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Epidermal Growth Factor Receptor

The epidermal growth factor receptor, EGFR, is a protein that drives cells to survive, proliferate, and spread. Certain mutations in EGFR cause the protein to activate, and some of these mutations are known to be vulnerable to medications that bind to and inhibit the protein.

EGFR stands for epidermal growth factor receptor, a protein that is present on the surface of both normal cells and cancer cells. When working correctly, EGFR proteins are involved in cell signaling pathways that control cell division and survival.

An EGFR mutation refers to a change (damage) to the portion of the DNA in a cell which carries the “recipe” for making EGFR (epidermal growth factor receptor) proteins. A mutation, or change in the EGFR gene causes the production of higher than normal amounts of EGFR proteins, leading to the growth and spread of cancer cells.

EGFR positive lung cancer refers to lung cancers that test positive for an EGFR mutation. Lung cancers that are positive for EGFR mutations are mostly found in people with lung adenocarcinoma (a form of non-small cell lung cancer) and are more common in women than in men.

The EGFR mutation was the first “actionable” mutation discovered in people with lung cancer and it is one of the most common mutations for which there are treatments available that directly target the lung cancer cells. Tremendous advances have been made in the treatment of lung cancers with this particular EGFR mutation in recent years, beginning with the approval of Iressa (gefitinib) in 2003. 

An EGFR mutation is present in roughly 15 percent of people with lung cancer in the United States, though this number increases to 35 to 50 percent in people of Eastern Asian descent.

It is most commonly found in people with the type of non-small cell lung cancer called lung adenocarcinoma. (These cancers are also referred to as “non-squamous” non-small cell lung cancer). At the present time around 85 percent of lung cancers are non-small cell lung cancers, and of these, over 50 percent are lung adenocarcinomas.

EGFR mutations are:

  • More common in women than men. (There are many other differences between lung cancer in women and lung cancer in men).
  • Most common in people with lung adenocarcinoma (but can be found in people with other subtypes of non-small cell lung cancer).
  • Often found in people with little or no smoking history. While 15 percent of lung cancers overall express EGFR, lung cancers in people with little or no smoking history are much more likely to have this mutation.
  • More common in young adults with lung cancer (EGFR mutations are present in roughly 50 percent of lung cancers in young adults).
  • More common in Asians, especially people of East Asian heritage.

It’s now recommended that everyone with non-small cell lung cancer—especially lung adenocarcinoma—have comprehensive biomarker testing done on their tumors to look for the presence of genetic abnormalities (oncogenes) in their lung cancer cells.

It can be confusing to hear about gene mutations in your cancer cells and mistake it for being the same type of mutations associated with a high risk for lung cancer. In contrast to hereditary gene mutations (germline mutations), those which you carry from birth, the mutations which are found with biomarker testing are usually acquired gene mutations (somatic mutations) found only in the cancer cells. Very rarely, T790M can be detected as a germline (existing from birth) mutation.

EGFR mutations are considered “oncogene-driven mutations.” While cancer cells can have many mutations, oncogene-driven mutations are the ones that are directly involved in the cancer process. In EGFR, these mutations “drive” the growth and spread of the cancer. Some, but not all, of the “driver mutations” are also targetable mutations or “actionable mutations” which refer to the fact that they can be targeted by a drug.

Many driver mutations have been discovered in people with lung adenocarcinoma, and this number, as well as driver mutations in other forms of lung cancer, is expected to grow as our understanding of the biology of cancer increases. Common drivers include:

  • EGFR
  • ALK
  • ROS1
  • MET
  • KRAS
  • HER2
  • RET
  • BRAF
  • NTRK

For most of these alterations, targeted therapies are now available. These medications target cancer cells specifically and often have fewer side effects than traditional chemotherapy drugs—drugs which target all rapidly growing cells.

In addition, many active clinical trials are studying treatments to target other types of mutations and genetic changes as well as for different types of lung cancer. There are also many active and ongoing trials to understand resistance to treatment and study therapeutic options to both prevent and reverse resistance.

Tissue Biopsy

In order for comprehensive biomarker testing to be done, a sample of your tumor will need to be obtained. Most of the time, testing requires a sample of tissue obtained during a biopsy. This may be done through a needle biopsy, a bronchoscopy, or through an open lung biopsy. Sometimes testing is done on a tumor which has been removed completely during lung cancer surgery.

Liquid Biopsy

Liquid biopsies are becoming increasingly used for detecting biomarkers in lung cancer. Unlike the more invasive tissue biopsies, this testing may be done through a simple blood test and is extremely helpful when tissue testing is unavailable either because there’s not adequate sample or the patient cannot undergo a biopsy. There can be false negative results in a small number of patients who undergo liquid biopsies, so it is always a good idea to ask your oncologist about the possibility of getting a tissue biopsy if your liquid biopsy does not provide useful information.

At the present time, the use of liquid biopsies is being investigated in a number of different settings, including initial diagnosis, progression, and monitoring.

There are currently five FDA-approved targeted therapies in the United States available to treat first line EGFR positive lung adenocarcinoma. Tagrisso is currently the standard-of-care. These medications are referred to as tyrosine kinase inhibitors (TKIs). They block the activity of the EGFR protein.

Approved medications for lung adenocarcinoma include: Tagrisso (osimertinib) (Standard of care for first-line treatment) and:

  • Tarceva (erlotinib)
  • Gilotrif (afatinib)
  • Iressa (gefitinib)
  • Vizimpro (dacomitinib)

You may hear your oncologist talk about “generations” of these drugs. Tarceva and Iressa are first generation EGFR inhibitors, Gilotrif and Vizimpro are second generation EGFR inhibitors, and Tagrisso is a third-generation EGFR inhibitor. Tagrisso is also approved for those who have had progression on a first or second generation inhibitor and developed a T790M mutation.

Resistance to Treatment

Unfortunately, though lung cancers may respond very well to tyrosine kinase inhibitors at first, they almost always become resistant over time. The amount of time before resistance develops, however, can vary significantly. While the median time between the beginning of therapy and the development of resistance when using Tagrisso is approximately 19 months, many people have had lasting reponses of many years.

At the current time, we usually find out that a tumor has become resistant when it begins to grow again or to spread. A repeat tissue or liquid biopsy, followed by comprehensive biomarker testing should be done at that time to determine if there is another actionable mutation that is driving the resistance. 

Treatment of Resistant EGFR Positive Lung Cancer

Just as there are several different types of EGFR mutations, there are several mechanisms by which cancers can become resistant. Cancer cells are always changing, and often develop mutations that make them resistant to current therapy.

There are many different types of resistance that have been identified and a variety of treatments and clinical trials are available and in development. Please view our 3-part webinar series sponsored by Blueprint Medicine that features expert oncologists in EGFR lung cancer.

Link to Brain Metastases

There is a high incidence of brain metastases in people with EGFR lung cancer. Fortunately, current standard-of-care Tagrisso is effective in crossing the blood-brain barrier—an area of tightly knit cells which line capillaries in the brain—and actively treating and reducing lung cancer that has spread to the brain.

There have also been advancements in radiation for treating limited numbers of brain metastases. This may be referred to as SRS, SBRT, gamma knife, cyber knife, etc. depending on where you are treated.

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