Clinical characteristics and prognostic value of the KRAS G12C mutation in Chinese non-small cell lung cancer patients

Yi-Long Wu,Jia-Ying Zhou,Jin-Ji Yang,Qing Zhou,Guang-Ling Jie,Yang Shao,Jun-Yi Ye,Hao Sun,Xian Zhang,Si-Yang Liu,Zhi Xie,Xu-Chao Zhang,Chun-Xiang Chen

doi:10.1186/s40364-020-00199-z

Abstract

BackgroundThe KRAS mutation is the second most common genetic variant in Chinese non-small cell lung cancer (NSCLC) patients. At the 2019th World Conference of Lung Cancer, the KRAS G12C-specific inhibitor AMG510 showed promising results in the phase I clinical trial. However, the frequency, clinical characteristics, and prognostic significance of the KRAS G12C mutation in Chinese NSCLC patients are rarely reported.MethodsNext-generation sequencing was used to confirm the KRAS mutation status in 40,804 NSCLC patients from multiple centers (mCohort). Survival data were collected retrospectively from 1456 patients at one of the centers, the Guangdong Lung Cancer Institute (iCohort).ResultsIn the mCohort, 3998 patients (9.8%) were confirmed to harbor a KRAS mutation, of whom 1179 (29.5%) had the G12C subtype. In the iCohort, 130 NSCLC patients (8.9%) had a KRAS mutation and 42 (32.3%) had the G12C subtype. The G12C subgroup included more male patients (85.2% vs 67.4%, P < 0.0001) and more smokers (76.2% vs 53.4%, P = 0.02) than did the non-G12C subgroup. Both the KRAS mutation group and KRAS G12C mutation subgroup were associated with a shorter median overall survival (OS) than wildtype tumors (15.1 vs 26.7 months, hazard ratio [HR]KRAS = 1.50, P = 0.002; 18.3 vs 26.7 months, HRG12C = 1.66, P = 0.007). In Cox regression analysis, smoking (HR = 1.39, P = 0.05) and stage IV disease (HR = 2.72, P < 0.001) remained as independent predictors of shorter OS. Both the KRAS mutation (HR = 1.30, P = 0.07) and KRAS G12C mutation (HR = 1.47, P = 0.07) reached borderline significance.ConclusionsIn the largest sample used thus for, our study found that approximately 10% of Chinese NSCLC patients had KRAS mutations. Of these, nearly 30% harbored the KRAS G12C mutation subtype, which was most common in male smokers. The KRAS G12C mutation is a biomarker of poor prognosis in Chinese NSCLC patients, which could potentially be improved by G12C-specific inhibitors in the future.(296 words)

Highlights

The KRAS mutation is the second most common genetic variant in Chinese non-small cell lung cancer (NSCLC) patients
Rapid developments have been achieved in the area of epidermal growth factor-receptor tyrosine kinase inhibitors (EGFR-TKIs) and immunotherapy with checkpoint inhibitors for lung cancer patients [1,2,3,4,5]
The World Conference of Lung Cancer in 2019 presented promising and up-to-date clinical data on the drug AMG510, which was given to 13 patients with non-small cell lung cancer (NSCLC) at a dose of 960 mg once per day

Summary

Introduction

At the 2019th World Conference of Lung Cancer, the KRAS G12C-specific inhibitor AMG510 showed promising results in the phase I clinical trial. The KRAS mutation is the second most common genetic variant in Chinese non-small cell lung cancer (NSCLC) patients [6]. Many retrospective and prospective studies have attempted to treat KRAS mutation patients with EGFR-TKIs [7] and MAP-ERK kinase (MEK) inhibitors [8, 9], but none were successful. The World Conference of Lung Cancer in 2019 presented promising and up-to-date clinical data on the drug AMG510, which was given to 13 patients with non-small cell lung cancer (NSCLC) at a dose of 960 mg once per day. A series of clinical trials targeting KRAS G12C mutations with G12C-specific inhibitors, including RMC4630 and MRTX849 are ongoing [14, 15]

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Discussion

Conclusion