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Abstract
BackgroundThis study was designed to determine whether advanced non-small-cell lung cancer (NSCLC) patients with high copy number of epidermal growth factor receptor (EGFR) can benefit from treatment with EGFR-tyrosine kinase inhibitors (TKIs).MethodsEGFR gene copy number was assessed by fluorescence in situ hybridization (FISH) and EGFR mutations was tested using Luminex xTAG technology in 502 TKI-treated NSCLC patients. The association between both biomarkers and clinical benefit from EGFR-TKI were analyzed.ResultsEGFR FISH + and EGFR mutations were significantly associated with higher response rates (37.2% and 43.7%, respectively), superior progression-free survival (PFS) (FISH+, 11.2 months; hazard ratio [HR], 0.51; 95% CI, 0.42 to 0.62; p < 0.001; mutation+, 11.7 months; HR, 0.37; 95% CI, 0.31 to 0.45; p < 0.001) and overall survival (OS) (FISH+, 30.2 months; HR, 0.51; 95% CI, 0.40 to 0.65; p < 0.001; mutation+, 30.2 months; HR, 0.45; 95% CI, 0.36 to 0.58; p < 0.001). In patients with wild-type EGFR, EGFR FISH + correlated with longer PFS than EGFR FISH- status (4.4 months vs. 2.0 months; HR, 0.56; 95% CI, 0.41 to 0.75; p < 0.001), so did amplification (5.0 months vs. 2.0 months; HR, 0.43; 95% CI, 0.24 to 0.76; p = 0.003). However, FISH + had no association with improved PFS in EGFR-mutated patients (HR, 0.77; 95% CI, 0.57 to 1.03; p = 0.076).ConclusionsA combined analysis of EGFR FISH and mutation is an effective predictor of EGFR-TKI therapy. Specifically, a high EGFR copy number may predict benefit from TKIs treatment for NSCLC patients with wild-type EGFR.
Highlights
Increasing evidence indicates that activation of somatic mutations in the epidermal growth factor receptor (EGFR) kinase domain [1,2] confers sensitivity to the EGFR Tyrosine kinase inhibitor (TKI), such as gefitinib and erlotinib for patients with advanced non-small-cell lung cancer (NSCLC)
EGFR fluorescence in situ hybridization (FISH) + and EGFR mutations were significantly associated with higher response rates (37.2% and 43.7%, respectively), superior progression-free survival (PFS) (FISH+, 11.2 months; hazard ratio [Hazard ratio (HR)], 0.51; 95% confidence intervals (CIs), 0.42 to 0.62; p < 0.001; mutation+, 11.7 months; HR, 0.37; 95% CI, 0.31 to 0.45; p < 0.001) and overall survival (OS) (FISH+, 30.2 months; HR, 0.51; 95% CI, 0.40 to 0.65; p < 0.001; mutation+, 30.2 months; HR, 0.45; 95% CI, 0.36 to 0.58; p < 0.001)
A combined analysis of EGFR FISH and mutation is an effective predictor of EGFR-TKI therapy
Summary
Increasing evidence indicates that activation of somatic mutations in the EGFR kinase domain (exons 18–21) [1,2] confers sensitivity to the EGFR TKIs, such as gefitinib and erlotinib for patients with advanced NSCLC. Recent studies have shown that high EGFR gene copy number is associated with increased response rates to TKI therapy, as well as improved PFS [12,13] and OS[14,15,16]. Several studies have demonstrated that increased EGFR gene copy number and mutations display a high degree of overlap and the fluorescence in-situ hybridization-positive (FISH+) rate in patients with EGFR mutations was approximately 62.5% to 77.6% [3,17,18,19,20]. This study was designed to determine whether advanced non-small-cell lung cancer (NSCLC) patients with high copy number of epidermal growth factor receptor (EGFR) can benefit from treatment with EGFR-tyrosine kinase inhibitors (TKIs)
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