Prognostic Impact of KRAS G12C Mutation in Patients With NSCLC: Results From the European Thoracic Oncology Platform Lungscape Project

Abstract

Introduction: KRAS mutations, the most frequent gain-offunction 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 "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 ¼ 0.031) and HR G12C versus no KRAS is equal to 1.32 (95% CI: 1.03 to 1.69, p ¼ 0.028) (both also significant in the "histologic-subtype" cohort). For time-to-relapse, HR G12C versus other KRAS is equal to 1.41 (95% CI: 1.03 to 1.92, p ¼ 0.030). In addition, among all patients, for relapsefree survival, HR G12C versus no KRAS is equal to 1.27 (95% CI: 1.04 to 1.54, p ¼ 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.

A retrospective observational study of the natural history of advanced non–small-cell lung cancer in patients with KRAS p.G12C mutated or wild-type disease

“…These findings are consistent with earlier studies in smaller populations showing that KRAS mutations, specifically the p.G12C mutation, are highly prevalent among current or former smokers, and that this mutation is associated with a high rate of brain metastases [18,20,30,31]. Similarly, the KRAS p.G12C mutation was found to be higher in current and former smokers in a large European data set in patients with earlier stage disease (stage Ia to IIIb NSCLC) [32]. Other studies have also demonstrated that nonsquamous cell carcinoma is the most common histology type associated with KRAS mutations in general, as well as KRAS p.G12C specifically [30,33].…”

“…This similarity in outcomes is consistent with other studies showing that in Western populations, the KRAS p.G12C mutation is not predictive of outcomes in patients with advanced NSCLC [17][18][19][20]39]. In earlier stage NSCLC, KRAS p.G12C mutations were associated with a trend toward shorter overall survival than those without KRAS mutations [32]. Taken together, these findings reflect an unmet need for effective treatments for patients with KRAS p.G12C mutation in both early and advanced NSCLC.…”

Targeting KRAS in Lung Cancer Beyond KRAS G12C Inhibitors: The Immune Regulatory Role of KRAS and Novel Therapeutic Strategies

“…These co-mutation partners lead to variances in gene expression and distinct patterns of inflammatory and immunecheckpoint molecules release, which models the tumor microenvironment and promotes different responses to therapies (12,17). Because of this tumor heterogeneity, the prognostic role of KRAS mutant cancers remains uncertain, although most studies report a major aggressive behavior of this type of cancer (18)(19)(20).…”

The Prognostic Effect of KRAS Mutations in Non-Small Cell Lung Carcinoma Revisited: A Norwegian Multicentre Study

“…Mutations of the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homology gene ( KRAS ) gene are the most common oncogenic drivers of non-squamous non-small cell lung carcinoma (NSCLC) and occur in approximately 25–38% of non-Asian and 8–10% of Asian lung adenocarcinoma patients [ 1 , 2 , 3 ]. Although associated with smoking, KRAS mutations also occur in approximately 5–15% of never-smoking patients [ 1 , 4 ]. KRAS ’ role as a prognostic factor has been investigated in numerous studies, but with conflicting results [ 5 , 6 , 7 , 8 , 9 , 10 , 11 ].…”