Investigation of the Prevalence of Associated Genetic Mutations (Co-Mutations) in Patients with Actionable Driver Mutations in Lung Cancer: A Retrospective Study

Background/Objectives: Lung cancer remains the leading cause of cancer-related mortality globally. Approximately 45% of these tumors harbor oncogenic mutations that drive carcinogenesis and are amenable to targeted therapies. Other predictive biomarkers—e.g., PD-L1, TMB, and MSI—play a crucial role in patients’ management. This study aims to investigate the existence of mutation clusters (co-mutations) and evaluate the correlation of these clusters with various clinical and laboratory parameters. Methods: A retrospective study was conducted utilizing pathological samples from lung cancer patients harboring mutations in EGFR, KRAS, ALK, BRAF, MET, HER2, ROS1, NTRK, and NRG1. Data were collected from the Institute of Pathology at Carmel Medical Center between the years 2022 and 2024. Patients were stratified using a Two-Step Cluster Analysis algorithm based on actionable mutations and co-mutations. Heatmaps and dendrograms were generated to assess the correlation between these genomic clusters, clinical metrics, and predictive biomarkers. Results: The study cohort included 129 patients with actionable mutations. Five distinct clusters were identified: Clusters 1, 2, and 3 exhibited a high expression of STK11 and TP53 co-mutations alongside KRAS drivers (n = 38, n = 12, and n = 23, respectively). Clusters 4 and 5 demonstrated high expression of ALK alterations and tumor suppressor gene mutations (n = 31 and n = 25, respectively). Cluster comparisons demonstrated statistically significant differences between clusters regarding age, gender, PD-L1 expression, and tumor mutational burden. No significant associations were found regarding ethnicity or microsatellite instability status. Conclusions: By constructing clusters based on the aggregate of genomic alterations in patients with actionable mutations, it is possible to predict associations with distinct demographic and clinical characteristics. Future research should apply this analytical approach to larger cohorts to further characterize these subgroups and investigate potential correlations with therapeutic efficacy.