Association of KRAS and EGFR Mutations With Survival in
Patients With Advanced Lung Adenocarcinomas
Melissa L. Johnson, MD1; Camelia S. Sima, MD2; Jamie Chaft, MD3; Paul K. Paik, MD3; William Pao, MD6;
Mark G. Kris, MD3,5; Marc Ladanyi, MD4; and Gregory J. Riely, MD3,5
BACKGROUND: Lung adenocarcinomas can be distinguished by identifying mutated driver oncogenes, including epidermal growth
factor receptor (EGFR) and KRAS. Mutations in EGFR are associated with both improved survival as well as response to treatment
with erlotinib and gefitinib. However, the prognostic significance of KRAS has not been evaluated in large numbers of patients and
remains controversial. For the current report, the authors examined the association of EGFR and KRAS mutations with survival among
patients with advanced lung adenocarcinomas. METHODS: Data were analyzed from patients with advanced lung adenocarcinomas
who had known EGFR and KRAS mutation status evaluated between 2002 and 2009. The collected clinical variables included age,
sex, Karnofsky performance status, smoking history, and treatment history. Overall survival from the diagnosis of advanced disease
was analyzed using Kaplan-Meier and Cox proportional hazard methods. RESULTS: In total, 1036 patients were evaluated, including
610 women (59%) and 344 never-smokers (33%). The median patient age was 65 years (range, 25-92 years), and the majority of
patients (81%) had a Karnofsky performance status ?80%. In multivariate analysis, EGFR mutations were associated with longer over-
all survival (hazard ratio, 0.6; P < .001), and KRAS mutations were associated with shorter survival (hazard ratio, 1.21; P ¼ .048). CON-
CLUSIONS: KRAS mutations predicted shorter survival for patients with advanced lung adenocarcinomas. The presence of EGFR and
KRAS mutations define distinct subsets of patients with lung adenocarcinomas and should be determined in patients when they are
diagnosed with advanced disease. Clinical trial reports should include EGFR and KRAS mutation status along with other prognostic
factors. Cancer 2013;119:356-62. V
C 2012 American Cancer Society.
KEYWORDS: nonsmall cell lung cancer, adenocarcinomas, EGFR, KRAS, survival, prognostic factors.
Recent therapeutic advances have highlighted the molecular heterogeneity underlying oncogene-driven lung adenocarcinomas.
For example, patients with mutations in the epidermal growth factor receptor (EGFR) make up approximately 10% to 15% of
patients in the United States who are diagnosed with advanced lung adenocarcinoma. These patients have high rates of radio-
graphic response when they receive treatment with erlotinib or gefitinib, tyrosine kinase inhibitors (TKIs) that target EGFR;
and they have longer progression-free survival compared with patients who have EGFR wild-type tumors.1-4
Kirsten rat sarcoma 2 viral oncogenehomolog (KRAS) mutations are presentin a larger number of patients: approxi-
mately 30% of patients with advanced lung adenocarcinoma in the United States. Efforts to develop effective therapies
that inhibit lung cancers with KRAS mutations have been largely unsuccessful, and the prognostic significance of KRAS
mutations remains in question. Several small studies5-9and 1 meta-analysis10evaluated the prognostic effects of KRAS
and few of the included patients received the modern chemotherapy regimens now considered standard. We hypothesized
ent outcomes. Here, we present the largest analysis to date examining a population of patients with advanced lung adeno-
carcinomas and known EGFR and KRAS mutation status. We report clinical characteristics, treatment histories, and
mutationanalysisfrom 1036patients andinvestigatetheirassociationwithsurvival.
MATERIALS AND METHODS
All patients whowere evaluated atMemorialSloan-Kettering Cancer Center(MSKCC)in the Thoracic Oncology Service
clinics between 2002 and 2009 were analyzed. Only those patients with stage IV lung adenocarcinoma (American Joint
DOI: 10.1002/cncr.27730, Received: March 28, 2012; Revised: May 31, 2012; Accepted: June 7, 2012, Published online July 18, 2012 in Wiley Online Library
Corresponding author: Melissa L. Johnson, MD, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, 676 North St. Clair, Suite 850.
Chicago, IL 60611; Fax: (312) 695-6189; email@example.com
1Feinberg School of Medicine, Northwestern University, The Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois;2Department of Epidemiology and
Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York;3Thoracic Oncology Service, Division of Solid Tumors, Department of Medicine, Memo-
rial Sloan-Kettering Cancer Center, New York, New York;4Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York;5Weill Cornell
Medical College, New York, New York;6Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee
January 15, 2013
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