How Biomarker Testing can Help With Lung Cancer Treatment
Lung cancer is one of the leading causes of cancer deaths worldwide. It is a complex disease that can be caused by a variety of factors, such as environmental exposure, smoking, and genetic predisposition. The treatment of lung cancer can be challenging and requires a personalized approach that takes into account the unique characteristics of each patient. One important tool in this effort is comprehensive biomarker testing.
What is Biomarker Testing?
Biomarker testing is a type of medical testing that looks for specific molecules in a patient's blood or tissue samples. These molecules, called biomarkers, can indicate the presence of a disease, the severity of the disease, or how well the patient is responding to treatment.Biomarker testing can be a crucial tool in the diagnosis and treatment of many diseases, including cancer.
Why is Biomarker Testing Important in Lung Cancer Patients?
Lung cancer is a complex disease that can be caused by many different factors. It can also vary significantly in terms of its molecular makeup and how it responds to treatment. Biomarker testing can help identify the specific type of lung cancer a patient has, which can in turn help determine the most effective treatment plan. This personalized approach can improve outcomes for patients and potentially extend their lives.
There are several biomarkers that are commonly found in lung cancer, and each of them requires a personalized treatment approach. Current guidelines recommend that all patients diagnosed with advanced-stage non-small cell lung cancer be tested for the EGFR, ALK, KRAS,ROS1, and BRAF V600E mutations, and the PD-L1 protein. In this blog post, we'll discuss these lung cancer biomarkers and how personalized treatment can be achieved.
Lung Cancer Biomarkers and Personalized Treatment
EGFR (Epidermal Growth Factor Receptor)
EGFR is a protein on cells that helps them grow. A mutation in the gene for EGFR can make it grow too much, which can cause cancer. Mutations in the EGFR gene are present in approximately 10-15% of all lung cancers. EGFR mutations are more common in patients who have never smoked and in patients of Asian descent. EGFR biomarker testing can help identify patients with EGFR mutations, which can in turn help determine the most effective treatment approach.
Typically, EGFR is a receptor on the surface of cells that binds to epidermal growth factor (EGF) molecules, which then trigger a signaling pathway inside the cell that regulates cell growth and division. However, in EGFR-mutated NSCLC, the mutations can cause the receptor to be constantly activated, leading to uncontrolled cell growth and division, and ultimately the formation of a tumor. This increased signaling can also lead to resistance to chemotherapy.
To treat EGFR-positive NSCLC, drugs called tyrosine kinase inhibitors (TKIs) are used. These drugs block the activity of EGFR and other proteins in the pathway, leading to reduced cell growth and division, and eventually tumor shrinkage. Examples of EGFR TKIs include erlotinib, gefitinib, and osimertinib.
ALK (Anaplastic Lymphoma Kinase)
The ALK gene is in your body when you are an embryo. It helps in the development of the gut and nervous system. It gets turned off while you are still in the womb. For some people, it gets turned back on and fuses (joins) with another gene. This gene change is called an ALK fusion or ALK rearrangement and can cause cancer. ALK fusions are present in approximately 3-5% of all lung cancers. ALK biomarker testing can help identify patients with ALK fusions, which can in turn help determine the most effective treatment approach.
Normally, ALK is involved in cell growth and division in certain types of cells, such as nerve cells. However, inALK-mutated NSCLC, the mutations cause the ALK protein to be constantly activated, leading to uncontrolled cell growth and division and the formation of a tumor. ALK mutations can also cause resistance to chemotherapy.
In patients with ALK fusions, targeted therapy with drugs like crizotinib, alectinib, brigatinib, and lorlatinib has been shown to be more effective than chemotherapy. These drugs block the activity of the ALK protein, leading to reduced cell growth and division, and eventually tumor shrinkage.
KRAS (Kirsten Rat Sarcoma)
The KRAS mutation is an error in a protein in normal cells. KRAS mutations are present in about 25% of NSCLC cases and are more commonly found in patients with a history of heavy smoking. Normally KRAS serves as an information hub for signals in the cell that lead to cell growth. When there is a mutation in KRAS, it signals too much and cells grow without being told to, which causes cancer.
KRAS mutations have been historically difficult to target with drugs, and there is only one FDA-approved targeted therapies for KRAS-mutated NSCLC. Sotorasib is a small molecule inhibitor that works by binding to the mutated KRAS protein and blocking its activity. It is only effective in patients with NSCLC that have the specific KRAS G12C mutation. However, new KRAS inhibitors are being developed and tested in clinical trials.
