Demystifying Microsatellite Instability in Stage 2 Colon Cancer

John L. Marshall, MD


June 29, 2010

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Good morning everyone. I'm John Marshall for Medscape Oncology. I just got back from a fairly nice medical meeting out on the West Coast. I learned something very important, and that is that general oncologists do not understand the concept of microsatellite instability (MSI) and what's going on with MSI in the world of colorectal cancer. We've been asking a series of questions at a medical meeting that I run about a physician's understanding of MSI and how one plays this out in stage II colorectal cancer, and I'm struck that over the last year there has been very little understanding, very little uptake on how to apply this information to a patient's care. In fact, we recently published an abstract from these data showing that oncologists really don't have this concept "right side up."

It's very simple actually. Just remember back to medical school, and remember that there are 2 kinds of colon cancer genetics. There is the familial polyposis genetics, rarely inherited but commonly acquired. Eighty percent of all colon cancer follows those genetics. In essence, all of those patients are microsatellite stable or proficient in mismatch repair (normal). They're doing okay. That leaves 20%, and these 20% share the genetics of the Lynch syndrome, HNPCC (hereditary nonpolyposis colorectal cancer), which has mismatch repair deficiencies or is deficient in mismatch repair, which leads to MSI. So, "MSI high" is mismatch repair deficient. Now, only about 20% of our patients are going to be MSI high, and about 6% of all colon cancer will have inherited MSI high.

Here's where it gets a little tricky. The broken gene, MSI (deficient mismatch repair), is actually a good prognostic sign, particularly in stage II metastatic colon cancer, and further still, it looks like chemotherapy may be harmful or at least not beneficial in that subgroup.[1] So, we are actually checking MSI status in almost all of our patients now, particularly the stage II patients, because I want to know if they are MSI high, then maybe I don't give that patient chemotherapy. One other little pinch on this is that patients who are MSI high may also be carrying a germline mutation for HNPCC and therefore probably should have formal genetic counseling. It is kind of a poor man's way of doing hereditary tests. It is not perfect either, so you cannot rely on it as the only way to measure for inherited risk, but it is an interesting way of getting a sense of where that patient is.

In our practice, stage II colon cancers are all getting tested for microsatellite stability, so either they are MSS (stable) or MSI high, meaning that they have deficient mismatch repair. Most of your patients will be MSS, and what to do with them in stage II is just as controversial but at least we are tending to leave that MSI high group alone and not giving chemotherapy to the average stage II colon cancer patient. We need to get this right; we are not doing a good job of learning this lesson. Hopefully this little tidbit will help.

I'm John Marshall for Medscape. Thanks.


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