Clinical characteristics and prognostic value of theKRAS G12Cmutation in Chinese non-small cell lung cancer patients

Background TheKRASmutation is the second most common genetic variant in Chinese non-small cell lung cancer (NSCLC) patients. At the 2019th World Conference of Lung Cancer, theKRAS G12C-specific inhibitor AMG510 showed promising results in the phase I clinical trial. However, the frequency, clinical characteristics, and prognostic significance of theKRAS G12Cmutation in Chinese NSCLC patients are rarely reported. Methods Next-generation sequencing was used to confirm theKRASmutation 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). Results In the mCohort, 3998 patients (9.8%) were confirmed to harbor aKRASmutation, of whom 1179 (29.5%) had theG12Csubtype. In the iCohort, 130 NSCLC patients (8.9%) had aKRASmutation and 42 (32.3%) had theG12Csubtype. TheG12Csubgroup 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-G12Csubgroup. Both theKRASmutation group andKRAS G12Cmutation 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 theKRASmutation (HR = 1.30,P = 0.07) andKRAS G12Cmutation (HR = 1.47,P = 0.07) reached borderline significance. Conclusions In the largest sample used thus for, our study found that approximately 10% of Chinese NSCLC patients hadKRASmutations. Of these, nearly 30% harbored theKRAS G12Cmutation subtype, which was most common in male smokers. TheKRAS G12Cmutation is a biomarker of poor prognosis in Chinese NSCLC patients, which could potentially be improved byG12C-specific inhibitors in the future. (296 words)