BRAF V600E
BRAF is a gene that can be mutated in NSCLC patients, with the most common mutation being BRAF V600E. BRAF V600E mutation occurs in approximately 1-2% of NSCLC cases and is more commonly found inpatients with a history of heavy smoking.
The BRAF protein helps control cell growth. When there is a mutation in the BRAF gene, it creates an abnormal protein that sends signals that lead to uncontrolled cell growth and cancer. The BRAF protein works with another protein called MEK to regulate the growth of cells.
Drugs called BRAF inhibitors, such asdabrafenib and vemurafenib, are used to target BRAF V600E mutations. Additionally, combination therapies with BRAF inhibitors and MEK inhibitors, which target a downstream signaling pathway, have also shown promise in clinical trials.
ROS1 (ROS1 Proto-Oncogene)
ROS1 is a gene that can also fuse with other genes, leading to the production of abnormal proteins that drive the growth of cancer cells. ROS1 fusions are present in approximately 1-2% of all lung cancers. ROS1 biomarker testing can help identify patients with ROS1 fusions, which can in turn help determine the most effective treatment approach.
In ROS1-positive lung cancer patients, theROS1 gene fuses (joins) with part of another gene. This activates the ROS1 gene in a way that causes uncontrolled cell growth and cancer. This gene change is called a ROS1 fusion or ROS1 rearrangement. The ROS1 gene can fuse with many different partners. The most common in lung cancer is the CD74 gene. When ROS1fuses or joins with another gene and causes lung cancer, a patient is said to be ROS1-positive. Similar to EGFR and ALK mutations, ROS1 rearrangements can also cause resistance to chemotherapy.
To treat ROS1-positive NSCLC, drugs calledROS1 inhibitors are used. These drugs block the activity of the ROS1 protein, leading to reduced cell growth and division, and eventually tumor shrinkage. Examples of ROS1 inhibitors include crizotinib and entrectinib.
PDL-1 (Programmed Death-Ligand 1)
PD-L1 is a protein that is expressed on the surface of some non-small cell lung cancer (NSCLC) cells. When PD-L1 binds to its receptor, PD-1 (programmed cell death protein 1), on T cells (a type of immune cell), it sends a signal to the T cell to become inactive and stop attacking the cancer cell. This mechanism is called immune checkpoint inhibition, and it is a way for cancer cells to evade the immune system.
Some NSCLC patients have high levels of PD-L1expression on their cancer cells, which can indicate that their cancer is more likely to respond to immunotherapy drugs that block the PD-L1/PD-1 interaction.PDL-1 biomarker testing can help identify patients who may benefit from immune checkpoint inhibitors like pembrolizumab, nivolumab, and atezolizumab. By blocking this interaction, these drugs can "re-activate" the T cells and help the immune system attack the cancer cells.
Recent advances in PDL-1 biomarker testing include the development of new scoring systems that can help determine which patients are most likely to benefit from immune checkpoint inhibitors.Different thresholds are used to determine "high" PD-L1 expression, depending on the drug and the clinical trial. For example, for the immunotherapy drug pembrolizumab, a PD-L1 expression level of 50% or higher on tumor cells is considered "high" and is associated with better response rates and survival outcomes.
It's important to note that not all NSCLC patients with high PD-L1 expression will respond to immunotherapy, and some patients with low or no PD-L1 expression may still benefit from these drugs. Therefore, PD-L1 expression is just one of several factors that are considered when deciding on the most appropriate treatment for NSCLC patients.
Key Takeaways
Biomarker testing is a crucial tool in the diagnosis and treatment of lung cancer. The most common biomarkers found in lung cancer are EGFR, ALK, ROS1, and PDL-1. Personalized treatment for these biomarkers includes targeted therapy, combination therapy, and immune checkpoint inhibitors. As we continue to learn more about the molecular makeup of lung cancer, biomarker testing will become even more important in determining the most effective treatment plan for each patient. These advancements have the potential to improve outcomes for lung cancer patients and potentially extend their lives.
With the use of our technology, Prana Thoracic aims to provide adequate tissue for both definitive diagnosis and biomarker testing, so each patient can be provided with the treatment pathway that will work best for them.
Reference
- Fox, AH, Nishino, M, Osarogiagbon, RU, et al. Acquiring tissue for advanced lung cancer diagnosis and comprehensive biomarker testing: a National Lung Cancer Roundtable best-practice guide. CA Cancer J Clin. 2023; 1- 18. doi:10.3322/caac.21774
