Are You Employing Genetic Testing Correctly for Colorectal Cancer?

The latest guidelines and data support wider use of germline testing for certain patients, says Dr David Johnson.
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-- TRANSCRIPT --
Hello. I'm Dr David Johnson, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School. Welcome back to another GI Common Concerns.
Today, I wanted to provide some perspective around genetic testing in colorectal cancer: what's required, what's standard, and what you need to know now.
Only in the past couple of decades have we had the ability to perform genetic testing for colorectal cancer. This started in 1991 with the discovery of the abnormality that identified the APC gene that predisposes to familial adenomatous polyposis. Just 2 years later, there was the recognition of the mismatch repair gene abnormalities - MLH1, MSH2, and PMS2 - which were the identifiers for what was then called hereditary polyposis colon cancer and is now known as Lynch syndrome. Since that time, the field has truly evolved and produced a number of other genetic tests.
That brings us to the present day and the question of what you need to be doing now and why you need to be doing it.
The Numbers of Likely Patients With Lynch Syndrome in Your Practice
It's estimated that approximately 1 million people in the United States have Lynch syndrome, but the vast majority of are unaware of this. Lynch syndrome is an autosomal dominant-type disease. The Lynch carrier frequency is estimated to be about 1 in 280 patients and accounts for an estimated 3%-4% of the cancers in the United States at the present time.
Doing a little bit of math here will help determine how often gastroenterologists may see this in our practices. First, we should recognize that there may be a referral bias that makes it even higher than that frequency. Because you are a gastroenterologist, patients may be sent to you because of polyps or a positive family history.
With this in mind, let's say the estimated frequency is approximately 1 in 200. Assuming that you've got 12 patients in a clinic for a half day, four sessions, this gives you 48 patients. If you perform 15 endoscopies for full days, 2 days a week, this is 30 patients. The math, therefore, would say that you should be encountering one to two hereditary colon cancer patients per month, or 12-24 with Lynch syndrome per year. And if you're in a practice of 10 GI providers, which is what I'm in, that would evolve into approximately 100-240 patients per year.
So I'll ask you: Where are those patients in your practice?
Standard Testing for Lynch Syndrome
When it comes to measuring and defining Lynch syndrome, we're particularly looking for mismatch repair frequency deficiency, which occurs in 15%-20% of sporadic cancers.
If we're doing laboratory testing, this requires either microsatellite instability (MSI) evaluation or immunohistochemistry (IHC) testing. They, in turn, require pathology-level expertise, which is certainly less demanding than doing the gene sequencing for the genetic abnormalities that we now identify in the germline testing for Lynch syndrome.
These two tests are not the same. The IHC measures the mismatch repair proteins expressed in the sample, and the MSI measures the mismatch repair function by detecting changes in DNA that occur when you have a major mismatch repair function loss.
The performance of both the MSI and the IHC tests is very good. As far as sensitivities for testing, they're about 95%-100%; the specificities are a little bit less than that.
The primary advantage of IHC, compared with genotyping with the MCI approach, is that these are available in routine services in general pathology labs, so it does not require a molecular laboratory on site.
There are a couple of caveats about the IHC staining. The IHC tests are most reliable if it's fresh or frozen tissue samples and tend to be much less reliable if you're using tissue preserved in wax or other chemicals. Therefore, you want to have testing on the front end rather than to go back and dig these out of the pathology archives.
Another caveat, although a very rarely occurring one, is to be aware of the mismatch repair protein expression following therapy. If the patient is now on chemotherapy or a checkpoint inhibitor, the neoadjuvant therapy may actually reduce the protein expression. This can lead to a false positive for IHC testing.
If you look at this and say the MSI or the IHC is "normal," what could that mean? Does it absolutely rule out Lynch syndrome? There clearly can be a false normal based on the testing done in your laboratory, which is rare. Or you can have a mismatch repair proficient microsatellite stable production. This is more common in the presence of PMS2 and the MHS6 genes, which are very much on the rarer side of the Lynch syndrome spectrum.
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