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About EGFR2018-02-26T14:06:56+00:00

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 positive lung cancer refers to lung cancers that test positive for an EGFR mutation. EGFR stands for epidermal growth factor receptor, a protein that is present on the surface of both normal cells cancer such as lung cancer cells.

EGFR mutations are most common in people with lung adenocarcinoma (a form of non-small cell lung cancer) are more common with lung cancer in non-smokers, and are more common in women than in men.

A mutation in a gene coding for EGFR is the most common “actionable” mutation among people with lung cancer, meaning that it is the most common genetic change 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 molecular profile in recent years. Beginning with the approval of Iressa (gefitinib) in 2003—at a time when we still had little understanding about EGFR—nearly half of the new medications approved for the treatment of lung cancer as of 2016 address this particular molecular profile.

What Is an EGFR Mutation?

An EGFR mutation refers to a mutation (damage) to the portion of the DNA in a lung cancer cell which carries the “recipe” for making EGFR (epidermal growth factor receptor) proteins.

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 never smokers or people who smoked only lightly (a never-smoker is defined as someone who has smoked 100 or fewer cigarettes over their lifetime).  While 15 percent of lung cancers overall express EGFR, lung cancers in non-smokers 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.
  • Less common in African Americans than Caucasians.

It’s now recommended that everyone with non-small cell lung cancer—especially lung adenocarcinoma—have molecular profiling (gene testing) done on their tumors to look for the presence of genetic abnormalities 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, those which you carry from birth, however, the mutations which are found with molecular profiling are acquired gene mutations (somatic mutations.) These mutations are not present at birth but develop later on in life in the process of a cell becoming a cancer cell.

Cancer cells can have many mutations, but only a few of them are directly involved in the cancer process. These mutations lead to the production of abnormal proteins which guide the growth and development of a cancer cell. These abnormal proteins “drive” the growth and spread of the cancer and therefore the genetic mutations responsible for their production and are called “driver mutations.” Some, but not all of the “driver mutations” are also targetable mutations or “actionable mutations” which refers to the fact that they can be targeted by a drug.

It’s estimated that driver mutations are present in 60 percent of 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 driver mutations include:

  • EGFR mutations
  • ALK rearrangements
  • ROS1 rearrangements
  • MET amplifications
  • KRAS mutations
  • HER2 mutations

For several of these abnormalities, 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, clinical trials are in place for other types of mutations and genetic changes as well as for different types of lung cancer. In general, people do not usually have more than one of these mutations. For example, it’s unlikely (but not impossible) for someone with an EGFR mutation to also have an ALK rearrangement or KRAS mutation in their lung cancer cells.

Tissue Biopsy

In order for gene 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 lung biopsy. This may be done through a needle biopsy, during 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

In June of 2016, a new liquid biopsy test was approved for detecting EGFR mutations. Unlike the more invasive tissue biopsies, this testing may be done through a simple blood test. At the present time, these tests are still considered investigational and are not used alone to guide diagnosis and treatment of lung cancer, but offer much promise. It’s hoped that these tests will offer the option of monitoring people with EGFR positive lung cancer in real time in the future. At the current time, we only learn that a tumor has become resistant to treatments that target EGFR when it fails to respond (begins to grow or spread) on lung scans. Liquid biopsies would grant physicians the opportunity to learn a tumor has become resistant—and hence change to a more effective therapy—sooner than is now possible.

To better understand molecular profiling and targeted therapies for lung cancer, it’s helpful to define a few basic genetic principles. There are several different types of genetic changes which may occur in cancer cells. These include:

  • Mutations – A mutation is a change in the DNA sequence that makes up a gene.
  • Rearrangements – In rearrangements, the sequence of DNA is rearranged.
  • Translocations – These changes occur when part of a gene on one chromosome is relocated to a different region of the DNA.
  • Gene fusion – A “fusion” gene occurs when a translocation brings together two genes that are ordinarily not together.
  • Amplification – Refers to the production of multiple copies of a gene and is common in cancer cells.

There are also different types of mutations. Some of these, simplistically, include:

  • Point mutations – A point mutation refers to a mutation in which one base is substituted for another.
  • Deletions – In a deletion, a piece of genetic material is lost or deleted from the gene.
  • Insertions – In an insertion, a piece of genetic material is added to the gene.

