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. 2013 Apr 4:11:90.
doi: 10.1186/1479-5876-11-90.

High EGFR copy number predicts benefits from tyrosine kinase inhibitor treatment for non-small cell lung cancer patients with wild-type EGFR

Fang Wang, Sha Fu, Qiong Shao, Yan-Bin Zhou, Xiao Zhang, Xu Zhang, Cong Xue, Jian-Guang Lin, Li-Xia Huang, Li Zhang, Wei-Min Zhang, Jian-Yong Shao

High EGFR copy number predicts benefits from tyrosine kinase inhibitor treatment for non-small cell lung cancer patients with wild-type EGFR

Fang Wang et al. J Transl Med. .

Abstract

Background: 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).

Methods: EGFR 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.

Results: EGFR 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).

Conclusions: A 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.

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Figures

Figure 1
Figure 1
Fluorescent in situ hybridization for epidermal growth factor receptor (EGFR) (orange signal) and centromere 7 (green signal) showing low (disomy = A; high triomy = B) copy number per cell (EGFR-FISH negative), high (high polysomy = C; gene amplification = D) copy number per cell (EGFR-FISH positive) (A-D, 1,000×).
Figure 2
Figure 2
Kaplan-Meier curves for progression-free survival (PFS) and overall survival (OS) by combined analysis of epidermal growth factor receptor (EGFR) mutation status and EGFR in fluorescent situ hybridization (FISH) status. (A) and (B), PFS and OS for FISH status in the subgroup of patients with EGFR mutations; (C) and (D), PFS and OS for FISH status in the subgroup of patients with wild-type EGFR; (E) and (F), PFS and OS for double-positive, double-negative, and single-positive EGFR mutations and FISH.
Figure 3
Figure 3
Kaplan-Meier curves for PFS (A) and OS (B) by analysis of epidermal growth factor receptor (EGFR) amplification, high copy number and low copy number in wild-type EGFR.
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