Non-Small Cell Lung Cancer (NSCLC) is the most common type of lung cancer, accounting for approximately 85% of all diagnosed cases. It often arises from DNA changes, or mutations, typically acquired during a person’s lifetime. These can be caused by external factors like tobacco smoke or pollution, or occur randomly. Understanding these genetic alterations is important as they directly influence cancer behavior and treatment.
Genetic Changes Driving NSCLC
Genetic mutations in NSCLC are “driver mutations,” directly contributing to uncontrolled cancer cell growth and survival. These changes vary, making each patient’s cancer unique. They disrupt normal cell signaling pathways that regulate growth and death, leading to uncontrolled proliferation and tumor formation.
EGFR gene mutations are important drivers in NSCLC, especially in adenocarcinoma, and are more common in non-smokers, younger individuals, females, and Asian patients. They lead to unregulated activation of cell survival and proliferation pathways, causing excessive cell growth. Similarly, ALK gene rearrangements (about 5% of NSCLC cases) promote cell growth and inhibit programmed cell death, often seen in younger, never-smoking patients with adenocarcinoma.
Other driver mutations include ROS1 gene rearrangements (1-2% of NSCLC patients), which, like ALK, promote proliferation and inhibit apoptosis. BRAF mutations (1-4% of lung adenocarcinomas, notably V600E) cause unregulated cell growth by activating the MAPK/ERK signaling pathway. MET exon 14 skipping mutations (1-10% of NSCLC cases) can lead to uncontrolled growth and spread. RET gene fusions (1-2% of NSCLCs) and rare NTRK gene fusions also involve receptor tyrosine kinases that can drive tumor growth.
Other mutations include KRAS, TP53, HER2, PIK3CA, and NRAS. KRAS mutations are present in approximately 30% of NSCLC cases, making them one of the most common, especially in Caucasian populations. TP53 mutations are also frequently found (40-51% of NSCLC cases), associated with a higher incidence of bone metastasis. HER2 (ERBB2) amplifications and PIK3CA mutations can contribute to cancer development, though their incidence and clinical significance vary. NRAS mutations are less frequent than KRAS or TP53.
Identifying NSCLC Mutations
Detecting specific genetic mutations in NSCLC is important to guide treatment and personalize patient care. Primary diagnostic approaches involve obtaining a tumor or blood sample for analysis. These methods identify the unique genetic profile of a patient’s cancer.
Tissue biopsy is the traditional method for obtaining a tumor sample. This involves surgically removing a small piece of cancerous tissue for pathological and molecular testing. While effective, tissue biopsies can be invasive and challenging to obtain depending on tumor location.
A newer, less invasive alternative is the liquid biopsy, which analyzes circulating tumor DNA (ctDNA) in a blood sample. Tumor cells release DNA fragments into the bloodstream, detectable and analyzable for mutations. Liquid biopsies offer advantages like easier repeated sampling for monitoring disease progression or as an alternative when tissue samples are insufficient.
Once a sample is collected, various molecular testing techniques identify the mutations. Next-Generation Sequencing (NGS) is a comprehensive method that simultaneously detects a wide range of mutations across many genes. This high-throughput approach provides a detailed genetic blueprint of the tumor.
Fluorescence In Situ Hybridization (FISH) is another technique used to detect gene rearrangements, such as those involving ALK or ROS1, by visualizing specific DNA sequences on chromosomes. Immunohistochemistry (IHC) detects the presence and overexpression of specific proteins associated with certain mutations, offering insights into the protein products of mutated genes. The choice of which test to use depends on the suspected mutation and available resources, with NGS often preferred for its comprehensive nature.
Targeted Treatments for NSCLC
Identifying specific mutations in NSCLC is important for selecting targeted therapies. These drugs specifically attack cancer cells with certain genetic alterations, offering a more precise approach than traditional chemotherapy. Targeted therapies interfere with specific molecular pathways activated by mutations, inhibiting cancer cell growth and survival while often sparing healthy cells.
Patients with EGFR mutations can be treated with tyrosine kinase inhibitors (TKIs) like osimertinib, gefitinib, or erlotinib, which block unregulated signaling pathways driven by the mutated EGFR protein. ALK and ROS1 rearrangements respond well to ALK inhibitors such as crizotinib, alectinib, or brigatinib, targeting abnormal fusion proteins. For BRAF V600E mutations, a combination of BRAF and MEK inhibitors (e.g., dabrafenib, trametinib) blocks the hyperactive signaling pathway.
Emerging therapies address other mutations. For example, capmatinib and tepotinib are approved for NSCLC with MET exon 14 skipping mutations, while selpercatinib and pralsetinib target RET fusions. Larotrectinib and entrectinib are available for NTRK gene fusions. Targeted therapies continue to expand, with recent approvals for KRAS G12C mutations (e.g., sotorasib, adagrasib) and some HER2 insertion mutations (e.g., trastuzumab deruxtecan), further personalizing treatment. This personalized approach has improved outcomes for many NSCLC patients by offering more effective and less toxic treatment options than general chemotherapy, which broadly attacks rapidly dividing cells.