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Dr. Jack West is a medical oncologist and thoracic oncology specialist, and Executive Director of Employer Services at the City of Hope Comprehensive Cancer Center in Duarte, CA.

Lung Cancer FAQ: What is EGFR, and what are the molecular tests related to it?
Mon, 09/20/2010 - 21:11
Howard (Jack) West, MD, Associate Clinical Professor, Medical Oncology, Executive Director, Employer Services, Founder, President and CEO of GRACE

EGFR stands for epidermal growth factor receptor, which is a molecule on the surface of many cancer cells that can be activated to activate signals that promote cell growth and cell division. Though this target may play a role for many kinds of cancer, non-small cell lung cancer (NSCLC) is one type in which this target protein is seen in a majority of people's cancers. In a minority (about 10% in North America and Europe, but closer to 20-30% in Asian populations) who typically have little or no history of smoking and have an adenocarcinoma subtype of NSCLC, there is a particular mutation that leads to activation of the receptor and the downstream cascade of cellular activity that appears to often do a large part of driving the cancer mechanism. Consequently, drugs that block the EGFR target, specifically oral drugs that inhibit the tyrosine kinase portion on the back end, intracellular (within the cell) portion of the receptor (EGFR tyrosine kinase inhibitors, or TKIs, with examples being Tarceva (erlotinib) and Iressa (gefitinib) can sometimes lead to dramatic and long lasting tumor shrinkage. In a larger proportion of patients with NSCLC, these agents can provide a more modest benefit, consistent with the concept that the EGFR pathway is a contributing pathway for the cancer but not the primary driving force.

Another mechanism of blocking the EGFR pathway is by blocking the extracellular (outside the cell) portion of the receptor with a monoclonal antibody that is administered intravenously. Erbitux (cetuximab) is an antibody against EGFR that has been studied and appears to have a very modest degree of activity in advanced NSCLC, though its benefit has been equivocal enough that it is not FDA approved nor widely used as a treatment for NSCLC at this time.

Several different molecular markers have been developed as potential correlates of the activity of EGFR inhibitors. The three main ones are EGFR mutations, which are specific changes in the DNA sequence of the EGFR gene, EGFR fluorescence in situ hybridization (FISH), which measures the number of copies of the EGFR gene in cancer cells, and EGFR immunohistochemistry (IHC), which measures the amount of the protein itself on the surface of the cancer cells. Though there is some evidence to support that being positive for EGFR IHC, FISH, and an activating mutation are all associated with a greater probability of benefiting from EGFR inhibitors, the evidence has converged on a consistent finding that patients with an EGFR mutation are highly likely to receive a very significant benefit from EGFR TKIs, while the trends are less strong and less consistent for those with a high EGFR gene copy number (or gene amplification) as measured by FISH, and the least clear and consistent results of all for EGFR status by IHC. Over time, EGFR mutation status has appeared as the key predictor of strongest benefit with EGFR TKIs. In contrast, none of these markers is clearly associated with benefit from EGFR monoclonal antibodies like Erbitux, though the study that demonstrated a benefit with Erbitux was restricted to patients who had at least some EGFR protein expression on their tumor cells, as measured by IHC.

Further information is available through these links:

Basics of EGFR biology, with figures

EGFR molecular markers

EGFR mutations demystified

Importance of EGFR mutations on IPASS trial of Asian never-smokers

EGFR TKIs for patients with an EGFR mutation

Erbitux with chemo: FLEX trial in advanced NSCLC

Podcast on molecular markers in lung cancer, with focus on EGFR

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