There are currently three FDA-approved medications available to treat EGFR positive lung adenocarcinoma and one for EGFR positive resistant lung cancer.  These medications are referred to as tyrosine kinase inhibitors. They block the activity of the EGFR protein.

Approved medications for lung adenocarcinoma include:

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

Approved medications for T790 mutations include:

  • Tagrisso (osimertinib)

You may hear your oncologist talk about “generations” of these drugs. Tarceva is a first-generation EGFR inhibitor, Gilotrif is a second generation, and Tagrisso, a third-generation EGFR inhibitor.

EGFR Inhibitors for Lung Adenocarcinoma

With three medications available first line for EGFR positive lung adenocarcinoma, how do doctors choose which of these tyrosine kinase inhibitors may work best for your specific cancer?

The choice of a particular EGFR inhibitor depends largely on your oncologist’s preference (and your location).   There are some small differences. Iressa has the reputation of having the fewest side effects and may be considered first choice for someone with other major medications conditions or in the elderly. In contrast, Gilotrif may have somewhat greater side effects (especially mouth sores) but may also have a larger overall survival benefit. Gilotrif may also work a little better for people with an exon 19 gene deletion. There are, however, many other factors that your oncologist will consider when recommending an individualized treatment plan for you.

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 is 9 to 13 months, these medications have remained effective for some people for 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 biopsy, followed by molecular profiling is often done at that time. As noted above, it’s hoped that liquid biopsies will become a way of determining when a tumor becomes resistant in the future.

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 the drugs being used.

In roughly half of people, a second mutation—an exon 20 deletion called EGFR T790 develops. This mutation affects the region of EGFR which first and second-line tyrosine kinase inhibitors (such as Tarceva) bind to, making all three medications above (Tarceva, Gilotrif, and Iressa) ineffective. For those with metastatic EGFR T790 mutation positive non-small cell lung cancer, the medication Tagrisso or Osimertinib has now been approved. Yet, just as resistance develops with first-generation medications, acquired resistance may develop to third generation tyrosine kinase inhibitors as well. Hopefully, drugs will continue to be developed for resistant tumors, so that many people will be able to live with lung cancer as a form of chronic disease—not cured, but controlled with these medicines.

Link to Bra​in Metastases

Unfortunately, due to the presence of the blood-brain barrier—an area of tightly knit cells which line capillaries in the brain—many of these medications are unable to reach cancer cells which have traveled to the brain. The blood-brain barrier is designed to limit the ability of toxins to access the brain, but unfortunately, often prevents chemotherapy and targeted therapies from reaching the brain as well. Since lung cancer has a tendency to spread to the brain, this has been a significant problem for those with lung cancer with brain metastases.

CNS

Central Nervous System – the brain and spinal cord.

EGFR

Epidermal Growth Factor Receptor – A widely studied protein and gene known to be associated with cancer.

FDA

Food and Drug Administration – the agency that regulates food and drugs in the US.

Irreversible inhibitor

An inhibitor that binds using a covalent bond, a much stronger molecular bond.

NCCN

National Comprehensive Cancer Network – a collection of leading cancer centers in the US, most widely used authority for cancer guidelines.

Median

The middle point, or 50% of a group.

Mutant, Mutated (gene)

A gene that has changed, often associated with disease.

Mutant Selective

A drug that is more active against a mutated version of a gene than than the wild-type gene.

Object Response

A tumor shrinkage. In clinical trials, usually based on RECIST criteria requiring >30% shrinkage.

ORR

Objective response rate – The fraction of people who had a RECIST defined Objective Response.

PFS

Progression Free Survival – the time from the start of treatment until either disease progression or death is observed.

Progression

The cancer has grown. In clinical trials, usually based on the RECIST criteria, growth beyond 30%.

RECIST

Response Evaluation Criteria In Solid Tumors – a standard for measuring tumor growth and shrinkage used in clinical trials.

TKI

Tyrosine Kinase Inhibitor – a drug that binds to a protein to prevent it from activating. Targeted therapies are often referred to as TKIs.

OS

Overall Survival – In clinical trials, the time from the start of the trial until death.

Wild-type

The normal version of the gene found in the general population.

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