To identify the Multiple Driver Gene Mutations in Non-Small Cell Lung Cancer (NSCLC): A Comprehensive Review

Medicine/Surgery

Non-small cell lung cancer (NSCLC) is genetically heterogeneous, with key genetic mutations guiding targeted therapy. While single driver mutations (e.g., EGFR, ALK) are well-characterized,the frequency and clinical impact of multiple driver gene mutations (MDGMs) is defined as concurrent pathogenic variants in two or more actionable driver genes which remain understudied till now. This comprehensive review synthesizes 68 studies (2015–2024) covering in total of  42,389 NSCLC patients to quantify MDGM incidence,characterize mutation co-occurrence patterns,and evaluate associations with clinicopathological features (histology, smoking status, stage) and treatment outcomes.MDGMs were detected in 8.3–15.7% of NSCLC cases,with the highest incidence in adenocarcinoma (10.1–18.4%) and lowest in squamous cell carcinoma (3.2–7.6%). The most common co-occurring mutation pairs were EGFR + KRAS (2.1–3.8%),EGFR + MET (1.7–2.9%), and ALK + ROS1 (0.8–1.5%). MDGM incidence was higher in never-smokers (12.4–16.8%) vs smokers (6.2–9.5%)and advanced-stage (III–IV) vs early-stage (I–II) disease (11.3–17.2% vs. 5.1–8.9%). Therapeutic response to single-agent targeted therapy was poorer in MDGM patients (progression-free survival [PFS]: 4.2–6.8 months) vs single driver mutation patients (PFS: 9.5–14.3 months),which reflects the need for mixed targeted strategies.This review underscores MDGMs as a distinct subgroup in NSCLC with unique clinical characteristics, which covers the importance of comprehensive genomic profiling to guide personalized therapy.

This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.