Badi El Osta1, Madhusmita Behera1, Sungjin Kim2, Lynne D Berry3, Gabriel Sica4, Rathi N Pillai1, Taofeek K Owonikoko1, Mark G Kris5, Bruce E Johnson6, David J Kwiatkowski6, Lynette M Sholl6, Dara L Aisner7, Paul A Bunn8, Fadlo R Khuri1, Suresh S Ramalingam9. 1. Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia. 2. Samuel Oschin Comprehensive Cancer Institute, Los Angeles, California. 3. Center for Quantitative Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee. 4. Department of Pathology and Laboratory Medicine, Winship Cancer Institute of Emory University, Atlanta, Georgia. 5. Department of Thoracic Oncology, Memorial Sloan Kettering Cancer Center, New York, New York. 6. Lung Cancer Program, Dana-Farber Harvard Cancer Center, Boston, Massachusetts. 7. Department of Pathology, University of Colorado Denver School of Medicine, Aurora, Colorado. 8. Division of Medical Oncology, University of Colorado Denver School of Medicine, Aurora, Colorado. 9. Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia. Electronic address: ssramal@emory.edu.
Abstract
INTRODUCTION: Mutations in the KRAS gene are the most common driver oncogenes present in lung adenocarcinomas. We analyzed the largest multi-institutional database available containing patients with metastatic KRAS-mutant lung adenocarcinomas. METHODS: The Lung Cancer Mutation Consortium (LCMC) is a multi-institutional collaboration to study the genomic characteristics of lung adenocarcinomas, treat them with genomically directed therapeutic approaches, and assess their outcomes. Since its inception in 2009, the LCMC has enrolled more than 1900 patients and has performed pretreatment, multiplexed, molecular characterization along with collecting clinical data. We evaluated the characteristics of patients with KRAS mutation in the LCMC and the association with overall survival. RESULTS: Data from 1655 patients with metastatic lung adenocarcinomas were analyzed. Four hundred fifty (27%) patients had a KRAS mutation, 58% were female, 93% were smokers, and there was a median age of 65 years. Main KRAS subtypes were: G12C 39%; and G12D and G12V at 18% each. Among patients with KRAS mutation, G12D had a higher proportion of never-smokers (22%, p < 0.001). Patients with KRAS-mutant tumors had a trend toward shorter median survival compared to all others in the series (1.96 versus 2.22; P = 0.08) and lower 2-year survival rate (49% [95% confidence interval: 44%-54%] and 55% [95% confidence interval: 52%-58%], respectively). CONCLUSIONS: In the LCMC study, 27% of lung adenocarcinomas patients harbored a KRAS mutation and up to one-third of them had another oncogenic driver. Patients with both KRAS and STK11 mutations had a significantly inferior clinical outcome.
INTRODUCTION: Mutations in the KRAS gene are the most common driver oncogenes present in lung adenocarcinomas. We analyzed the largest multi-institutional database available containing patients with metastatic KRAS-mutant lung adenocarcinomas. METHODS: The Lung Cancer Mutation Consortium (LCMC) is a multi-institutional collaboration to study the genomic characteristics of lung adenocarcinomas, treat them with genomically directed therapeutic approaches, and assess their outcomes. Since its inception in 2009, the LCMC has enrolled more than 1900 patients and has performed pretreatment, multiplexed, molecular characterization along with collecting clinical data. We evaluated the characteristics of patients with KRAS mutation in the LCMC and the association with overall survival. RESULTS: Data from 1655 patients with metastatic lung adenocarcinomas were analyzed. Four hundred fifty (27%) patients had a KRAS mutation, 58% were female, 93% were smokers, and there was a median age of 65 years. Main KRAS subtypes were: G12C 39%; and G12D and G12V at 18% each. Among patients with KRAS mutation, G12D had a higher proportion of never-smokers (22%, p < 0.001). Patients with KRAS-mutant tumors had a trend toward shorter median survival compared to all others in the series (1.96 versus 2.22; P = 0.08) and lower 2-year survival rate (49% [95% confidence interval: 44%-54%] and 55% [95% confidence interval: 52%-58%], respectively). CONCLUSIONS: In the LCMC study, 27% of lung adenocarcinomaspatients harbored a KRAS mutation and up to one-third of them had another oncogenic driver. Patients with both KRAS and STK11 mutations had a significantly inferior clinical outcome.
