Τίτλος:
Prognostic Impact of KRAS G12C Mutation in Patients With NSCLC: Results From the European Thoracic Oncology Platform Lungscape Project
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. © 2021 International Association for the Study of Lung Cancer
Συγγραφείς:
Finn, S.P.
Addeo, A.
Dafni, U.
Thunnissen, E.
Bubendorf, L.
Madsen, L.B.
Biernat, W.
Verbeken, E.
Hernandez-Losa, J.
Marchetti, A.
Cheney, R.
Warth, A.
Speel, E.-J.M.
Quinn, A.M.
Monkhorst, K.
Jantus-Lewintre, E.
Tischler, V.
Marti, N.
Dimopoulou, G.
Molina-Vila, M.A.
Kammler, R.
Kerr, K.M.
Peters, S.
Stahel, R.A.
European Thoracic Oncology Platform Lungscape Investigators
Περιοδικό:
Journal of Thoracic Oncology
Εκδότης:
HANLEY & BELFUS-ELSEVIER INC
Λέξεις-κλειδιά:
adagrasib; cytosine; guanine; sotorasib; KRAS protein, human; piperazine derivative; protein p21; pyridine derivative; pyrimidine derivative; sotorasib, adult; aged; Article; cancer chemotherapy; cancer patient; cancer prognosis; cancer radiotherapy; cancer recurrence; cancer staging; cancer surgery; cohort analysis; confidence interval; controlled study; Europe; European; female; follow up; gene mutation; hazard ratio; histology; human; major clinical study; male; microfluidics; multiplex polymerase chain reaction; non small cell lung cancer; oncogene K ras; overall survival; prevalence; recurrence free survival; genetics; lung tumor; mutation; prognosis; tumor recurrence, Humans; Lung Neoplasms; Mutation; Neoplasm Recurrence, Local; Piperazines; Prognosis; Proto-Oncogene Proteins p21(ras); Pyridines; Pyrimidines
DOI:
10.1016/j.jtho.2021.02.016
