Originally published as JCO Early Release 10.1200/JCO.2005.02.857 on July 25 2005

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Mutations in the Epidermal Growth Factor Receptor and in KRAS Are Predictive and Prognostic Indicators in Patients With Non–Small-Cell Lung Cancer Treated With Chemotherapy Alone and in Combination With Erlotinib

From the Departments of Pathology, Molecular Diagnostics, Molecular Biology, Biostatistics and BioOncology, Genentech Inc, San Francisco, CA; Department of Medical Oncology, Dana-Farber Cancer Institute, and Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; The University of Texas M.D. Anderson Cancer Center, Houston, TX; Vanderbilt Medical Center, Nashville, TN; and Thoracic Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY

Address reprint requests to Kenneth J. Hillan, MD, Genentech Inc, 1 DNA Way, San Francisco, CA 94080: e-mail: kjh{at}gene.com

PURPOSE: Epidermal growth factor receptor (EGFR) mutations have been associated with tumor response to treatment with single-agent EGFR inhibitors in patients with relapsed non–small-cell lung cancer (NSCLC). The implications of EGFR mutations in patients treated with EGFR inhibitors plus first-line chemotherapy are unknown. KRAS is frequently activated in NSCLC. The relationship of KRAS mutations to outcome after EGFR inhibitor treatment has not been described.

PATIENTS AND METHODS: Previously untreated patients with advanced NSCLC in the phase III TRIBUTE study who were randomly assigned to carboplatin and paclitaxel with erlotinib or placebo were assessed for survival, response, and time to progression (TTP). EGFR exons 18 through 21 and KRAS exon 2 were sequenced in tumors from 274 patients. Outcomes were correlated with EGFR and KRAS mutations in retrospective subset analyses.

RESULTS: EGFR mutations were detected in 13% of tumors and were associated with longer survival, irrespective of treatment (P < .001). Among erlotinib-treated patients, EGFR mutations were associated with improved response rate (P < .05) and there was a trend toward an erlotinib benefit on TTP (P = .092), but not improved survival (P = .96). KRAS mutations (21% of tumors) were associated with significantly decreased TTP and survival in erlotinib plus chemotherapy–treated patients.

CONCLUSION: EGFR mutations may be a positive prognostic factor for survival in advanced NSCLC patients treated with chemotherapy with or without erlotinib, and may predict greater likelihood of response. Patients with KRAS-mutant NSCLC showed poorer clinical outcomes when treated with erlotinib and chemotherapy. Further studies are needed to confirm the findings of this retrospective subset analysis.

This work was supported by Genentech Inc.

Presented in an oral presentation by P. Jänne at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 7, 2004; and in a poster presentation at European Organization for Research and Treatment of Cancer National Cancer Institute–American Association for Cancer Research Conference on "Molecular Targets and Cancer Therapeutics," Geneva, Switzerland, September 30, 2004.

Drs Eberhard and Johnson contributed equally to the article.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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				E. Massarelli, M. Varella-Garcia, X. Tang, A. C. Xavier, N. C. Ozburn, D. D. Liu, B. N. Bekele, R. S. Herbst, and I. I. Wistuba KRAS Mutation Is an Important Predictor of Resistance to Therapy with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-Small-Cell Lung Cancer Clin. Cancer Res., May 15, 2007; 13(10): 2890 - 2896. [Abstract] [Full Text] [PDF]

				S. Dubey and C. A. Powell Update in Lung Cancer 2006 Am. J. Respir. Crit. Care Med., May 1, 2007; 175(9): 868 - 874. [Full Text] [PDF]

				F. Hirsch, M Varella-Garcia, F Cappuzzo, J McCoy, L Bemis, A. Xavier, R Dziadziuszko, P Gumerlock, K Chansky, H West, et al. Combination of EGFR gene copy number and protein expression predicts outcome for advanced non-small-cell lung cancer patients treated with gefitinib Ann. Onc., April 1, 2007; 18(4): 752 - 760. [Abstract] [Full Text] [PDF]

