Mutations that Matter in Lung Cancer & Their Treatments
- Treatment for lung cancer can differ significantly based on the type of disease, the stage, a patient’s overall health and medical history, and DNA mutations.
- EGFR and ALK mutations are commonly tested for regardless of stage.
- In early stage lung cancer, sometimes having a specific mutation in the EGFR gene can lead to the use of a targeted therapy called Osimertinib after definitive therapy with surgery. In locally advanced lung cancer, if a specific EGFR mutation is present, Osimertinib is often incorporated into treatment as well.
- More comprehensive molecular testing for DNA mutations, often with next generation sequencing, is employed in advanced or metastatic disease. There are several mutations that are tested for which have specific targeted therapies.
In this article we will delve further into some of those medical advancements for lung cancer, specifically mutations in lung cancer DNA that can be targeted by specific medications. This field of ongoing research has already improved outcomes in lung cancer — with many new potential therapies and treatment considerations available or currently being explored.
Read MoreWhat are DNA mutations?
DNA is the genetic code of your cell, or the blueprint. Everything your cells make to keep them alive and functioning is all stored in the DNA. Normally, there are checkpoints and safeguards in your cells that identify changes in the DNA in order to correct them. This can be through either fixing the DNA change or mutation itself, or killing the cell if the DNA change or damage is too difficult to fix. When enough of certain parts of the DNA are mutated and not fixed by your cells’ protective mechanisms, this can result in unregulated growth and division of the cells which can result in cancer. For many types of cancer there are specific mutations in parts of the DNA that we know directly attribute to cancer growth and spread. There are still many mutations that are unknown in terms of their significance or role in causing cancer.There are some drugs available that can target these specific DNA mutations — or medications that doctors know are very effective against these changes. Just as cancers that arise in various parts of the body are different, common DNA mutations that cause these cancers can also be different, resulting in different medications to target these DNA mutations.
In the next few sections we will talk specifically about DNA mutations in lung cancer and when these are used to identify targeted treatment options.
Lung Cancer Work Up and Staging
Dr. Chul Kim, a medical oncologist specializing in lung cancer and thoracic tumors at MedStar Health in Washington D.C., broke down the different types of lung cancer for SurvivorNet.
“There are two primary types of lung cancer. The first type is called non-small cell lung cancer (NSCLC), accounting for about 85% of lung cancer cases. The second type, small cell lung cancer (SCLC), represents about 15% of lung cancer cases.”
The mutations we are discussing pertain to non-small lung cancer, the most common form of the disease, and the remainder of the discussion will focus on testing and treatment for non-small cell lung cancer.
Even among non-small cell lung cancer there are different subtypes.
“The first most common form of non-small cell lung cancer is adenocarcinoma followed by squamous cell carcinoma, which is the second most common form of lung cancer,” Dr. Kim explained. “Each subtype of lung cancer has different characteristics. It is important to highlight that not all lung cancers are the same. Even if two lung cancers are looking alike under a microscope, they can have different traits. Molecular testing … allows us to develop better understanding of those characteristics of the cancer at the molecular level.”
Just like most other cancers, a workup will be done prior to considering treatment options. This workup may include:
- A detailed health history and physical exam
- Pulmonary function tests to check the function of your lungs
- Blood work
- Imaging such as CT imaging, PET scan, and sometimes a brain MRI
- Biopsy where a piece of the tissue is obtained and studied
The lung cancer will be staged based on the results of several tests. When the initial biopsy is performed it will be tested for a series of well-known DNA mutations that potentially have targeted therapies. With the initial biopsy, specific DNA mutations tested often include EGFR and ALK. PD-L1 status is also tested; this is a marker of how the tumor is suppressing your immune system.
Staging refers to the degree of local and distant spread of the cancer. Earlier stage lung cancers are smaller and less invasive, while locally advanced lung cancer refers to larger cancers or ones that have spread to nearby lymph nodes in the chest.
Metastatic lung cancer refers to cancer that has spread to distant sites in the body. Additional DNA mutation testing, or broad molecular testing, can be done based on the stage of the disease, and is often reserved for metastatic lung cancer disease.
