EGFR and K-ras mutations as determinants of gefitinib sensitivity in non-small-cell lung cancer (NSCLC)

Abstract

7078 Background: EGFR mutation is associated with response and prolonged survival in NSCLC patients treated with gefitinib. We have previously observed negative correlation of p-Erk and efficacy of gefitinib. K-ras mutation may constitutively activate p-Erk. Recently, HER2 mutation was found in NSCLC. We have investigated EGFR, HER2, and K-ras mutations in NSCLC treated with gefitinib. Methods: Advanced NSCLC patients (pt) received gefitinib 250mg/day. EGFR (exons 18, 19, 21, and 23), HER2 (exons 19 and 20), and K-ras (codons 12 and 13) mutations (mt) were identified by direct sequencing of PCR products of DNA extracted from archival paraffin embedded tissue. P-Erk and p-Akt expression was determined by immunohistochemistry (IHC). Baseline characteristics, mutational status, IHC data and efficacy of gefitinib were analyzed in respect to each other. Results: 59 pt were analyzed. 13 pt harbored EGFR mt and 8 pt harbored K-ras mt, whereas HER2 mt was found in none. EGFR mutation was significantly associated with response [response rate (RR) 61.5% in mt(+) vs.13.0% in mt(-), p=0.001], time-to-progression (TTP) [13.7 months (M) in mt(+) vs. 1.3 M in mt(-), p=0.001], and overall survival (OS) [not reached in mt(+) vs. 5.8 M in mt(-), p=0.001]. Among 8 pt with K-ras mt, 2 pt had stable disease (SD), 6 pt had progressive disease (PD), and no pt had response to gefitinib [RR 0% vs. 27.5% in K-ras mt (-), p=0.18]. No association was found between K-ras mt and TTP or OS. 2 pt concomitantly had EGFR and K-ras mt; 1 pt had SD and the other PD. RR in EGFR mt(+)/K-ras mt(-), EGFR mt(-)/K-ras mt(-), and K-ras mt(+) were 72.7%, 15.0%, and 0%, respectively (p<0.001). K-ras mutation was more frequently found in male (p=0.067), squamous cell carcinoma (p=0.095), and smokers (p=0.008). 6/7 pt with K-ras mt exhibited positive p-Erk expression [85.7% vs. 58.8% in K-ras mt (-), p=0.24]. Conclusion: These results support the assumption that K-ras mutation may have role in gefitinib resistance via activation of Ras/Raf/Erk pathway. Together with EGFR mutation, K-ras mutation may aid in patient selection for treatment with gefitinib in NSCLC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca