Stephen P Finn1, Alfredo Addeo2, Urania Dafni3, Erik Thunnissen4, Lukas Bubendorf5, Line Bille Madsen6, Wojciech Biernat7, Eric Verbeken8, Javier Hernandez-Losa9, Antonio Marchetti10, Richard Cheney11, Arne Warth12, Ernst-Jan M Speel13, Anne Marie Quinn14, Kim Monkhorst15, Eloisa Jantus-Lewintre16, Verena Tischler17, Nesa Marti18, Georgia Dimopoulou19, Miguel A Molina-Vila20, Roswitha Kammler18, Keith M Kerr21, Solange Peters22, Rolf A Stahel18. 1. Cancer Molecular Diagnostics Laboratory, Institute of Molecular Medicine, St. James Hospital, Dublin, Ireland. Electronic address: stephen.finn@tcd.ie. 2. Department of Oncology, University Hospital Geneva, Geneva, Switzerland. 3. ETOP Statistics Center, Frontier Science Foundation-Hellas, Athens, Greece; Department of Nursing, School of Health Sciences, National and Kapodistrian University of Athens, Athens, Greece. 4. Department of Pathology, Free University Medical Center, Amsterdam, the Netherlands. 5. Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland. 6. Department of Pathology, Aarhus University Hospital, Aarhus, Denmark. 7. Department of Pathology, Medical University of Gdansk, Gdansk, Poland. 8. Department of Pathology, University Hospital KU Leuven, Leuven, Belgium. 9. Department of Pathology, Vall d'Hebron University Hospital, Barcelona, Spain. 10. Department of Pathology, Ospedale Clinicizzato Chieti, Chieti, Italy. 11. Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, New York. 12. Department of Pathology, Universitätsklinikum Heidelberg, Heidelberg, Germany. 13. Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands. 14. Department of Histopathology, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, United Kingdom. 15. Division of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. 16. Department of Biotechnology, Universitat Politècnica de València, Valencia, Spain; Mixed Unit TRIAL (General University Hospital Valencia Research Foundation and Píncipe Felipe Research Center), Valencia, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Valencia, Spain. 17. Division of Pathology, University Hospital Zurich, Zurich, Switzerland. 18. European Thoracic Oncology Platform, Bern, Switzerland. 19. ETOP Statistics Center, Frontier Science Foundation-Hellas, Athens, Greece. 20. Laboratory of Oncology, Pangaea Oncology S.A, Barcelona, Spain. 21. Department of Pathology, Aberdeen Royal Infirmary, Aberdeen, United Kingdom. 22. Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Abstract
INTRODUCTION: KRAS mutations, the most frequent gain-of-function alterations in NSCLC, are currently emerging as potential predictive therapeutic targets. The role of KRAS-G12C (Kr_G12C) is of special interest after the recent discovery and preclinical analyses of two different Kr_G12C covalent inhibitors (AMG-510, MRTX849). METHODS: KRAS mutations were evaluated in formalin-fixed, paraffin-embedded tissue sections by a microfluidic-based multiplex polymerase chain reaction platform as a component of the previously published European Thoracic Oncology Platform Lungscape 003 Multiplex Mutation study, of clinically annotated, resected, stage I to III NSCLC. In this study, -Kr_G12C mutation prevalence and its association with clinicopathologic characteristics, molecular profiles, and postoperative patient outcome (overall survival, relapse-free survival, time-to-relapse) were explored. RESULTS: KRAS gene was tested in 2055 Lungscape cases (adenocarcinomas: 1014 [49%]) with I or II or III stage respective distribution of 53% or 24% or 22% and median follow-up of 57 months. KRAS mutation prevalence in the adenocarcinoma cohort was 38.0% (95% confidence interval (CI): 35.0% to 41.0%), with Kr_G12C mutation representing 17.0% (95% CI: 14.7% to 19.4%). In the "histologic-subtype" cohort, Kr_G12C prevalence was 10.5% (95% CI: 9.2% to 11.9%). When adjusting for clinicopathologic characteristics, a significant negative prognostic effect of Kr_G12C presence versus other KRAS mutations or nonexistence of KRAS mutation was identified in the adenocarcinoma cohort alone and in the "histologic-subtype" cohort. For overall survival in adenocarcinomas, hazard ratio (HR)G12C versus other KRAS is equal to 1.39 (95% CI: 1.03 to 1.89, p = 0.031) and HRG12C versus no KRAS is equal to 1.32 (95% CI: 1.03 to 1.69, p = 0.028) (both also significant in the "histologic-subtype" cohort). For time-to-relapse, HRG12C versus other KRAS is equal to 1.41 (95% CI: 1.03 to 1.92, p = 0.030). In addition, among all patients, for relapse-free survival, HRG12C versus no KRAS is equal to 1.27 (95% CI: 1.04 to 1.54, p = 0.017). CONCLUSIONS: In this large, clinically annotated stage I to III NSCLC cohort, the specific Kr_G12C mutation is significantly associated with poorer prognosis (adjusting for clinicopathologic characteristics) among adenocarcinomas and in unselected NSCLCs.
INTRODUCTION: KRAS mutations, the most frequent gain-of-function alterations in NSCLC, are currently emerging as potential predictive therapeutic targets. The role of KRAS-G12C (Kr_G12C) is of special interest after the recent discovery and preclinical analyses of two different Kr_G12C covalent inhibitors (AMG-510, MRTX849). METHODS: KRAS mutations were evaluated in formalin-fixed, paraffin-embedded tissue sections by a microfluidic-based multiplex polymerase chain reaction platform as a component of the previously published European Thoracic Oncology Platform Lungscape 003 Multiplex Mutation study, of clinically annotated, resected, stage I to III NSCLC. In this study, -Kr_G12C mutation prevalence and its association with clinicopathologic characteristics, molecular profiles, and postoperative patient outcome (overall survival, relapse-free survival, time-to-relapse) were explored. RESULTS: KRAS gene was tested in 2055 Lungscape cases (adenocarcinomas: 1014 [49%]) with I or II or III stage respective distribution of 53% or 24% or 22% and median follow-up of 57 months. KRAS mutation prevalence in the adenocarcinoma cohort was 38.0% (95% confidence interval (CI): 35.0% to 41.0%), with Kr_G12C mutation representing 17.0% (95% CI: 14.7% to 19.4%). In the "histologic-subtype" cohort, Kr_G12C prevalence was 10.5% (95% CI: 9.2% to 11.9%). When adjusting for clinicopathologic characteristics, a significant negative prognostic effect of Kr_G12C presence versus other KRAS mutations or nonexistence of KRAS mutation was identified in the adenocarcinoma cohort alone and in the "histologic-subtype" cohort. For overall survival in adenocarcinomas, hazard ratio (HR)G12C versus other KRAS is equal to 1.39 (95% CI: 1.03 to 1.89, p = 0.031) and HRG12C versus no KRAS is equal to 1.32 (95% CI: 1.03 to 1.69, p = 0.028) (both also significant in the "histologic-subtype" cohort). For time-to-relapse, HRG12C versus other KRAS is equal to 1.41 (95% CI: 1.03 to 1.92, p = 0.030). In addition, among all patients, for relapse-free survival, HRG12C versus no KRAS is equal to 1.27 (95% CI: 1.04 to 1.54, p = 0.017). CONCLUSIONS: In this large, clinically annotated stage I to III NSCLC cohort, the specific Kr_G12C mutation is significantly associated with poorer prognosis (adjusting for clinicopathologic characteristics) among adenocarcinomas and in unselected NSCLCs.