TY - JOUR
T1 - Prognostic Impact of KRAS G12C Mutation in Patients With NSCLC
T2 - Results From the European Thoracic Oncology Platform Lungscape Project
AU - Finn, Stephen P.
AU - Addeo, Alfredo
AU - Dafni, Urania
AU - Thunnissen, Erik
AU - Bubendorf, Lukas
AU - Madsen, Line Bille
AU - Biernat, Wojciech
AU - Verbeken, Eric
AU - Hernandez-Losa, Javier
AU - Marchetti, Antonio
AU - Cheney, Richard
AU - Warth, Arne
AU - Speel, Ernst-Jan M.
AU - Quinn, Anne Marie
AU - Monkhorst, Kim
AU - Jantus-Lewintre, Eloisa
AU - Tischler, Verena
AU - Marti, Nesa
AU - Dimopoulou, Georgia
AU - Molina-Vila, Miguel A.
AU - Kammler, Roswitha
AU - Kerr, Keith M.
AU - Peters, Solange
AU - Stahel, Rolf A.
AU - European Thoracic Oncology Platform Lungscape Investigators
N1 - Funding Information:
The analysis of the prognostic impact did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The original KRAS research was supported by F. Hoffmann-La Roche Ltd. and Genentech Inc. , South San Francisco, California.
Publisher Copyright:
© 2021 International Association for the Study of Lung Cancer
PY - 2021/6
Y1 - 2021/6
N2 - Introduction: KRAS mutations, the most frequent gain-of function alterations in NSCLC, are currently emerging as potential predictive therapeutic targets. The role of KRASG12C (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 "histologicsubtype" 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. (C) 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
AB - Introduction: KRAS mutations, the most frequent gain-of function alterations in NSCLC, are currently emerging as potential predictive therapeutic targets. The role of KRASG12C (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 "histologicsubtype" 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. (C) 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
KW - NSCLC
KW - KRAS
KW - Kr_G12C
KW - Multiplex PCR platform
KW - CELL LUNG-CANCER
KW - CLINICAL-ASSOCIATION
KW - PREDICTIVE-VALUE
KW - PD-1 BLOCKADE
KW - PREVALENCE
KW - LANDSCAPE
KW - OUTCOMES
U2 - 10.1016/j.jtho.2021.02.016
DO - 10.1016/j.jtho.2021.02.016
M3 - Article
C2 - 33647504
SN - 1556-0864
VL - 16
SP - 990
EP - 1002
JO - Journal of Thoracic Oncology
JF - Journal of Thoracic Oncology
IS - 6
ER -