risk factors.
Main Results:
- High EGFR gene copy number (33/102 patients) and high protein expression (58/98 patients) were significantly associated with better response rates, disease control, time to progression, and overall survival.
- EGFR mutations (15/89 patients) correlated with response and progression-free survival but not significantly with overall survival.
- Multivariable analysis identified high EGFR gene copy number as the sole significant predictor of improved survival (hazard ratio = 0.44). Patients with EGFR+/P-Akt+ status showed significantly better outcomes.
Conclusions:
- High EGFR gene copy number, detected by FISH, serves as an effective molecular predictor for gefitinib efficacy in advanced NSCLC.
- EGFR gene copy number is a valuable biomarker for patient selection in gefitinib-treated NSCLC.
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