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

Authors' Affiliations: Departments of ¹ Thoracic/Head and Neck Medical Oncology, ² Biostatistics and Applied Mathematics, and ³ Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas and ⁴ University of Colorado Health Sciences Center, Cancer Center, Aurora, Colorado

Requests for reprints: Ignacio I. Wistuba, Department of Pathology, M. D. Anderson Cancer Center, Unit 85, 1515 Holcombe Boulevard, Houston, TX 77030-4009. Phone: 713-563-9184; Fax: 713-563-1848; E-mail: iiwistuba{at}mdanderson.org.

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 PCR-based 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 71 patients (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.

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