KRAS Mutation in NSCLC Linked to Female Sex, Presence of CNS Metastasis

The treatment armamentarium for non-small cell lung cancer (NSCLC) is evolving, with increased focus on biomarkers for individualized treatment decisions. Current diagnostic guidelines include treatment-predictive molecular testing for several oncogenic drivers for targeted therapy. Adenocarcinoma and squamous cell carcinoma (SCC) are the two largest histologic subgroups of NSCLC and are genetically different regarding patterns of acquired oncogenic mutations.

KRAS-mutated NSCLC represents a large and markedly heterogenous group of tumors. KRAS mutations are strongly linked to tobacco smoking, particularly regarding the most common KRAS variant in NSCLC—KRAS p.G12C. Additionally, co-mutations are of interest in KRAS-mutated tumors as some of the common co-mutations are associated with prognosis, distinct immune response patterns, and treatment response.

“Given the variability in mutation prevalence in different patient populations linked to ethnicity and smoking patterns and lack of knowledge on the specific biological properties of different KRAS-mutation variants, real-life data based on large population-based NSCLC cohorts are highly warranted,” wrote Johan Isaksson, MD, and colleagues in Clinical Oncology [2023;24(6):507-518]. In the current study, the researchers examined the demographic and clinical outcomes in patients with KRAS-mutated tumors, with a focus on the KRAS p.G12C variant, using a cohort of patients with NSCLC from the Swedish National Lung Cancer Registry.

The registry includes data on diagnostic procedures and parameters, including date of diagnosis, stage, location of primary tumor, and metastatic pattern at diagnosis. Between 2015 and 2018, reflex next-generation sequencing (NGS) panel analysis (including KRAS status) for all NSCLC was slowly introduced throughout Sweden using clinically validated commercial platforms or in-house designed panels with relevant coverage of aberrations in oncogenic driver genes.

Outcome measures included demographics, clinical baseline characteristics, and survival with KRAS mutation status.

A total of 13,671 patients with an NSCLC diagnosis between 2016 and 2019 were identified from the registry, and 7680 patients had a corresponding record in the molecular pathology module. Patients with a molecular test other than NGS or with NGS failure were excluded. Following exclusion of other targetable drivers, three cohorts were studied: KRAS p.G12C (KRAS-G12C; n=848), non-G12C KRAS  mutation variants (KRAS-other; n=1161), and driver-negative KRAS (KRAS-wild-type [wt]; n=3349). Most patients were women (54.3%) with stage IV diagnosis (50.4%). For subgroup analysis based on histology, the cohorts were further divided into three groups—adenocarcinoma (77.1%), SCC (14.2%), and NSCLC not otherwise specified (NSCLC NOS; 8.7%).

The prevalence of KRAS mutations in the overall NGS cohort was 38%. As expected, prevalence varied by histology, with the most common in adenocarcinoma (38%), followed by NSCLC NOS (28%) and SCC (6%). The KRAS-G12C mutation was found in 13.7% of the total cohort. The occurrence of KRAS-G12C was 15.9% in adenocarcinoma, 13.2% in NSCLC NOS, and 2.1% in SCC. The researchers noted that the results indicate a significant number of KRAS mutations, including KRAS-G12C, will be overlooked if NSCLC NOS and SCC are not routinely tested.

The fraction of female patients was high in KRAS-G12C and KRAS-other (65.0% and 58.7%, respectively) compared with the KRAS-wt subgroup (47.5%). A total of 86.2% of the total NGS cohort reported a history of smoking, with a higher number in the KRAS-G12C subgroup (97.6%).

Survival outcomes showed no significant impact of KRAS status in stage I-IIIB disease. In stage IV, median overall survival (mOS) from date of diagnosis was shorter for KRAS-G12C and KRAS-other (5.8 months and 5.2 months, respectively) versus KRAS-wt (6.4 months). Overall, survival data from diagnosis in stage IV adenocarcinoma stratified by sex and KRAS mutation status showed no statistical difference in mOS between men and women in the KRAS-G12C cohort (6.1 months vs 6.6 months, respectively). In the KRAS-other cohort, mOS for women was 6.4 months versus 4.5 months for men, and in the KRAS-wt cohort, mOS for women was 8.0 months versus 6.0 months for men. Although not statistically significant, the researchers noted that the trend in multivariable analysis supports a discordant survival impact related to female sex in the KRAS-G12C cohort after adjusting for age, performance status, and presence of central nervous system (CNS) metastasis.

CNS metastasis was more common in KRAS-G12C (27.5%) compared with KRAS-other (18.8%) and KRAS-wt (18.5%). Survival in the KRAS-G12C group was similar in patients with and without CNS metastasis—mOS was 6.1 months with CNS metastasis and 6.2 months without. However, a significant difference in survival was observed in the KRAS-other subgroup (mOS of 4.3 months with CNS metastasis and 6.0 months without). The KRAS-wt mOS was 5.2 months with CNS metastasis and 7.3 months without.

The authors cited some study limitations, including the lack of follow-up data after systemic treatments relating to survival results in stage IV adenocarcinoma subgroups. Also, as co-mutations beyond driver mutations such as TP53, KEAP1, and STK11 were not reported to the registry, they were unable to assess their impact in the respective mutation subcohorts.

“Real-world data from the national lung cancer registry indicate that KRAS p.G12C is the most common targetable aberration in the Swedish NSCLC population and significantly linked to baseline parameters such as smoking, female sex, and presence of brain metastasis,” concluded the researchers.

“We believe that the distribution of KRAS p.G12C across all histologic subtypes warrants molecular testing of all NSCLC patients. Reflex radiologic brain scans at diagnosis in patients with KRAS p.G12C mutations should be discussed based on the high frequency of CNS metastasis and hypothesis-generating data indicating the brain as a vulnerable compartment for early metastatic dissemination.”