Predictive molecular markers for EGFR-TKI in non-small cell lung cancer patients: new insights and critical aspects

Abstract

In recent years, a number of novel agents have been investigated that target specific molecular pathways in non-small cell lung cancer (NSCLC). A great deal of effort has been focused on identifying specific markers that predict treatment response, given that a tailored approach would maximize both the therapeutic index and the cost-effectiveness. The epidermal growth factor receptor (EGFR) pathway has emerged as a key regulator of cancer cell proliferation and invasion, and several specific EGFR inhibitors have been examined. Gefitinib and erlotinib are selective EGFR tyrosine kinase inhibitors (EGFR-TKIs), demonstrating good results in selected cases both in terms of objective response rate and of overall survival. At present, EGFR gene mutations are the best positive predictive factors for TKI therapy, and a number of other potential biomarkers are being investigated as additional positive or negative predictors of response. The correct selection of patients that could benefit from these innovative therapies, based on an accurate molecular characterization, is mandatory to provide the best clinical management. Currently, the main factor limiting the characterization of metastatic NSCLC patients is the small quantity of tumor cells available for molecular analysis. In this paper we provide an overview of the most important molecular predictive markers for EGFR-TKIs therapy in NSCLC patients, and focus attention on biological samples suitable for analysis and alternative sampling approaches such as plasma-or serum-derived DNA.

Personalized Targeted Therapy for Lung Cancer

“…In 2004, three influential studies discovered a series of somatic mutations in the kinase domain of EGFR which are associated with the response to EGFR TKI therapy [ 23 – 25 ]. To date, EGFR mutations are presumed to be the strongest predictive biomarker for the efficacy of EGFR TKI therapy [ 26 ] due to much higher response rate (RR, 37.5%–100% vs. 2.9%–23% [ 27 ]; 70% vs. 33.2% as a first-line treatment; 47.4% vs. 28.5% as a second-line treatment [ 28 ]) and longer overall survival (OS, 13–23 months vs. 5–17 months [ 27 ]) in mutant patients. Mok [ 29 ] summarized six clinical trials to compare the response to EGFR TKIs and chemotherapy in patients carrying positive mutations.…”