In addition to histology, somatic gene alterations play a crucial role in determining treatment for NSCLC patients. These alterations are known as oncogenic driver mutations, which drive normal cells to become cancerous.

Driver mutations occur in genes that regulate cell proliferation and survival signaling proteins. They provide cancer cells with a growth advantage and are not found in non-cancerous cells. Typically, a tumor harbors only one driver mutation at a time.

The prevalence of these genomic alterations varies across populations and countries. According to the NCCN (National Comprehensive Cancer Network) guidelines, certain genomic changes (or biomarkers) must be investigated in NSCLC patients to predict treatment response.

• ALK Gene Rearrangement: The anaplastic lymphoma kinase (ALK) gene rearrangement leads to the formation of ALK fusion proteins, which promote uncontrolled cancer cell growth and survival. It is mostly observed in non-smokers or light smokers. ALK-positive patients can benefit from targeted therapies that inhibit ALK signaling and induce tumor cell death.

• EGFR Mutations: The epidermal growth factor receptor (EGFR) is a signaling protein on the cell membrane. When epidermal growth factor (EGF) binds to EGFR, it triggers cell growth and division. Mutations in EGFR result in continuous signaling, leading to tumor formation. NSCLC patients with EGFR mutations can benefit from targeted therapies that block EGFR signaling and induce cancer cell death.

• ROS1 Gene Fusion: Present in 1-2% of NSCLC cases, ROS1 is a tyrosine kinase involved in regulating cell growth and proliferation. When ROS1 gene fusions occur, cancer cells grow and divide uncontrollably. This alteration is most frequently found in young non-smokers with NSCLC. Patients with ROS1 gene fusions can benefit from targeted therapies that inhibit ROS1 activity.

• RET Gene Alterations: RET gene fusions and mutations are key oncogenic drivers in various cancers, including NSCLC. Around 1-2% of NSCLC cases harbor RET fusions. Patients with RET alterations may benefit from selective RET-targeted therapies, which offer better clinical efficacy and tolerability compared to multi-targeted TKIs.

• NTRK: NTRK gene fusions are very rare in NSCLC, occurring in <1% of cases. Despite their low frequency, they are highly actionable, with TRK inhibitors showing significant and durable responses in patients with NTRK-driven tumors.

• BRAF: BRAF mutations are found in approximately 1–3% of NSCLC cases, with the V600E mutation being the most clinically relevant. This mutation activates the MAPK pathway, and patients may benefit from BRAF inhibitors, often in combination with MEK inhibitors.

• MET: MET alterations, particularly exon 14 skipping mutations, are present in about 3–4% of NSCLC cases. These mutations prevent degradation of the MET receptor, resulting in sustained oncogenic signaling. MET inhibitors have shown promising results in this subset.

• PD-L1 Expression: PD-L1 is a regulatory molecule that can be expressed on tumor cells, inhibiting T-cell-mediated immune responses. Due to its role in guiding treatment decisions, PD-L1 expression is considered a predictive biomarker.