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KRAS Mutation Is a Significant Prognostic Factor in Early-stage Lung Adenocarcinoma

Kadota, Kyuichi MD, PhD; Sima, Camelia S. MD, MS; Arcila, Maria E. MD; Hedvat, Cyrus MD; Kris, Mark G. MD; Jones, David R. MD; Adusumilli, Prasad S. MD, FACS, FCCP; Travis, William D. MD

The American Journal of Surgical Pathology: December 2016 - Volume 40 - Issue 12 - p 1579–1590
doi: 10.1097/PAS.0000000000000744
Original Articles

The potential clinical impact of KRAS and epidermal growth factor receptor (EGFR) mutations has been investigated in lung adenocarcinomas; however, their prognostic value remains controversial. In our study, we sought to investigate the prognostic significance of driver mutations using a large cohort of early-stage lung adenocarcinomas. We reviewed patients with pathologic early-stage, lymph node–negative, solitary lung adenocarcinoma who had undergone surgical resection (1995 to 2005; stage I/II=463/19). Tumors were classified according to the IASLC/ATS/ERS classification and genotyped by Sequenom MassARRAY system and polymerase chain reaction–based assays. In stage I disease, the Kaplan-Meier method and cumulative incidence of recurrence analyses were used to estimate the probability of overall survival (OS) and recurrence, respectively. Of all, 129 (27%) patients had mutations in KRAS, 86 (18%) in EGFR, 8 (2%) in BRAF, 8 (2%) in PIK3CA, 4 (1%) in NRAS, and 1 (0.2%) in AKT1. EGFR L858R mutation correlated with lepidic predominant histology (P=0.006), whereas exon 19 deletion correlated with acinar predominant histology (P<0.001). EGFR mutations were not detected in invasive mucinous adenocarcinomas (P=0.033). The 5-year OS of patients with KRAS-mutant tumors was significantly worse (n=124; 5-year OS, 63%) than those with KRAS wild-type (n=339; 77%; P<0.001). In solid predominant tumors, KRAS mutations correlated with worse OS (P=0.008) and increased risk of recurrence (P=0.005). On multivariate analysis, KRAS mutation was an independent prognosticator of OS in all patients (hazard ratio, 1.87; P<0.001) and recurrence in solid predominant tumors (hazard ratio, 4.73; P=0.012). In patients with resected stage I lung adenocarcinomas, KRAS mutation was an independent prognostic factor for OS and recurrence, especially in solid predominant tumors.

*Department of Surgery, Thoracic Service

Department of Pathology

§Department of Epidemiology and Biostatistics

Department of Medicine, Thoracic Oncology Service, Division of Solid Tumor Oncology

Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY

Department of Diagnostic Pathology, Faculty of Medicine, Kagawa University, Kagawa, Japan

Conflicts of Interest and Source of Funding: Supported by grants from the National Institutes of Health (R21 CA164568-01A1, R21 CA164585-01A1, R01 CA136705-06, U54 CA137788, P50 CA086438-13, and P30 CA008748), the US Department of Defense (PR101053 and LC110202), and the Mr William H. Goodwin and Mrs Alice Goodwin, the Commonwealth Foundation for Cancer Research, and the Experimental Therapeutics Center of Memorial Sloan Kettering Cancer Center. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Correspondence: William D. Travis, MD, Department of Pathology, Surgical Pathology Diagnostic Services, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065 (e-mail:

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