The Use of Next Generation Sequencing and Immunotherapy In Advanced Endometrial Cancer
- Next-generation sequencing (NGS) identifies genetic mutations in tumors for targeted treatments in endometrial cancer.
- Based on test results, doctors can offer Immunotherapy drugs that help boost the immune system’s ability to combat cancer by targeting specific cell characteristics.
- Testing for biomarkers like microsatellite instability (MSI) and mismatch repair status helps guides treatment decisions.
- Combination therapies with immunotherapy drugs like pembrolizumab and dostarlimab show promise in advanced endometrial cancer management.
“Next generation sequencing is a type of somatic tumor testing that we commonly get in advanced or recurrent cancers,” says Dr. Michael Toboni, an assistant professor in the division of gynologic oncology at the University of Alabama at Birmingham. “We do this to try to find markers in the tumor that medications might work well against.”
Read MoreHow Does Immunotherapy Testing Work?
Immunotherapy is commonly used for advanced endometrial cancer, especially in its later stages (III-IV). Doctors consider this treatment option when the cancer has significantly spread or has not been effectively managed by traditional methods such as surgery, chemotherapy, and radiation.
Tests will look at a cancer characteristic known as microsatellite instability (MSI) where cancer cells have numerous genetic mistakes or mutations. These extensive mutations result in the formation of abnormal proteins on the cancer cells, making them easily recognizable to the immune system.
- pMMR (Proficient Mismatch Repair): This status indicates that the cancer cells have a functioning system to repair errors in their DNA that occur during cell division. Cancers with proficient mismatch repair are less likely to respond to certain types of immunotherapy.
- dMMR (Deficient Mismatch Repair): In dMMR, the cancer cells lack the ability to correct mistakes made during DNA replication, leading to an accumulation of errors. This condition is often linked to a higher response rate to immunotherapy, as the increased number of mutations can make the cancer cells more recognizable to the immune system.
- MSI-H (Microsatellite Instability-High): MSI-H describes cancer cells that show a high level of instability in microsatellites, which are short, repetitive sequences of DNA. This high level of instability is usually due to deficient mismatch repair. Cancers with MSI-H often have many mutations, making them more likely to be targeted effectively by the immune system under immunotherapy treatment.
Immunotherapy can boost the immune system’s capability to identify and destroy these uniquely mutated cells. Consequently, cancers exhibiting high MSI levels are typically more responsive to immunotherapy, allowing for more precise and targeted treatment.
Doctors test for mutations by taking a small sample pf tissue from the tumor and sending it to the lab for analysis, a procedure known as a biopsy.
There are two kinds of laboratory tests for this biomarker:
- Microsatellite Instability Testing (MSI Testing): This test examines the DNA of cancer cells for abnormalities. A large number of mistakes indicates MSI-High status, suggesting that the cancer cells may have a defective mismatch repair system.
- Immunohistochemistry (IHC) for Mismatch Repair Proteins: IHC tests are used to detect the presence or absence of mismatch repair proteins in tumor cells by using specific proteins known as antibodies. Absence or abnormal expression of these proteins (such as MLH1, MSH2, MSH6, and PMS2) indicates a mismatch repair deficiency (dMMR), which means high microsatellite instability.
“A defect can suggest Lynch syndrome, which is a common cause hereditarily for endometrial cancer,” Dr. Toboni says, adding that about 70% of endometrial cancers are pMMR which signals no genetic defects.
Immunotherapy for Endometrial Cancer
Cancer cells are not necessarily difficult to fight but they are very good at hiding from the white cells of the immune system. If the immune system can’t find and attack the cancer cells, they continue to grow and spread.
Immunotherapy drugs offer a more targeted approach to treating endometrial cancer by ensuring that the white blood cells can identify cancer cells, while avoiding normal tissue. By focusing on cancer cells alone, immunotherapy can offer a more effective and tolerable treatment option.
“The immuno-oncology agents are interesting. They don’t cause the conventional chemotherapy side effects, so they don’t cause hair loss and nausea and low blood counts and things like that,” Dr. Marta Crispens, an oncologist and director of gynecologic oncology at Vanderbilt Health, tells SurvivorNet.
For late-stage cancer or cancer that has a high chance of returning, the National Comprehensive Cancer Network (NCCN) guidelines recommend a mix of chemotherapy and immunotherapy or various immunotherapy drugs alone. These treatment recommendations are category 1 recommendations, the highest form of NCCN treatment recommendations that are given.
These are the most common immunotherapy oprtions:
- Pembrolizumab (brand name Keytruda): This is a type of immunotherapy called a checkpoint inhibitor that works by blocking the PD-1 protein on the surface of T-cells, a type of immune cell. The drug prevents cancer cells from using PD-1 to hide from the immune system so that the immune cells can recognize and destroy the cancer cells.
- Lenvatinib (brand name Lemvima): A targeted therapy that inhibits multiple proteins known as tyrosine kinase receptors which control the growth and replication of cancer cells, as well as the formation of blood vessels that supply tumors (angiogenesis). By blocking these pathways, lenvatinib helps to slow down the growth of cancer cells and reduce their supply of nutrients. Having NGS can determine how many and which genetic mutations your tummor has. This will assess whether lenvatinib is a suitable treatment option for you.
- Dostarlimab (brand name Jemperli): An immunotherapy drug that functions as a checkpoint inhibitor, similar to pembrolizumab. By binding PD-1 receptors on immune cells, specifically T-cells it prevents cancer cells from signaling these receptors to evade immune detection. It helps the immune system to better recognize and attack cancer cells, enhancing the body’s natural defense against the tumor.
“You would be eligible for lenvima and pembrolizumab commonly called Len-Pen if you recur, meaning if the cancer does come back,” Dr Toboni says.
This combinations could reduced the risk of certain types of advanced endometrial cancer spreading, growing, or getting worse by 40% compared to chemotherapy alone, he notes.
Related: Chemotherapy Can Play A Vital Role In Treating Advanced and Aggressive Endometrial Cancers
What are the Side Effects?
Though they may be easier on most patients, immunotherapy drugs do carry some side effects. The decision to use these treatments involves weighing the potential benefits against the risks, tailored to each patient’s situation and health condition.
Dr. Crispens says that immunotherapy is a way to target a drug directly to the cancer cells which can, “hopefully increasing how effective the drug could be while decreasing the side effects the effects on normal cells.”
Some of the more common side effects of this treatment include:
- Muscle and or joint pain
- Fatigue (feeling tired)
- Anemia (low red blood cells)
- Loss of appetite
- Skin rashes
- Gastrointestinal issues such as nausea, vomiting, abdominal pain or diarrhea
- Respiratory symptoms such as cough, shortness of breath or chest pain
- Thyroid disease, type 1 diabetes or other autoimmune-like symptoms
It’s important to see a doctor right away if you experience any of these symptoms during treatment. Your doctor can help you manage them.
Questions to Ask Your Doctor
- Should I get tested to see if I can benefit from immunotherapy?
- What do the tests say about genetic mutations in my cancer?
- Which drugs are a good choice for me?
- What improvements can I expect, and how will we track progress?
- What side effects can I expect and how will we manage them?
- What is the cost, and is there financial assistance available?
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