Revolutionizing Personalized Medicine in CRC


John Marshall, MD: We have just started a new decade. If you reflect back on the last decade, we began that just entering into this concept of precision medicine in GI [gastrointestinal] cancers and colorectal cancer. We did not know about RAS or MSI [microsatellite instability] or all of those basic targets that we now incorporate. And if you flash forward to today, what we are seeing more and more of is broad molecular profiling. We’ve gone away from the tests where you do RAS and BRAF and HER2, to now testing much more broadly. So that requires new technology such as next-generation sequencing.

It’s no longer really being run in our laboratories in our basements. We are more and more partnering with different companies, different laboratories to perform this testing. And with that has come what I will say is an increased knowledge gap. We, as oncologists, are busy. We’re not keeping track of all of this new technology. And so, it’s incredibly important for us to pause for a second and look at the new technology going from single gene mutations to panels of next-generation sequencing.

Axel Grothey, MD: MRD [minimal residual disease] is the concept of minimal residual disease, or molecularly defined residual disease in patients, for instance, after resection of solid tumors when we do not have any evidence of macroscopic disease by scans but we might suspect that patients have residual cancer cells in their body—the idea of micrometastatic disease. We now use technologies like ctDNA, circulating tumor DNA, or methylation markers of DNA to detect subclinical clones that would predict a higher rate of recurrence in patients with solid tumors. The idea of minimal residual disease is actually not new. It has been around in hematologic disease for quite some time. BCR-ABL in chronic myelogenous leukemia, certain subclones of lymphomas, etcetera, have been detected in hematologic disease for quite some time and have actually been used as treatment guidance markers in these diseases. The concept of MRD in solid tumors really goes along with the idea that we have technologies that can now detect this molecular residual, or minimal residual disease.

John Marshall, MD: When one thinks about the different tests that are out there, one is to inform a therapy, or to be prognostic. So, predictive or prognostic for a particular therapy. The classic is RAS mutations for EGFR therapy, or microsatellite instability for checkpoint inhibition. We need to know those test results for specific therapy.

What we’re now seeing is a newer technology using something called circulating tumor DNA, or ctDNA. This is basically DNA that’s shed from dying cells, and we can detect the presence or absence of cancer DNA. And so, this is really kind of cool. Right now, what do we do? We do CT [computed tomography] scans. Maybe we do CEA [carcinoembryonic antigen] blood tests to determine if a patient still has cancer or not. It’s a very course measure. The ctDNA is a much more refined measure where if we can detect persistent circulating DNA from a tumor, we know that patient, regardless of what the scan shows, still has cancer. This is different from saying, “Okay, you have a RAS mutation,” or not. This is basically saying, “You still have cancer,” or not.

We are used to now doing more next-generation sequencing, again to find targets for our cancer therapies. MRD is essentially genetic testing. It’s the same basic test, but it is looking at different mutations and not necessarily ones that we are going to use as therapeutic targets. It’s just genes that are broken within the cancer that aren’t broken within the normal human. And by detecting them, we can tell you, yes or no, whether there’s minimal residual disease. It doesn’t further characterize the cancer or its nature, its mutations, like you get with next-generation sequencing.

An important point about this is that you talk about whether the circulating tumor DNA was informed by the tumor. If I’m just looking at DNA, if I don’t really know what’s abnormal, I can’t tell you whether cancer is there or not. So the best testing is when next-generation sequencing is done on the tumor, and then using those broken genes to look for what’s circulated, right? Now I know what I’m fishing for. If I find the presence or absence of those genes, I can tell you whether cancer is there or not.

These 2 tests are used in completely different scenarios. Next-generation sequencing, or any molecular profile of the tumor, is really all about trying to uncover the secrets of that individual patient’s tumor so you can make predictive and prognostic decisions.

MRD, or just presence or absence of ctDNA in the circulation, is a yes-no. It’s like doing a CT scan, in some ways. How’s the cancer? Is it good or bad? And so, ctDNA is more of a measure of the current state, whereas next-generation sequencing is a totally separate test, or molecular profiling, in general, to understand what therapies to offer a patient.

Transcript Edited for Clarity

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