Circulating Tumor DNA, an Emerging Prognostic Marker

Heather Greene

Hi Kevin. I’m looking forward to talking with you about metastatic colorectal cancer. I wanted to start off by discussing circulating tumor DNA, or ctDNA. I work with patients with colon cancer, but I also work with patients with different malignancies, so I see ctDNA’s use with other tumor types. What about you?

Kevin Krise

We're using it a lot in our practice, but I know it’s used with other types. I've spent some time recently in the cutaneous malignancy clinics and it's used in the patients with Merkel cell carcinoma. It’s useful in a patient with cholangiocarcinoma, particularly when imaging isn't really showing much of anything. It’s also helpful with patients who are at high risk for recurrent or progressive disease. Seeing the ctDNA rising helps us identify what’s going on and consider initiating treatment in an effort to control their disease. I've seen that with patients with colon, cholangiocarcinoma, pancreatic cancer, etc.

Heather Greene

Do the physicians you work with order ctDNA sporadically, or do you have protocols in place, such as in the adjuvant setting or in the metastatic setting? In my practice, we order ctDNA in the metastatic setting on a fairly routine basis. We time the imaging so that we have the results of the ctDNA at the same time we receive the imaging results back, which really helps us from a clinical standpoint. Like you were saying, if you have scans that make you question if there’s disease progression or if there might be something else going on, it’s helpful to check the ctDNA.

Having the ctDNA testing results is a huge clinical benefit to us. In the case of a patient not having symptoms and their CT scans are ambiguous, to see that the ctDNA is trending down helps us feel like we're on the right track. Or conversely, you get those CT results and you’re not sure what's going on, but the ctDNA is really going up, so it prompts you to consider shorter-term follow-up CT. Has that been your experience?

Kevin Krise

Yes, I see a mix of that. It's an evolving biomarker for sure. We need to think about what the carcinoembryonic antigen looks like if we're monitoring the ctDNA. If the CEA is helpful and we initially see some response with a decline in the ctDNA, but then it starts to rise, it can make us think, “Oh, we might be going in the wrong direction.” At this point ctDNA isn’t well-defined enough to make it a specific biomarker. It’s used as a complement to what we've been doing as standard of care. But as we’ve said, in the case of questionable scans, questionable symptoms, or a stable scan but the patient is clinically worsening, I think it can help us to solidify a plan for how we're going to manage and address their disease.

Heather Greene

Having said that, ctDNA is indeed helpful, but there are times it's not useful at all. For instance, imagine a patient with colon cancer who has completed their adjuvant therapy but has never had a positive ctDNA, and all of a sudden it pops positive. You look at their imaging and you don't see anything there. Do you find that with the physicians you work with or in your clinical practice, experiencing cases like this prompts you to consider scanning a little earlier? Do you repeat ctDNA, or do you take it with a grain of salt and keep monitoring? Does it change what you do?

Kevin Krise

It's hard because, again, it's not guideline-driven, but we do know that if there's ctDNA, there's a high risk that something of concern could be brewing. The decisions are nuanced and provider-dependent when it comes to the collaborating physicians that I work with. We know patients can have scan anxiety, or “scanxiety,” for a long time, and I feel like this has prompted patients to really fixate on another test. Having said that, repeating the ctDNA, monitoring their symptoms more closely, and potentially getting other imaging does help us keep track of things a little bit more closely.

Heather Greene

Yes, it does. I know that the collaborating physicians you work with are NCCN guideline-driven.

Kevin Krise

Our physicians are very guideline-driven. The physician I primarily worked with would order the ctDNA, but it was never the end-all, be-all because it's not part of the guidelines. In January 2024 the NCCN put out a statement that although CtDNA is an emerging prognostic marker in the post-surgical setting, the NCCN is not recommending the use of the multigene assay outside of clinical trials to inform of recurrence risk or whether or not a patient should have adjuvant treatment.¹ I think many of our physicians are potentially doing this, but still thinking about it in a guideline-driven fashion too.

When I started in my career in 2005, people were talking about this thing called circulating tumor DNA. It’s interesting to see it starting to play out in clinical practice.

Heather Greene

It really is. Most physicians are guideline-driven, but one of my collaborating physicians in particular is also personally interested in ctDNA. Besides having open clinical trials here, like CIRCULATE-US,² we just closed BESPOKE,³ and these trials are about finding other ways we can help improve patient care. In the ctDNA world, people were very anxious about the COBRA trial, perhaps expecting it to be a positive study, and it was pretty shocking when it didn't meet its endpoints.⁴ How did you take that information into your practice?

Kevin Krise

Even with those results, I think folks know there's probably some value to it. It's just figuring out how to make this a more specific and sensitive study. We know that all the other next-generation sequencing companies are developing their assays. One is tumor-informed DNA.

Each of the trials use different ways of testing this as well. There has to be a way to standardize the testing being done in clinical trials to help find the one that will give us the best information so that we can use this to guide our treatment decisions and risk assessment of recurrence.

Heather Greene

Absolutely. I'm glad you touched on that because I think for some folks out there who aren't using a lot of ctDNA or don't know a lot about it, there is a difference between a tumor-informed assay and an agnostic or non-tumor–informed assay. Some practices have certain tests that they already use, but if you have the choice to use others, certainly look at the pros and cons of using tumor-informed vs. tumor-agnostic.

Kevin Krise

Heather, how do you explain ctDNA to your patients?

Heather Greene

Great question. I try to keep the information very basic. As you and I know, it can be complex. We know many patients are going to go home and Google “ctDNA” to learn more about it. We primarily use a tumor-informed test in my clinic, so I try to explain to them that the initial testing looks at 16 mutations that are specific to their cancer, and then we match those with the blood sample that's looking for those same truncated mutations to see if any of those mutations are floating around in their blood.

A lot of times patients think that this is screening for all types of cancer in their blood, and we do have some patients who've had more than one malignancy, unfortunately. I try to make sure that they understand that this is just helping us look for the mutations specific to the one that we're monitoring. But I also try to make sure that they know--just like with other labs that we do, including CEA--that although it's very specific, it's not 100% accurate regarding whether they do or don’t have cancer. It’s just another tool in our armamentarium that we can use to try to figure out what's going on. We want to keep the patient’s anxiety level as low as possible.

Kevin Krise

I think that really highlights the need to provide really good patient education and reassurance about what’s happening. There’s a lot of hope regarding the CIRCULATE-US trial, whether or not treatment could be de-escalated in patients with minimal residual disease-negative findings or escalating to get better outcomes for patients with early-stage disease who have positive minimal residual disease. It'll be fascinating to see the results, and hopefully it’ll result in a useful tool to help people either have better outcomes or avoid the potential toxicities related to the treatment.

There haven't been a lot of changes when it comes to adjuvant therapy, particularly in the colon cancer setting, for a long, long time, and we know that the drugs that we're giving patients have potential toxicities. If this becomes more of a validated guideline-driven tool, that would be helpful for patients.

Heather Greene

I agree. We've been doing this a long time, and we saw in the breast cancer world back in the day that a lot of women got adjuvant therapy who really didn't need it. And while we know that now, we didn't have anything to prove that then. I'm hoping, as are you, that in the colon cancer world we can see that happen for our patients too.

Kevin Krise

Absolutely.

Heather Greene

Thanks for chatting with me today, Kevin.

Kevin Krise

It was my pleasure, Heather. I look forward to future conversations with you.