The Epidermal Growth Factor Receptor (EGFR) is a protein found on the surface of many cells throughout the body. This receptor acts like an antenna, receiving signals that instruct cells to grow, divide, and repair themselves. Normally, this process is tightly regulated, ensuring controlled cell proliferation. When a signal binds to EGFR, it triggers a cascade of events inside the cell, promoting cell maintenance and renewal.
The Role of EGFR Mutations in Cancer
When the EGFR gene undergoes a mutation, its normal function can be disrupted. These mutations cause the receptor to become continuously active, even without external signals. This constant “on” state leads to uncontrolled cell growth and division, a hallmark of cancer. These mutations are particularly relevant in non-small cell lung cancer (NSCLC), where they drive tumor growth in many patients.
Several distinct activating mutations within the EGFR gene are commonly observed in NSCLC. The most frequent types include deletions in exon 19 and a specific point mutation known as L858R in exon 21. These genetic alterations are responsible for making the EGFR protein overactive, promoting the rapid proliferation of cancer cells. They are more frequently identified in certain demographics, such as individuals who have never smoked or have a light smoking history, and those of East Asian descent.
Identifying EGFR Gene Mutations
Detecting an EGFR gene mutation is a crucial step in guiding treatment decisions for patients with non-small cell lung cancer. The primary method for identifying these mutations involves molecular testing performed on a tumor tissue sample. This sample is typically obtained through a biopsy, where a small piece of the cancerous tissue is removed from the lung or another affected area. Pathologists then analyze the tissue in a laboratory to pinpoint specific genetic alterations within the EGFR gene.
An alternative to tissue biopsy is a liquid biopsy, which involves analyzing a blood sample for circulating tumor DNA (ctDNA). This method can detect fragments of DNA shed by cancer cells into the bloodstream. Liquid biopsies are often used when a traditional tissue biopsy is not feasible due to the tumor’s location or the patient’s health status. It is also used to monitor for new mutations during treatment. The results from either a tissue or liquid biopsy provide information about the genetic profile of the cancer.
Targeted Therapy for EGFR-Positive Cancers
Identifying an EGFR gene mutation allows for a specialized treatment approach known as targeted therapy. Unlike traditional chemotherapy, which broadly attacks rapidly dividing cells, targeted therapies are designed to specifically interfere with the molecular pathways that drive cancer growth. These treatments leverage the unique genetic characteristics of the tumor.
Tyrosine Kinase Inhibitors (TKIs) are the cornerstone of targeted therapy for EGFR-positive cancers. TKIs work by blocking the signaling pathways initiated by the mutated EGFR protein. By binding to the active site of the EGFR receptor, TKIs prevent the constant “on” signal that promotes uncontrolled cell division. This action halts the growth and spread of cancer cells while minimizing damage to healthy cells.
TKIs have progressed through several generations, each offering advancements in efficacy and specificity. First-generation TKIs, such as gefitinib and erlotinib, were among the initial drugs used to treat EGFR-positive NSCLC. Second-generation TKIs, including afatinib and dacomitinib, were developed to provide more potent and irreversible inhibition of the EGFR protein. More recently, third-generation TKIs like osimertinib have emerged, offering improved effectiveness and the ability to overcome resistance mechanisms that can develop over time. These targeted drugs represent a personalized medicine strategy, tailoring treatment directly to the genetic makeup of an individual’s cancer.
Acquired Resistance to Treatment
While targeted therapies for EGFR-positive cancers can be highly effective, cancer cells often evolve, leading to a phenomenon known as acquired resistance. The initial treatment becomes less effective as the cancer adapts and finds new ways to grow. This resistance develops because the cancer cells acquire additional genetic mutations that circumvent the drug’s mechanism of action.
The most common mechanism of acquired resistance to first and second-generation EGFR TKIs is the T790M mutation in exon 20 of the EGFR gene. This mutation alters the binding site of the TKI, preventing the drug from effectively attaching to and inhibiting the EGFR protein. When treatment resistance is suspected, further molecular testing, often through a liquid biopsy, identifies any new mutations that have emerged. Detecting mutations like T790M helps guide subsequent treatment decisions, allowing for the selection of next-generation TKIs designed to overcome these new resistance mechanisms.