The Epidermal Growth Factor Receptor (EGFR) is a protein found on the surface of various cells throughout the body. Its normal function involves receiving signals from outside the cell, which then trigger pathways inside the cell that regulate growth, division, and survival.
How EGFR Contributes to Cancer Growth
When the EGFR gene undergoes specific changes called mutations, its normal function can be disrupted. These mutations can lead to the EGFR protein becoming overactive or constantly “on,” even without external growth signals. This abnormal activation sends continuous signals for cells to grow and divide without control, a hallmark of cancer development.
This uncontrolled proliferation leads to the formation of tumors. Cancer cells can become highly dependent on this abnormal EGFR activity for their survival and continued growth, a phenomenon referred to as “oncogene addiction.” Targeting this specific dependency can be an effective strategy for treatment.
Detecting EGFR Mutations in Cancer
Identifying EGFR mutations is a significant step in determining the best treatment approach for cancer patients. These mutations are particularly common in non-small cell lung cancer (NSCLC), accounting for about 10-15% of cases in the United States, with a higher incidence in Asian populations and in individuals with minimal to no smoking history. Adenocarcinoma, a subtype of NSCLC, is the most frequently associated with EGFR mutations.
Various methods are used to detect these mutations, including tissue biopsy, which involves analyzing a tumor sample. Liquid biopsy, a less invasive option, can detect tumor DNA shed into the bloodstream. Molecular testing techniques like Polymerase Chain Reaction (PCR) and Next-Generation Sequencing (NGS) are employed to pinpoint specific EGFR mutations, such as exon 19 deletions or L858R point mutations in exon 21. This testing is crucial for guiding personalized treatment decisions.
Targeted Treatments for EGFR-Positive Cancers
Targeted therapies have significantly improved the treatment of EGFR-positive cancers by specifically addressing the underlying genetic alterations. These drugs are known as EGFR Tyrosine Kinase Inhibitors (TKIs) and work by blocking the abnormal signaling pathway driven by the mutated EGFR protein. By binding to the ATP-binding site within the EGFR, TKIs prevent the constant activation that promotes cancer cell growth and survival, often leading to programmed cell death.
Different generations of EGFR TKIs have been developed, each with distinct characteristics and targets. First-generation TKIs, such as gefitinib (Iressa) and erlotinib (Tarceva), reversibly bind to the EGFR and were among the first approved for patients with common EGFR mutations like exon 19 deletions and L858R. Second-generation TKIs, including afatinib (Gilotrif) and dacomitinib (Vizimpro), are irreversible inhibitors that covalently bind to EGFR, offering broader inhibition. Third-generation TKIs, exemplified by osimertinib (Tagrisso), were developed to overcome acquired resistance mechanisms, particularly the T790M mutation, which can develop after initial treatment with earlier generations. These medications are typically taken orally, offering a convenient treatment option for many patients.
Life with EGFR-Positive Cancer: Treatment and Prognosis
Patients undergoing EGFR TKI treatment often experience common side effects, including skin rash, dry skin, and diarrhea. Skin changes, such as an acne-like rash, can appear within the first two weeks of treatment, primarily on the face, chest, and back. Diarrhea is another frequent side effect, and both can usually be managed with appropriate medical guidance and supportive care, allowing most patients to maintain a relatively normal life.
Despite initial positive responses, cancer cells can eventually develop new mutations, leading to “acquired resistance,” meaning the TKI treatment becomes less effective. The T790M mutation is a common mechanism of acquired resistance to first and second-generation TKIs, occurring in about 50-60% of patients. When resistance develops, further molecular testing is often recommended to identify new mutations and guide subsequent treatment strategies, which might include third-generation TKIs or other therapies. While EGFR-targeted therapies are not a cure, they have significantly improved the outlook for patients with EGFR-positive cancers, often extending life and enhancing quality of life compared to traditional chemotherapy.