The Epidermal Growth Factor Receptor (EGFR) is a protein found on the surface of cells throughout the body. This receptor acts like an antenna, receiving signals that instruct cells to grow, divide, and repair themselves. In its normal state, EGFR plays an important role in maintaining healthy tissue development and function.
The Role of EGFR Mutations in Cancer
A gene mutation represents a permanent change in the DNA sequence that makes up a gene. When a mutation occurs in the EGFR gene, it can alter the normal function of the EGFR protein. This change can be compared to a light switch getting stuck in the “on” position, causing cells to receive continuous growth signals. Such uncontrolled signaling leads to accelerated cell division and growth, a hallmark of cancer development.
These genetic alterations are most frequently identified in non-small cell lung cancer (NSCLC), accounting for a significant percentage of cases. While some individuals may encounter the term “EGFR 56,” this is not a standard or medically recognized name for a specific EGFR mutation. It is likely a misunderstanding or misinterpretation of other mutation classifications, such as those involving specific exons like exon 19 or exon 21. Instead, medical professionals focus on precisely identified mutations that guide treatment decisions.
Common Types of EGFR Mutations
The most prevalent and clinically significant EGFR mutations are known as “classic” activating mutations. These include deletions within exon 19 and the L858R point mutation in exon 21. Exon 19 deletions are typically found in about 45-50% of classic EGFR-mutated NSCLC cases, while the L858R mutation accounts for approximately 40-45%. Both types lead to increased activation of the EGFR pathway, promoting tumor growth.
Other important types of EGFR mutations also exist, though they may respond differently to therapies. Exon 20 insertions represent about 4-12% of all EGFR mutations in NSCLC and often present a challenge for older targeted treatments. These specific insertions, such as A763_Y764insFQEA, create unique structural changes in the receptor. Their distinct molecular configuration reduces their sensitivity to first- and second-generation tyrosine kinase inhibitors.
Another notable mutation is T790M, which typically arises after initial treatment with EGFR-targeted therapies. This mutation, located in exon 20, acts as a common mechanism of acquired resistance, developing in tumor cells over time. The T790M mutation reduces the binding affinity of earlier targeted drugs, allowing cancer cells to resume uncontrolled growth. Detecting this mutation indicates a need for different therapeutic strategies.
Testing for EGFR Mutations
Identifying EGFR mutations is an important step in determining appropriate treatment strategies for patients, particularly those with non-small cell lung cancer. Doctors utilize diagnostic methods to detect these genetic changes within tumor cells. This testing confirms if a patient is a candidate for targeted therapies designed to block the mutated EGFR protein.
One method for mutation detection is tissue biopsy, where a small sample of tumor tissue is removed. This sample is sent to a laboratory for genetic analysis, often using next-generation sequencing. Tissue biopsies provide a direct analysis of the tumor’s genetic makeup, offering comprehensive mutation profiling. However, they are invasive procedures and may not always be feasible due to tumor location or patient health.
An alternative is a liquid biopsy, which analyzes a blood sample for circulating tumor DNA (ctDNA). Tumor cells release DNA fragments into the bloodstream, which can be detected and analyzed for specific mutations. Liquid biopsies are less invasive than tissue biopsies and can be performed more frequently to monitor treatment response or detect acquired resistance mutations like T790M. While convenient, liquid biopsies may have lower sensitivity compared to tissue samples, especially if the tumor burden is small.
Targeted Therapies for EGFR-Positive Cancers
Targeted therapies represent an advancement in cancer treatment, differing from traditional chemotherapy by focusing on specific molecular pathways that drive cancer growth. For EGFR-positive cancers, these therapies aim to block the aberrant signals originating from the mutated EGFR protein. This precise approach leads to fewer side effects compared to chemotherapy, which broadly attacks all rapidly dividing cells.
Tyrosine Kinase Inhibitors (TKIs) are the primary class of drugs used for EGFR-mutated non-small cell lung cancer. These medications bind to the ATP-binding pocket of the EGFR protein, preventing the signaling pathway from activating. By blocking this “on” switch, TKIs inhibit the uncontrolled growth and division of cancer cells. The effectiveness of different TKIs can vary based on the specific EGFR mutation present.
Examples of TKIs include gefitinib and erlotinib, which were first-generation drugs effective against classic mutations like Exon 19 deletions and L858R. Osimertinib is a third-generation TKI with broader efficacy. It is effective in treating cancers with the T790M resistance mutation, which develops after initial TKI treatment. Osimertinib also demonstrates activity against the original Exon 19 deletions and L858R mutations, making it a preferred initial treatment in many cases.