KRASMutation Is an Important Predictor of Resistance to Therapy with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non–Small-Cell Lung Cancer

Abstract

Purpose: EGFR gene mutations and increased EGFR copy number have been associated with favorable response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKI) in patients with non^small-cell lung cancer (NSCLC). In contrast, KRAS mutation has been shown to predict poor response to such therapy. We tested the utility of combinations of these three markers in predicting response and survival in patients with NSCLC treated with EGFR-TKIs. Experimental Design: Patients with advanced NSCLC treated with EGFR-TKI with available archival tissue specimens were included. EGFR and KRAS mutations were analyzed using PCRbased sequencing. EGFR copy number was analyzed using fluorescence in situ hybridization. Results:The study included 73 patients, 59 of whom had all three potential markers successfully analyzed. EGFR mutation was detected in 7 of 71patients (9.8%), increased EGFR copy number in 32 of 59 (54.2%), and KRAS mutation in 16 of 70 (22.8%). EGFR mutation (P < 0.0001) but not increased EGFR copy number (P = 0.48) correlated with favorable response. No survival benefit was detected in patients with either of these features. KRAS mutation correlated with progressive disease (P = 0.04) and shorter median time to progression (P = 0.0025) but not with survival. Patients with both EGFR mutation and increased EGFR copy number had a >99.7% chance of objective response, whereas patients with KRAS mutation with or without increased EGFR copy number had a >96.5% chance of disease progression.Conclusion: KRAS mutation should be included as indicator of resistance in the panel of markers used to predict response to EGFR-TKIs in NSCLC.

Overview of molecular testing in non-small-cell lung cancer: mutational analysis, gene copy number, protein expression and other biomarkers of EGFR for the prediction of response to tyrosine kinase inhibitors

“…Pao et al (2005b) first suggested that patients with NSCLC whose tumors harbor mutations are resistant to EGFR TKI. To date, among 75 NSCLC patients harboring KRAS mutations who were treated with TKIs (Pao et al, 2005b;Hirsch et al, 2006;Massarelli et al, 2007;Miller et al, 2008;Zhu et al, 2008), only one patient has been reported to respond (Zhu et al, 2008). Interestingly, this patient's tumor also had an EGFR gene amplification.…”

The epidermal growth factor receptor family: Biology driving targeted therapeutics

“…Activating mutations in EGFR and less commonly ErbB2 occur in lung cancer and activate the Ras/MAPK pathway. However, mutational activation of KRAS is seen in lung cancers as well and can render these tumors resistant to ErbB receptor targeting TKIs [179]. Such a phenomenon is seen in approximately 14 % of lung adenocarcinomas [155,180].…”

Effectiveness of erlotinib treatment in advanced KRAS mutation-negative lung adenocarcinoma patients: Results of a multicenter observational cohort study (MOTIVATE)

“…Earlier studies indicated that KRAS mutant NSCLC patients fail to benefit either from adjuvant chemotherapy or from EGFR inhibitors [7,16,[27][28][29]. Lack of EGFR mutation status of the KRAS WT patients represents a major limitation of our study (i.e.…”

“…In the western world, in patients with lung adenocarcinoma, KRAS mutations are the most common (18-38% of cases), followed by mutations in the epidermal growth factor receptor (EGFR) gene (5-15% of cases) [5][6][7][8]. In Hungary, the incidence of KRAS mutation in lung adenocarcinoma is 29.5% (based on the analysis of 6250 patients; unpublished data).…”