Microsatellite instability-high (MSI-H) status is something that may play a huge role in patient’s treatment options and outcomes, yet it is an area that is hard for some to understand, unless you are an oncologist.
CURE spoke with Scott Paulson, M.D., medical oncologist with Texas Oncology, an affiliate of The US Oncology Network, to break down exactly what MSI-H status is, and the effects it may have on certain malignancies.
In simple terms, can you explain what MSI-H status is?
MSI-H stands for microsatellite instability-high. It is a feature of cancer’s genetic coding, which results in it behaving and “looking” a certain way on a microscopic level. Due to defects in the way that DNA in the cancer cells repairs itself, it creates changes and mutations to normal body cells that can eventually let them turn into cancer. However, these cells become so abnormal, because of this feature, that the immune system, which is used to protecting the body against bacteria and viruses and other foreign invaders, can actually look at the cancer and recognize that something is very wrong. This can call the body’s normal defenses against invaders to try to attack the cancer.
What causes MSI-H?
Most commonly it is caused by genetic lack of certain proteins which, when working normally, help repair DNA in cells when it breaks. When these proteins aren’t present, or if they breakdown over time, then a healthy cell can’t repair itself normally and it starts making many mistakes in its own genetic code. Suddenly, the “instruction manual” on how a normal cell should work becomes incorrect, causing the cell to become increasingly abnormal, and leading to disordered growth, which is a hallmark feature of cancer.
What are the common malignancies associated with MSI-H status, and what is its significance in these tumors?
Colorectal cancer (CRC) is the disease most commonly associated here, but essentially any cancer can be implicated, just at variable and relatively low percentages (single-digits). We have known for some time that the behavior of MSI-H CRC is different from so-called Microsatellite Stable (MSS, or non-MSI-H) CRC. Generally, they are associated with a better prognosis, although this is not universal. Most importantly, they are now associated with a change in the way we treat them. While traditional chemotherapy drugs are still used frequently in MSI-H CRC, immunotherapy drugs affecting the interaction of something called PD-1, or programmed death receptor-1, have shown truly remarkable promise in treating these types of cancers. Therefore MSI-H status may dramatically change the way we treat tumors, both in decisions to treat in a post-surgical setting and the types of drugs used.
It is important to note that the FDA has approved some of these immunotherapy drugs, known as checkpoint inhibitors, in the treatment of all MSI-H tumors, regardless of whether it comes from the colon, lung, breast, or any other organ. This is truly a big step forward, even though it affects such a small percentage of tumors.
Why is it important to test for MSI-H status following a patient’s diagnosis?
Since this is frequently associated with genetic deficiencies that can be hereditary, it is important to understand the implications for family members. MSI-H findings on a cancer can be sporadic though, meaning that they don’t always change a family member’s risk of developing the same types of cancer. it is important to understand the MSI status as it may change the drugs we use. That being said, universal testing for all cancer is not an accepted practice, as there are often implications of trying to get that information (in other words, exposing patients to the risk of another biopsy and the cost of testing) relative to its infrequency in many types of cancers.
Deficiencies of the genes most frequently responsible for causing MSI-H cancers are most often associated with a syndrome called HNPCC or hereditary non-polyposis colorectal cancer syndrome. It is commonly referred to as Lynch syndrome. There are a number of other cancers involved in this syndrome including uterine, bile duct, stomach, pancreatic, bladder and small intestine cancer, among many others.
How does MSI-H status change the way oncology teams go about treating a patient?
It may change decisions on whether to treat a patient with chemotherapy or to use immunotherapy. The decisions behind this are highly applicable to each individual’s presentations, so it is important not to assume that there are universal “rules” about how we treat these cancers. The situation (stage, type of cancer, extent of disease, and patient’s other medical problems) may greatly change the appropriate approach, as well.
How does MSI-H status affect the immune system, for example, in the use of immunotherapies?
The immune system is more easily able to “recognize” these tumors, meaning that they respond far more readily to the wave of immunotherapy drugs that have recently hit the market.
Is there anything we have not touched upon, that you think would help patients understand the significance of MSI-H?
I think it is a complex issue that requires the input of an oncologist knowledgeable with the implications of such testing, with which most oncology professionals are well-acquainted. There has been tremendous excitement as we have come to understand how different these cancers are in their response to treatment, and new drugs, such as checkpoint inhibitors, have been game-changers for them. But not all MSI-H cancers melt away with immunotherapy drugs or have better prognoses, and we need to do more work to understand why that is and how to change it.
For patients, I would understand that such a finding may have significant implications on genetics and screening for family members and may change what types of treatments your doctor prescribes. But, like everything in medicine, every test value should be used in the context of an individual patient. Cancers are very complex and individual, not unlike the patients that must face them!