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

Abstract

Background: The 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. Methods: Next-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). Results: In 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, HR G12C = 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. Conclusions: In 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.

KRAS G12C-mutated advanced non-small cell lung cancer: A real-world cohort from the German prospective, observational, nation-wide CRISP Registry (AIO-TRK-0315)

“…The proportion of patients with the specific KRAS mutation subtype G12C was 38.9 % of patients with any KRAS mutation in our cohort, which is in line with previously published numbers, ranging between 42.9 % in Germany [25], 34.9 % in the US [26], and 28-33 % in China [17,27,28].…”

“…A German study reported an association of KRAS G12C mutations in NSCLC with an intermediate prognosis [25]. A retrospective survival analysis on 1456 patients with any stage NSCLC from the Guangdong Lung Cancer Institute in China reported shorter survival for KRAS-G12C-mutated tumors (n = 42) compared to KRAS wildtype tumors (n = 304) with a median OS of 18.3 vs. 26.7 months, but the KRAS mutation status did not reach significance in a Cox regression analysis [28]. Likewise, a study on surgically resected stage I lung adenocarcinoma samples from Shanghai reported worse OS for KRAS-mutated (n = 54) compared to KRAS-wildtype patients (n = 585), and the KRAS-mutations status was also identified as independent risk factor for OS in a Cox regression analysis in this patient subgroup [30].…”

The Prevalence and Concurrent Pathogenic Mutations of KRASG12C in Northeast Chinese Non-small-cell Lung Cancer Patients

“…KRAS G12C (c.34G>T) alteration is a transversion and KRAS transversion mutations (G→T or G→C) were more common in smokers, in contrast, transition mutations (G→A) were more common in never-smokers in lung adenocarcinomas (n=500). 29 Our data showed that smokers more commonly harbored KRAS G12C mutations than KRAS wt (70% vs 37.5%), which is consistent with reports by Liu et al and Dogan et al 11,30 Data showed that KRASmutant NSCLC is genetically complex, with a higher frequency of co-occurring mutations with TP53, STK11, MET and ERBB2 amplifications, 29 however, no conclusions implied that the co-occurrence mutations were related to the transversion. In comparison to KRAS other , KRAS G12C showed higher mutation frequency in patients older than 60 years, and stage I-III.…”

“…Our findings were supported by other studies. 11,13,31 In summary, our study indicated that KRAS G12C mutations were the most frequent mutant subtype of KRAS in northeast Chinese NSCLC patients and might be involved in the smoking, age, and clinical stage, especially we demonstrated a high frequency of KRAS G12C concomitant TP53/PTEN/EGFR. In addition, no difference was observed between tissue and plasma in the KRAS G12C subgroup of the northeast Chinese NSCLC patients.…”

If Virchow and Ehrlich Had Dreamt Together: What the Future Holds for KRAS-Mutant Lung Cancer

“…Despite some uncertainty regarding the prognostic impact of KRAS mutations due to the confounding effects of co-occurring genetic events (e.g., mutations in STK11 or KEAP1), many studies suggest a more aggressive tumor biology (frequent brain/central nervous system metastases), therapeutic resistance and poorer overall survival for affected lung cancer patients compared to those with other genotypes [7][8][9][10]42,[51][52][53][54].…”