Ernest Nadal, MD, Guoan Chen, MD, PhD, John R

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KRAS-G12C Mutation Is Associated with Poor Outcome in Surgically Resected Lung Adenocarcinoma Ernest Nadal, MD, Guoan Chen, MD, PhD, John R. Prensner, MD, PhD, Hiroe Shiratsuchi, PhD, Christine Sam, MD, Lili Zhao, PhD, Gregory P. Kalemkerian, MD, Dean Brenner, MD, Jules Lin, MD, Rishindra M. Reddy, MD, Andrew C. Chang, MD, Gabriel Capellà, MD, PhD, Felipe Cardenal, MD, PhD, David G. Beer, PhD, Nithya Ramnath, MD Journal of Thoracic Oncology Volume 9, Issue 10, Pages 1513-1522 (October 2014) DOI: 10.1097/JTO.0000000000000305 Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 A and B, Kaplan–Meier plots of DFS according to KRAS status (mutant versus wild-type) in lung AC patients of all stages (n = 179) and stage I (n =121). C, Kaplan–Meier plot of OS according to KRAS status (mutant versus wild-type) in lung AC patients of all stages (n = 179). D and E, Kaplan–Meier plots of DFS for KRAS wild-type, KRAS-G12C and KRAS–non-G12C in lung AC patients of all stages (n = 179) and stage I (n = 121). F, Kaplan–Meier plot of OS for KRAS wild-type, KRAS-G12C, and KRAS–non-G12C in lung AC patients of all stages (n = 179). DFS, disease-free survival; AC, adenocarcinoma; OS, overall survival. Journal of Thoracic Oncology 2014 9, 1513-1522DOI: (10.1097/JTO.0000000000000305) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 A, Bar plot showing the frequency of TP53, STK11, PTEN, and PIK3CA mutation according to specific codon variants in 16 KRAS mutant NSCLC cell lines. B, Bar plot showing the frequency of KRAS independence according to specific KRAS mutations in 53 mutant cancer cell lines. C, Heat-map showing supervised clustering based on genes associated with KRAS dependency (SYK, ITGB6, RBM35B, LYN, MST1R, LCK, ERBB3, PAK1, and MET) and EMT genes for a panel of KRAS mutant NSCLC cell lines. The central panel displays the presence (black) or absence (white) of activating mutations in TP53, STK11, and PIK3CA genes and whether these cells were classified as KRAS-dependent (green) or independent cells (red). Most KRAS-G12C mutant cells clustered together with other KRAS-independent cells and displayed an EMT phenotype. NSCLC, non–small-cell lung cancer. Journal of Thoracic Oncology 2014 9, 1513-1522DOI: (10.1097/JTO.0000000000000305) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 A, Bar plot showing the number of mutations according to specific codon variants in 59 lung AC tumors. B, KRAS gene copy number using SNP 250K data available from 59 lung AC harboring KRAS mutations. Dashed lines indicate the criteria for considering the samples amplified (≥2.5) or deleted (⩽1.5). Tumors with KRAS–non-G12C mutations had higher mean copy number (2.29 ± 0.51) as compared with KRAS-G12C (2.06 ± 0.24, t test p = 0.019). C, Box plots of average expression of upregulated genes in EMT and angiogenesis as well as validated genes involved predicting KRAS dependency, in a cohort of 102 lung AC. Tumors were categorized according to their mutation profile in EGFR/KRAS wild-type (WT, n = 42), EGFR mutant (EGFR, n = 24), KRAS-G12C mutant (G12C, n = 18), and KRAS–non-G12C (non-G12C, n = 18). Average expression of each gene set was calculated for each individual tumor. Lung AC harboring KRAS-G12C mutations expressed lower median level of KRAS-dependent genes and higher level of EMT and angiogenesis genes. AC, adenocarcinoma; EMT, epithelial to mesenchymal transition. Journal of Thoracic Oncology 2014 9, 1513-1522DOI: (10.1097/JTO.0000000000000305) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions