KRAS G12C Mutation Associated with Female Sex and Risk of Central Nervous System Metastasis

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Lung cancer is the leading cause of cancer-related death, resulting in 1.8 million deaths globally in 2020, and it has a low 5-year survival rate.1 Immune checkpoint inhibitor use and targeting the oncogenic driver, such as the KRAS oncogene, have improved the treatment of advanced and metastatic non–small-cell lung cancer (NSCLC), but mutations can challenge the effectiveness of these treatments through resistance mechanisms.1 The most common mutation in NSCLC is the KRAS oncogene, and it occurs in approximately 20% to 25% of patients.1 KRAS mutations induce inflammatory cytokines, chemokines, and signaling pathways that promote tumor growth and invasiveness.1 This mutation is most commonly found in patients with adenocarcinoma and in 90% of patients who smoke.1 The most common KRAS mutation in NSCLC is the KRAS G12C mutation, which occurs in 40% of all patients with NSCLC.1 The subtypes of KRAS mutations each have distinct biology and activate different signaling pathways that determine which treatment is effective against the specific KRAS mutation.1

A recent study evaluated 6183 patients with NSCLC with known KRAS mutation status using data from the National Swedish Lung Cancer Registry.2 Researchers focused on 3 cohorts during the study: KRAS G12C–positive patients (n = 484), KRAS-other patients (n = 1161), and driver negative patients (WT; n = 3349). The cohorts were assessed regarding sex, age, smoking status, cancer histology, patient performance status, metastatic patterns, and overall survival (OS) from diagnosis. In NSCLC patients, the presence of KRAS mutation was 32%, and 14% had KRAS G12C mutation. In patients with adenocarcinoma, 38% had KRAS mutation, and 16% had KRAS G12C mutation. In NSCLC not otherwise specified, 28% had KRAS mutation and 13% had KRAS G12C mutation. In squamous-cell carcinoma, 6% had KRAS mutation and 2% had KRAS G12C mutation. Women comprised 65% of the KRAS G12C mutation cohort, 59% of the KRAS-other cohort, and 48% of the WT cohort. Only 2.5% of the patients who had never smoked had the KRAS G12C mutation. No difference was found in OS in patients with clinical stage I-IIIA disease between the cohorts. In stage IV patients, 28% of KRAS G12C–positive patients had central nervous system (CNS) metastasis at diagnosis, compared with 19% of KRAS-other patients and 18% of WT patients. Among patients with stage IV disease, those with KRAS G12C mutation had a 5.8-month OS, those with KRAS-other had a 5.2-month OS, and those in the WT group had a 6.4-month OS. In all mutational subgroups of patients with stage IV disease, except KRAS G12C, women had a better outcome. In the KRAS G12C group, the OS rates were similar between men (6.6 months) and women (6.1 months). In patients with stage IV disease and KRAS G12C, a similar OS with or without CNS metastasis was seen (6.1 months and 6.2 months, respectively). CNS metastasis conveyed a poor survival in the KRAS-other and WT cohorts. The KRAS G12C mutation was associated with smoking, adenocarcinoma histology, the presence of CNS metastases, and female sex in this study.


  1. Addeo A, Banna GL, Friedlaender A. KRAS G12C mutations in NSCLC: from target to resistance. Cancers (Basel). 2021;13(11):2541.
  2. Isaksson J, Berglund A, Louie K, et al. KRAS-G12C NSCLC linked to female sex and high risk of CNS metastasis: real-world data from the National Swedish Lung Cancer Registry 2016-2019. Ann Oncol. 2022;33(2):S95-S96.

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