				S. Benvenuti, A. Sartore-Bianchi, F. Di Nicolantonio, C. Zanon, M. Moroni, S. Veronese, S. Siena, and A. Bardelli Oncogenic Activation of the RAS/RAF Signaling Pathway Impairs the Response of Metastatic Colorectal Cancers to Anti-Epidermal Growth Factor Receptor Antibody Therapies Cancer Res., March 15, 2007; 67(6): 2643 - 2648. [Abstract] [Full Text] [PDF]

				D. M. Jackman, B. Y. Yeap, N. I. Lindeman, P. Fidias, M. S. Rabin, J. Temel, A. T. Skarin, M. Meyerson, A. J. Holmes, A. M. Borras, et al. Phase II Clinical Trial of Chemotherapy-Naive Patients >= 70 Years of Age Treated With Erlotinib for Advanced Non-Small-Cell Lung Cancer J. Clin. Oncol., March 1, 2007; 25(7): 760 - 766. [Abstract] [Full Text] [PDF]

				R Dziadziuszko, B Holm, B. Skov, K Osterlind, M. Sellers, W. Franklin, P. Bunn Jr, M Varella-Garcia, and F. Hirsch Epidermal growth factor receptor gene copy number and protein level are not associated with outcome of non-small-cell lung cancer patients treated with chemotherapy Ann. Onc., March 1, 2007; 18(3): 447 - 452. [Abstract] [Full Text] [PDF]

				X. Zhang and A. Chang Somatic mutations of the epidermal growth factor receptor and non-small-cell lung cancer J. Med. Genet., March 1, 2007; 44(3): 166 - 172. [Abstract] [Full Text] [PDF]

				L. V. Sequist, D. W. Bell, T. J. Lynch, and D. A. Haber Molecular Predictors of Response to Epidermal Growth Factor Receptor Antagonists in Non-Small-Cell Lung Cancer J. Clin. Oncol., February 10, 2007; 25(5): 587 - 595. [Abstract] [Full Text] [PDF]

				M. V. Karamouzis, P. A. Konstantinopoulos, and A. G. Papavassiliou The Activator Protein-1 Transcription Factor in Respiratory Epithelium Carcinogenesis Mol. Cancer Res., February 1, 2007; 5(2): 109 - 120. [Abstract] [Full Text] [PDF]

				E. Buck, A. Eyzaguirre, S. Barr, S. Thompson, R. Sennello, D. Young, K. K. Iwata, N. W. Gibson, P. Cagnoni, and J. D. Haley Loss of homotypic cell adhesion by epithelial-mesenchymal transition or mutation limits sensitivity to epidermal growth factor receptor inhibition Mol. Cancer Ther., February 1, 2007; 6(2): 532 - 541. [Abstract] [Full Text] [PDF]

				L. Toschi and F. Cappuzzo Understanding the New Genetics of Responsiveness to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Oncologist, February 1, 2007; 12(2): 211 - 220. [Abstract] [Full Text] [PDF]

				D. B. Solit and N. Rosen Targeting HER2 in Prostate Cancer: Where to Next? J. Clin. Oncol., January 20, 2007; 25(3): 241 - 243. [Full Text] [PDF]

				N van Zandwijk, A Mathy, L Boerrigter, H Ruijter, I Tielen, D de Jong, P Baas, S Burgers, and P Nederlof EGFR and KRAS mutations as criteria for treatment with tyrosine kinase inhibitors: retro- and prospective observations in non-small-cell lung cancer Ann. Onc., January 1, 2007; 18(1): 99 - 103. [Abstract] [Full Text] [PDF]

				T. M. Chin, D. Anuar, R. Soo, M. Salto-Tellez, W. Q. Li, B. Ahmad, S. C. Lee, B. C. Goh, K. Kawakami, A. Segal, et al. Detection of Epidermal Growth Factor Receptor Variations by Partially Denaturing HPLC Clin. Chem., January 1, 2007; 53(1): 62 - 70. [Abstract] [Full Text] [PDF]

