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EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR)
Abnormalities in the function of the epidermal growth-factor receptor (EGFR) may be caused by three different mechanisms—genetic mutation (mistakes in the genetic code for EGFR), gene amplification (extra copies of the genes for EGFR), and/or protein overexpression (excessive production of EGFR). Whatever the cause of the EGFR abnormality, the result is an overgrowth of cells and tumor formation.
Biomarkers for Susceptibility to EGFR Inhibitors
The most common EGFR mutations are exon 19 deletions and L858R substitutions. Patients whose tumors carry these mutations respond well to a family of drugs known as EGFR inhibitors (1-3). In NSCLC, these EGFR mutations are most common in certain patient groups, including women, Asians, nonsmokers, and patients with a specific type of tumor called adenocarcinoma. Although these clinical factors are used to help decide whether a patient is a candidate for treatment with EGFR inhibitors, genetic analysis of the specific EGFR mutation driving an individual's cancer may identify other patients who can also benefit from this therapy.
Gene amplification of EGFR (extra copies of the EGFR gene in tumor cells) can be detected using a technique called Fluorescence In Situ Hybridization (FISH). Although early studies found that patients with extra copies of EGFR were more responsive to EGFR inhibitor therapy, subsequent studies have yielded conflicting results (5-9). Researchers believe that ethnicity is likely to be a factor in these conflicting findings (4-7).
Biomarkers for Resistance to EGFR Inhibitors
Other, less common EGFR mutations have been identified in lung cancer tumors, but more studies are required to determine whether these mutations are sensitive to EGFR inhibitors. In fact, some of these mutations appear to increase the likelihood of tumor resistance to EGFR inhibitors (8).
Resistance to EGFR inhibitors frequently develops even in patients who initially respond to these drugs. A mutation known as T790M is associated with a large proportion of resistant tumors. Although the mechanism of the resistance is not understood, scientists are developing drugs to treat tumors that bear T790M mutations (e.g., irreversible EGFR inhibitors and HSP90 inhibitors)—these drugs are able to inhibit EGFR regardless of T790M status (9, 10).
Another marker of resistance to EGFR inhibitors is additional copies of a gene called MET, which encodes a receptor tyrosine kinase similar to EGFR. MET can activate the same biochemical signaling pathway that is activated by EGFR. Therefore, in tumors with MET amplification, signaling by MET is able to override the signal-blocking effects of an EGFR inhibitor and continue to stimulate tumor growth. For tumors with both an EGFR mutation and MET amplification, concurrent use of an EGFR inhibitor and MET inhibitor may be an effective way to control tumor growth (11).
Targeted Therapy
Erlotinib (Tarceva)/Gefitinib (Iressa)
Erlotinib (Tarceva) and gefitinib (Iressa) are drugs, called kinase inhibitors, that bind to the intracellular portion of EGFR and thereby prevent the receptor from sending signals to the rest of the cell. Both erlotinib and gefitinib have been approved by the FDA for use as second-line therapy for NSCLC—that is, after the first round of traditional chemotherapy has failed. More specifically, erlotinib is currently approved in the US for treatment of locally advanced or metastatic NSCLC patients after failure of at least one prior chemotherapy regimen. Gefitinib is similarly approved for patients with locally advanced or metastatic NSCLC who have previously received chemotherapy or are not suitable for chemotherapy. Both agents are most effective in patients whose tumors bear activating mutations in EGFR. Erlotinib is also indicated for the treatment of pancreatic cancer.
Both erlotinib and gefitinib are currently being evaluated for use as first-line therapy for NSCLC. Because EGFR inhibitors can be administered orally and are less toxic than traditional chemotherapeutic drugs, trials are in progress to evaluate the efficacy of erlotinib as a first-line treatment for elderly patients with NSCLC (13). In addition, a recent clinical trial has demonstrated that gefitinib is effective as a first-line treatment for NSCLC patients with mutations in EGFR (14). Although skin rash, which may be severe, is a common side effect of both erlotinib and gefitinib, the appearance of a rash is frequently correlated with a positive response to the drug (15).
Unfortunately, most patients who respond to erlotinib and gefitinib eventually develop resistance, either through the acquisition of additional mutations (such as T790M or MET amplification) or other unknown mechanisms. Scientists are currently developing drugs, such as HSP90 inhibitors and MET inhibitors, which they hope will be effective against the resistant tumors.
Cetuximab (Erbitux)
Cetuximab (Erbitux) is a monoclonal antibody that binds to EGFR and prevents it from receiving a signal that would cause it to trigger cell growth. Cetuximab is currently approved by the FDA for the treatment of metastatic colorectal cancer and locally advanced head and neck cancer. In NSCLC, a phase II clinical trial of cetuximab in combination with traditional cytotoxic chemotherapy as a first-line treatment did not find any statistically significant difference between patients treated with and without cetuximab (16). However, a large Phase III trial comparing traditional chemotherapy with and without cetuximab in NSCLC patients whose tumors overexpress EGFR found that the patients treated with cetuximab do have a survival advantage (17).
As with erlotinib and gefitinib, a common side effect of cetuximab is rash, which may be severe. Although the presence of a rash appears to be predictive of a positive response to the drug in metastatic colorectal cancer (MCRC) and squamous cell carcinoma of the head and neck (SCCHN) (15), this correlation is still being studied in NSCLC. Also being studied is the correlation between a high number of copies of the EGFR gene in the tumor and response to cetuximab—this correlation has been observed in MCRC.