Role of ctDNA Testing/Monitoring in Early-Stage CRC

Christopher Lieu, MD: When you think about this concept of low- and high-risk colon cancer, something that we’ve traditionally done—looking at the T stage and N stage—is subdivide out patients into low- and high-risk groups. This brings us into this concept of ctDNA [circulating tumor DNA] testing, and that’s what I’d like to talk about in terms of early stage colorectal cancer.

I’m sure a lot of people are already aware of this, but circulating tumor DNA is found in the bloodstream, and it basically refers to the DNA that shows up in our bloodstream from cancerous cells or tumors. In the body there’s a lot of cell-free DNA that circulates in our bodies. But in our patients with cancer, a fraction of that cell-free DNA is actually circulating tumor DNA. Of course, the advances in technology where we can detect this ctDNA is a novel concept and a really groundbreaking technology, because it can help detect disease when there’s no clinical evidence of cancer, either by physical examination or by CT , MRI, or PET [positron emission tomography] imaging.

Some of the things to consider when thinking about ctDNA testing is that there are 2 ways to think about how we might test for ctDNA in what we call the minimal residual disease setting, or when we think there’s no evidence of disease. One way is a tumor-based profiling method, where they take the tumor and sequence it and then an assay is essentially built to look for those tumor-specific mutations. I want to isolate this from what we consider panel-based testing, which is essentially spreading out a wide net and looking for a large panel to assess for any detectable mutations.

The other interesting thing about ctDNA is it’s got an incredibly short half-life. What I mean by that is it can be minutes of half-life vs just a couple of hours. What makes that important is that, when you monitor ctDNA or look for ctDNA, it gives you a real-time look at the tumor and what is happening in that moment in time. When Dr Gholami goes in and takes out a colon cancer tumor, and then you check for ctDNA a couple of weeks later after an operation, you can assume—because of the short half-life of the ctDNA—that what you’re detecting is not just residual ctDNA from the primary tumor but what you’re detecting at that moment in time. It gives you a real-time look at what’s going on inside the body.

One question I want to ask you, Dr Gholami: When you think about getting a ctDNA test after surgery, how might it be used after surgery in helping to detect early relapse of disease.

Sepideh Gholami, MD, FACS: That’s a great question. As you already alluded to, based on the specificity as well as this notion that we can use it in the adjuvant setting, the way I think about it is that it can be a good marker to detect disease—way earlier than the conventional serum markers that we use for CEA [carcinoembryonic antigen], even imaging. If you review the studies, there’s almost 8 months, up to 10 months in some of the studies, where you can really detect the disease earlier than with what we have. It really has almost 100% positive predictive value. We think it is 1 of the strongest prognostic factors we have for risk stratification.

Christopher Lieu, MD: I totally agree. Earlier you gave a great description of what we consider low-risk disease vs high-risk disease. I think 1 of the unique things about ctDNA is that we no longer think about things as being low risk or high risk; this is something that’s really well established in hematologic malignancies like CML [chronic myeloid leukemia]. When you know that you cannot detect any of the CML alterations in the blood, you know that you have that complete molecular response. In the same way, if you can detect it, then you worry that there is a minimal residual disease of CML there.

When Dr Gholami and I talk about low risk and high risk, these are clinical features that we sometimes use to determine whether a patient gets chemotherapy. But if you can detect ctDNA in the blood, in the patient who has had a curative surgical resection, that person is no longer low risk or high risk. They have minimally detectable stage IV disease. They’re no longer considered to be high risk, but they have active disease that we cannot see. Just as Dr Gholami said, sometimes the lead time from detecting the ctDNA to actually seeing something on a scan can be as long as 8 months, which is really impressive when you think about how often even we get the CT scans in the surveillance setting.

Sepideh Gholami, MD, FACS: Based on what we know, if you have a patient who is stage II, now we have something that’s much more specific to that patient and more individualized. I agree, if that is positive, that patient should get treatment because there is still clinical evidence of tumor DNA circulating; it really changes our treatment paradigm.

Transcript Edited for Clarity