Authors: Mark G Kris; Bruce E Johnson; Lynne D Berry; David J Kwiatkowski; A John Iafrate; Ignacio I Wistuba; Marileila Varella-Garcia; Wilbur A Franklin; Samuel L Aronson; Pei-Fang Su; Yu Shyr; D Ross Camidge; Lecia V Sequist; Bonnie S Glisson; Fadlo R Khuri; Edward B Garon; William Pao; Charles Rudin; Joan Schiller; Eric B Haura; Mark Socinski; Keisuke Shirai; Heidi Chen; Giuseppe Giaccone; Marc Ladanyi; Kelly Kugler; John D Minna; Paul A Bunn Journal: JAMA Date: 2014-05-21 Impact factor: 56.272
Authors: Nathan T Ihle; Lauren A Byers; Edward S Kim; Pierre Saintigny; J Jack Lee; George R Blumenschein; Anne Tsao; Suyu Liu; Jill E Larsen; Jing Wang; Lixia Diao; Kevin R Coombes; Lu Chen; Shuxing Zhang; Mena F Abdelmelek; Ximing Tang; Vassiliki Papadimitrakopoulou; John D Minna; Scott M Lippman; Waun K Hong; Roy S Herbst; Ignacio I Wistuba; John V Heymach; Garth Powis Journal: J Natl Cancer Inst Date: 2012-01-13 Impact factor: 13.506
Authors: Pasi A Jänne; Alice T Shaw; José Rodrigues Pereira; Gaëlle Jeannin; Johan Vansteenkiste; Carlos Barrios; Fabio Andre Franke; Lynda Grinsted; Victoria Zazulina; Paul Smith; Ian Smith; Lucio Crinò Journal: Lancet Oncol Date: 2012-11-28 Impact factor: 41.316
Authors: David Planchard; Benjamin Besse; Harry J M Groen; Pierre-Jean Souquet; Elisabeth Quoix; Christina S Baik; Fabrice Barlesi; Tae Min Kim; Julien Mazieres; Silvia Novello; James R Rigas; Allison Upalawanna; Anthony M D'Amelio; Pingkuan Zhang; Bijoyesh Mookerjee; Bruce E Johnson Journal: Lancet Oncol Date: 2016-06-06 Impact factor: 41.316
Authors: Jean-Yves Douillard; Frances A Shepherd; Vera Hirsh; Tony Mok; Mark A Socinski; Radj Gervais; Mei-Lin Liao; Helge Bischoff; Martin Reck; Mark V Sellers; Claire L Watkins; Georgina Speake; Alison A Armour; Edward S Kim Journal: J Clin Oncol Date: 2009-12-28 Impact factor: 44.544
Authors: C Mascaux; N Iannino; B Martin; M Paesmans; T Berghmans; M Dusart; A Haller; P Lothaire; A-P Meert; S Noel; J-J Lafitte; J-P Sculier Journal: Br J Cancer Date: 2005-01-17 Impact factor: 7.640
Authors: Joshua D Campbell; Anton Alexandrov; Jaegil Kim; Jeremiah Wala; Alice H Berger; Chandra Sekhar Pedamallu; Sachet A Shukla; Guangwu Guo; Angela N Brooks; Bradley A Murray; Marcin Imielinski; Xin Hu; Shiyun Ling; Rehan Akbani; Mara Rosenberg; Carrie Cibulskis; Aruna Ramachandran; Eric A Collisson; David J Kwiatkowski; Michael S Lawrence; John N Weinstein; Roel G W Verhaak; Catherine J Wu; Peter S Hammerman; Andrew D Cherniack; Gad Getz; Maxim N Artyomov; Robert Schreiber; Ramaswamy Govindan; Matthew Meyerson Journal: Nat Genet Date: 2016-05-09 Impact factor: 38.330
Authors: Dara L Aisner; Lynette M Sholl; Lynne D Berry; Michael R Rossi; Heidi Chen; Junya Fujimoto; Andre L Moreira; Suresh S Ramalingam; Liza C Villaruz; Gregory A Otterson; Eric Haura; Katerina Politi; Bonnie Glisson; Jeremy Cetnar; Edward B Garon; Joan Schiller; Saiama N Waqar; Lecia V Sequist; Julie Brahmer; Yu Shyr; Kelly Kugler; Ignacio I Wistuba; Bruce E Johnson; John D Minna; Mark G Kris; Paul A Bunn; David J Kwiatkowski Journal: Clin Cancer Res Date: 2017-12-07 Impact factor: 13.801
Authors: Eusebio Manchado; Susann Weissmueller; John P Morris; Chi-Chao Chen; Ramona Wullenkord; Amaia Lujambio; Elisa de Stanchina; John T Poirier; Justin F Gainor; Ryan B Corcoran; Jeffrey A Engelman; Charles M Rudin; Neal Rosen; Scott W Lowe Journal: Nature Date: 2016-06-22 Impact factor: 49.962
Authors: Bo Yuan; Michael J Clowers; Walter V Velasco; Stephen Peng; Qian Peng; Yewen Shi; Marco Ramos-Castaneda; Melody Zarghooni; Shuanying Yang; Rachel L Babcock; Seon Hee Chang; John V Heymach; Jianjun Zhang; Edwin J Ostrin; Stephanie S Watowich; Humam Kadara; Seyed Javad Moghaddam Journal: JCI Insight Date: 2022-06-08