Correlative study of EGFR mutations or protein expressions of EGFR, phosphorylated EGFR, HER2, phosphorylated HER2 and IGFR-1 with gefitinib sensitivity in patients with non-small cell lung cancer: Results of West Japan Thoracic Oncology Group trial (WJTO)

Abstract

14008 Background: Both epidermal growth factor receptor (EGFR) mutation and gene copy number of HER2, a member of EGFR family, are associated with gefitinib sensitivity. We carried out a correlative study to determine the relationships between EGFR mutations, EGFR or HER2 protein expressions, their activation status (pEGFR, pHER2) or insulin-like growth factor receptor 1 (IGFR-1) protein expressions and clinical outcomes after gefitinib treatment in advanced NSCLC. Method: Tumors from patients (pts) were evaluated for EGFR mutations by DNA sequence, and for protein expressions of EGFR, pEGFR, HER2, pHER2 and IGFR-1 by immuno-histochemistry. Time to progression (TTP) was calculated by the Kaplan-Meier method; groups were compared using the log-rank test. Risk factors associated with TTP were evaluated with Cox proportional hazard regression modeling. Correlation between EGFR mutation and response was evaluated by Fisher’s direct method. Relationship between each protein expression and response was tested by two-sided. Primary endpoint was to detect biomarkers to predict gefitinib sensitivity. Results: From Dec. 2003 to Dec. 2005, 103 consecutive pts were enrolled onto the study, and received gefitinib until disease progression. Median age was 68 years, female (58%), adenocarcinoma (83%), never smoker (55%) and no previous chemotherapy (49%). 98 pts were evaluable for efficacies, toxicities and gene analyses. Forty-one pts (42%) had EGFR mutations; 14 pts had deletional mutation in exon 19, 27 pts had missense mutation (L858R) in exon 21. EGFR mutations were significantly related to response (62 vs. 26%; P = 0.001), disease control rate (92 vs. 65%; P = 0.003) and TTP (median, 10.1 vs. 5.1months; hazard ratio = 0.64; P = 0.048). Both pEGFR (0, +1 vs. =+2; P = 0.002,) and pHER2 (0 vs. =+1; P = 0.001) expressions are significantly associated with incidence of EGFR mutation. Conclusions: EGFR mutation was a significant predictive biomarker of response to gefitinib. Phosphorylated EGFR protein expression is a potent replaceable biomarker for EGFR mutation. No significant financial relationships to disclose.