Are There Any Ethnic Differences in Molecular Predictors of Erlotinib Efficacy in Advanced Non-Small Cell Lung Cancer?

Abstract

Purpose: This study investigated possible molecular predictors of outcome in Korean patients with advanced non-small cell lung cancer treated with erlotinib. Experimental Design: One hundred and twenty patients received erlotinib and were followed prospectively. Ninety-two tissue samples were analyzed for epidermal growth factor receptor (EGFR) gene mutations (exons 18, 19, and 21), 88 for EGFR gene amplification by real-time PCR, and 75 for EGFR protein expression by immunohistochemistry. Results:The overall tumor response rate was 24.2% (complete response, 4; partial response, 25) with 56.7% of disease control rate. With a median follow-up of 23.6 months, the median time to progression (TTP) was 2.7 months and the median overall survival was 12.9 months. EGFR gene mutations were found in 26.1% (24 of 92), EGFR gene amplification in 40.9% (36 of 88), and EGFR protein expression in 72% (54 of 75). There was a strong association between EGFR gene mutations and gene amplification (c = 0.241). Patients with EGFR gene mutations or gene amplification showed both better response rate (58.3% versus 16.2%, P < 0.001; 41.7% versus 17.3%, P = 0.012) and TTP (8.6 versus 2.5 months, P = 0.003; 5.8 versus 1.8 months, P < 0.001) and overall survival (not reached versus 10.8 months, P = 0.023; not reached versus 10.1 months, P = 0.033). By multivariate analysis, EGFR gene mutation was the only significant molecular predictor for TTP (hazard ratio, 0.47; 95% confidence interval, 0.25-0.89). Conclusions: Our findings indicate that EGFR gene mutation is a more predictive marker for improved TTP than EGFR gene amplification in erlotinib-treated Korean non-small cell lung cancer patients. Prospective studies from diverse ethnic backgrounds are required to determine the exact role of these molecular markers.

Comparison of gefitinib versus erlotinib in patients with nonsmall cell lung cancer who failed previous chemotherapy

“…16 Recently, we reported that the incidence of EGFR mutations for all patients who were treated with erlotinib was higher (26.1%) in Korean patients when compared with Western countries (<10%). 17 This is consistent with previously reported data. Therefore, the high response rate in this analysis might be explained because of high EGFR-positive rate.…”

“…17,20 More recently, ISTANA (IRESSA as Second-Line Therapy in Advanced NSCLC-Korea) showed longer PFS and a significantly improved overall response rate compared with docetaxel in Korean patients. 21 It is unclear why no survival benefit with gefitinib was found in the Iressa Survival Evaluation in Lung Cancer study, despite apparent similar antitumor activity as that seen in previous studies with erlotinib.…”

“…Also, cumulative data with gefitinib demonstrated consistently high response rates of >25% in Asian patients. 16 More recently, a large randomized phase 3 trial (Iressa NSCLC Trial Evaluating Response and Survival vs Taxotere; INTEREST) comparing gefitinib with docetaxel as standard second-line chemotherapy regimens in pretreated advanced NSCLC 17 demonstrated that survival with gefitinib was equivalent (noninferior) to docetaxel in a broad unselected population.…”

Clinical Outcomes and Prognostic Factors Associated with the Response to Erlotinib in Non-Small-Cell Lung Cancer Patients with Unknown EGFR Mutational Status

“…The current focus is on the predictive power of EGFR mutations, a high EGFR gene copy number, and k-ras mutations (Eberhard et al, 2005;Shepherd et al, 2005;Ahn et al, 2008). Unfortunately, standardised clinical tests for the molecular predictors of erlotinib treatment outcome are expensive and not readily accessible in most hospitals.…”

Increased EGFR mRNA Expression Levels in Non-Small Cell Lung Cancer

“…Many publications have shown that EGFR mutations are associated with increased EGFR gene copy number and EGFR expression. EGFR gene mutations and increased amplification were found to be the best parameter in determining clinical progression in the Korean patients treated with erlotinib [32] and in Japanese patients treated with gefitinib [5]. In addition, researchers have suggested investigating the effects of these molecular markers in different ethnic groups.…”