Management of EGFR Positive Lung Cancer
What is an EGFR mutation and why is it important with lung cancer? How is this tested and how is it treated? Who usually has an EGFR mutation and what does it mean with regard to your prognosis?
EGFR positive lung cancer refers to lung cancers that test positive for an EGFR mutation. EGFR stands for epithelial growth factor receptor, a protein that is present on the surface of both normal cells cancer cancer cells 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 which 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. The nucleus of each of our cells contains our DNA, which in turn is made up of genes. These genes act as a blueprint for all of the proteins produced in our bodies. In other words, our genes are like words in an instruction manual describing how to build all of the components of our body.
Some of the proteins produced using these genetic instructions are involved in the process of regulating the growth and division of cells. When a gene that carries the instructions for creating EGFR is damaged—mutated—it is translated into abnormal proteins.in this case, abnormal epithelial growth receptor (EGFR) proteins. These abnormal proteins, in turn, perform an “abnormal” function in regulating the growth of the cell. There are several different ways in which this gene can be mutated (see below).
What Exactly Is EGFR?
Our cells have many antigens (unique proteins) on the surface. EGFR (epidermal growth factor receptor) is one of these proteins that are found on the surface of cancer cells as well as normal cells. EGFR can be thought of as a light switch. When growth factors (in this case tyrosine kinases) attach to EGFR on the outside of the cell, it results in a signal being sent to the nucleus of the cell telling it to grow and divide.
In some cancer cells, his protein is overexpressed. The result is analogous to a light switch being left in the “on” position, telling a cell to continue to grow and divide even when it should otherwise stop. In this way, an EGFR mutation is sometimes referred to as an “activating mutation.”
Risk Factors and Prevalence
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.)
- Are 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 with all of the talk about genes and breast 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 are therefore the genetic mutations responsible for their production 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 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.
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.
Genetic Changes in Cancer Cells
To better understand molecular profiling and targeted theapies 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.
An EGFR mutation does not refer to a single gene abnormality. Rather, there are many different types of EGFR mutations which vary both in the type of mutation (as described above) and in in the location of the mutation in a gene. In other words, there are many ways in which EGFR can be changed genetically
Mutations in EGFR can occur at different locations on exon 18 to 21. The most commonEGFR mutations (around 90 percent) are either exon 19 deletions (missing genetic material) or exon 21 L858 point mutations. (See T790 mutations below which often occur with resistance.)
There are currently three FDA-approved medications available to treat EGFR positive lung adenocarcinoma, as well as one for squamous cell carcinoma 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 four 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.
For people with EGFR mutations who also have brain metastases or leptomeningeal metastases, Tagrisso is now recommended first line has it has a high rate of penetration into the cerebrospinal fluid. (Many drugs are unable to reach the brain and spinal cord as they are unable to pass through the blood-brain barrier.)There are, however, many other factors which your oncologist will wish to consider with your particular cancer.
EGFR and Squamous Cell Carcinoma of the Lungs
The EGFR pathway may also be targeted for people with squamous cell carcinoma of the lungs who do not have EGFR mutations, but by a different mechanism.
Instead of an EGFR mutation driving these cancers, growth is instead related to EGFR amplification. And instead of using tyrosine kinase inhibitors to target an EGFR mutation, anti-EGFR antibodies are a class of medications used which bind to EGFR on the outside of the cell (in cancers which do not have an EGFR mutation) to interrupt the signaling pathway.
Portrazza (necitumumab) was approved in 2015 along with chemotherapy for people with advanced squamous cell carcinoma of the lungs who have not received prior treatment. Portrazza is a monoclonal antibody (man-made antibody) that blocks the activity of EGFR. Anti-EGFR antibody therapy drugs—such as the medications Erbitux (cetuximab) and Vectibix (panitumumab)—have been used with other cancers as well.Unlike the drugs used for adenocarcinoma above which are given orally, the anti-EGFR therapy drug Portrazza is given intravenously.
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 which 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 AZD9291 (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 Brain 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.
One medication currently being studied in clinical trials – AZD3759 was designed to penetrate through the blood-brain barrier, and it’s hoped that this drug, or others being evaluated, may help those with EGFR mutation positive lung cancer who also have brain metastases or leptomeningeal disease.
Treatment Side Effects
The most common side effect of tyrosine kinase inhibitors, which is present in roughly 80 percent of people, is a skin rash. Less frequently, diarrhea may also occur.
Tarceva (erlotinib) skin rashes (and rashes from other tyrosine kinase inhibitors) resemble acne, occurring on the face, upper chest, and back. According to the aspect of the rash, if no white heads are present, a topical corticosteroid cream (a hydrocortisone cream, for example) is used. If white heads are present and the rash looks infected, oral antibiotics are used. Some of the time the dose of the medications will need to be reduced.
As noted earlier, tremendous progress has been made in both the identification of genetic changes with lung cancer and targeted therapies to treat these changes. There are many clinical trials currently in place looking at other medications to treat EGFR mutation positive lung cancer, as well as treatments for other molecular changes in cancer cells.
According to the National Cancer Institute, people with lung cancer should consider participating in clinical trials. Many of the medications now being used were only available as part of a clinical trial just a short while ago. Several of the lung cancer organizations have worked together to form a lung cancer clinical trial matching service for anyone with lung cancer. Through this free service, clinicians can match your specific lung cancer to clinical trials taking place anywhere in the world.
Support and Coping
If you’ve recently been diagnosed with lung cancer, you are doing one of the best things you can be doing—taking the time to learn about your cancer. Here are a few tips on how to find good cancer information online, as well as some of the first steps to take when you are newly diagnosed.
In addition to learning about your cancer, learning how to advocate for yourself as a cancer patient is making a difference for many. While you may be more accustomed to pink ribbons than white lung cancer ribbons, the lung cancer support community, is strong and getting stronger. Many people find it helpful to become involved in these support groups and communities not only as a way to find support from someone who has “been there” but as a method of staying abreast with the latest research on the disease.
The treatment—and thankfully survival rates—for lung cancer are improving, and there is a lot of hope. There were more new treatments approved between 2011 and 2015 than during the 40 year period preceding 2015. Still, cancer is a marathon, not a sprint. If you are coping with cancer, reach out to your family and friends and allow them to help you. Keeping a positive attitude with cancer is helpful at times, but make sure you have a few close friends you can be completely open with and express your not-so-positive and frightened feelings. If it is your loved one who has been diagnosed, check out these thoughts on what it is really like to live with cancer.