				L. V. Sequist, V. A. Joshi, P. A. Janne, A. Muzikansky, P. Fidias, M. Meyerson, D. A. Haber, R. Kucherlapati, B. E. Johnson, and T. J. Lynch Response to treatment and survival of patients with non-small cell lung cancer undergoing somatic EGFR mutation testing. Oncologist, January 1, 2007; 12(1): 90 - 98. [Abstract] [Full Text] [PDF]

				G. J. Riely, K. A. Politi, V. A. Miller, and W. Pao Update on Epidermal Growth Factor Receptor Mutations in Non-Small Cell Lung Cancer Clin. Cancer Res., December 15, 2006; 12(24): 7232 - 7241. [Abstract] [Full Text] [PDF]

				S. Kobayashi, T. Shimamura, S. Monti, U. Steidl, C. J. Hetherington, A. M. Lowell, T. Golub, M. Meyerson, D. G. Tenen, G. I. Shapiro, et al. Transcriptional Profiling Identifies Cyclin D1 as a Critical Downstream Effector of Mutant Epidermal Growth Factor Receptor Signaling Cancer Res., December 1, 2006; 66(23): 11389 - 11398. [Abstract] [Full Text] [PDF]

				P Ceppi, M Volante, S Novello, I Rapa, K. Danenberg, P. Danenberg, A Cambieri, G Selvaggi, S Saviozzi, R Calogero, et al. ERCC1 and RRM1 gene expressions but not EGFR are predictive of shorter survival in advanced non-small-cell lung cancer treated with cisplatin and gemcitabine Ann. Onc., December 1, 2006; 17(12): 1818 - 1825. [Abstract] [Full Text] [PDF]

				G. Giaccone, M. Gallegos Ruiz, T. Le Chevalier, N. Thatcher, E. Smit, J. A. Rodriguez, P. Janne, D. Oulid-Aissa, and J.-C. Soria Erlotinib for Frontline Treatment of Advanced Non-Small Cell Lung Cancer: a Phase II Study. Clin. Cancer Res., October 15, 2006; 12(20): 6049 - 6055. [Abstract] [Full Text] [PDF]

				A. K. Das, M. Sato, M. D. Story, M. Peyton, R. Graves, S. Redpath, L. Girard, A. F. Gazdar, J. W. Shay, J. D. Minna, et al. Non-Small Cell Lung Cancers with Kinase Domain Mutations in the Epidermal Growth Factor Receptor Are Sensitive to Ionizing Radiation Cancer Res., October 1, 2006; 66(19): 9601 - 9608. [Abstract] [Full Text] [PDF]

				H. M. Linden, K. A. Krohn, R. B. Livingston, and D. A. Mankoff Monitoring targeted therapy: is fluorodeoxylucose uptake a marker of early response? Clin. Cancer Res., October 1, 2006; 12(19): 5608 - 5610. [Full Text] [PDF]

				G. Amicarelli, D. Adlerstein, E. Shehi, F. Wang, and G. M. Makrigiorgos Genotype-Specific Signal Generation Based on Digestion of 3-Way DNA Junctions: Application to KRAS Variation Detection Clin. Chem., October 1, 2006; 52(10): 1855 - 1863. [Abstract] [Full Text] [PDF]

				K. D. Carey, A. J. Garton, M. S. Romero, J. Kahler, S. Thomson, S. Ross, F. Park, J. D. Haley, N. Gibson, and M. X. Sliwkowski Kinetic Analysis of Epidermal Growth Factor Receptor Somatic Mutant Proteins Shows Increased Sensitivity to the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, Erlotinib Cancer Res., August 15, 2006; 66(16): 8163 - 8171. [Abstract] [Full Text] [PDF]