The lung cancer stage as well as specific factors like your overall health and treatment goals determine what potential therapies might be available. Based on all of these factors, the DNA mutations, and potential therapies targeting these mutations, can take a greater role.
A general rule of thumb: the earlier stage the lung cancer is, the less important DNA mutations and targeted therapies are in treatment, with DNA mutation testing being much more important in metastatic disease.
Let’s break this down further based on the stage of lung cancer and how DNA mutations play a role.
Early-stage lung cancer and mutations
Again, early stage lung cancer typically refers to smaller lung cancers that have not invaded into surrounding areas, spread to lymph nodes, or spread distantly in the body. Treatment typically entails surgery or radiation alone depending on your overall health and medical history. Sometimes systemic treatment (which treats the whole body) is used before or after surgery depending on the specific stage and what is found during surgery. Systemic therapy can be chemotherapy, immunotherapy, or targeted therapy depending on the patient and the lung cancer type.
In these cases if there is a specific EGFR mutation, a targeted therapy called Osemirtinib can be used following surgery.
Locally advanced lung cancer and mutations
Locally advanced lung cancers typically describe lung cancer that is larger, locally invasive into surrounding structures, or has lymph nodes which are involved. The treatment can vary but typically entails a combination of surgery and systemic therapy when feasible.
If surgery is not possible systemic therapy and radiation is used. Again systemic therapy can involve chemotherapy, immunotherapy, and targeted therapies.
In these cases if there is a specific EGFR mutation, a targeted therapy called Osemirtinib can be used as well following primary treatment — often with a combination of chemotherapy and radiation or chemotherapy and surgery. The specific treatment recommended will depend on several factors including stage, tumor location, and overall health.
Metastatic disease and mutations
If you have very advanced or metastatic disease, systemic therapy is often the mainstay of treatment. Additional testing for DNA mutations will be performed based on your subtype of non-small cell lung cancer. The subtypes include adenocarcinoma, large cell, and squamous cell carcinoma.
Molecular profiling, also called next generation sequencing, is commonly used to test for several changes in DNA throughout the cancer.
“Next generation sequencing is a high speed scanner for body’s genetic code such as DNA and RNA. It rapidly reads the code to identify any errors or changes. These changes can assist doctors in determining the best treatment for patients with lung cancer,” Dr. Kim explained.
Next generation sequencing and testing for DNA mutations is a field of ongoing research. New targets for drugs are constantly being explored and developed as well as new ways for testing for changes in the tumor DNA.
“While next generation sequencing has been traditionally used for tissue samples, it can now also be utilized for other types of specimens such as blood to characterize the cancer’s features. And this process is sometimes called liquid biopsy,” Dr. Kim explained.
In cases of advanced or metastatic lung cancer, instead of getting repeat biopsies — which can be invasive and costly — doctors can test the blood alone with a liquid biopsy to check for any changes in the cancer throughout the course of treatment.
There are well established mutations for each subtype which are specifically examined during molecular testing and are included below:
If you have adenocarcinoma, large cell, or NSCLC not otherwise specified (NOS), the mutations that should be included in broad molecular testing include:
- EGFR
- ALK
- ROS1
- BRAF
- NTRK1/2/3
- METex14 skipping
- RET
- ERBB2 (HER2)
This should all be performed as part of a broad molecular test and also PD-L1 status should be tested.
If you have squamous cell carcinoma, the mutations that should be included in broad molecular testing include:
- EGFR
- ALK
- KRAS
- ROS1
- BRAF
- NTRK1/2/3
- METex14 skipping
- RET
- ERBB2 (HER20
This should all be performed as part of a broad molecular test and also PD-L1 status should be tested.
If your lung cancer is found to have one of these mutations, a targeted systemic therapy could be recommended for you based on the specific DNA mutation.
Depending on the specific DNA mutation, there can be several targeted therapies which can be used. These can change throughout the course of your disease based on your response to current therapies.
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