ctDNA and MRD Testing in Nonmetastatic Colorectal Cancer

A focused discussion on the respective roles of circulating tumor DNA and minimal residual disease testing in the management of patients with nonmetastatic colorectal cancer.


John L. Marshall, MD: This has been a focus around metastatic disease, but increasingly we are seeing molecular testing of different sorts even in stage 1, 2, and 3 disease. Maybe walk us through a little of that and where that space is.

Stacey Cohen, MD: I think it’s interesting in that we know so many different markers that can influence metastatic disease, and yet we really don’t have a lot of specific gene markers to help us guide adjuvant therapy. We know that microsatellite instability [MSI] is really important, but at the same time we don’t know that BRAF matters [or] that KRAS matters. They could be prognostic but not necessarily changing our therapy.

In addition to the type of liquid biopsy that you were talking about, [Dr Bekaii-Saab], we also have ctDNA or circulating tumor DNA, which is a different concept. You’re not looking for specific gene mutations to act upon those genes, but more looking for the presence of DNA that would be found in the blood, small fragments of different sizes than classic cell-free DNA that we all have, and that could have specific tumor-specific mutations that allow us to pick up on the presence of tumor activity on a microscopic level. [It’s] not visible on a CEA [carcinoembryonic antigen] [test], often not visible on a CT scan, and we’re now finding that that is prognostic and maybe even starting to be predictive for who we need to adjust their adjuvant therapy.

John L. Marshall, MD: Are we all addicted to this test now? Is everybody doing MRD [minimal residual disease], or no? Any dissenters?

Aparna R. Parikh, MD: In very specific settings.

John L. Marshall, MD: So not everybody?

Aparna R. Parikh, MD: Not everyone. It is incredibly exciting, but there’s so many caveats still. There’s a lot to be learned about the sensitivity of the test [and] the patients we’re actually missing with the test. Many of the patients—some great data from the MD Anderson group here at ASCO [American Society of Clinical Oncology Annual Meeting] showing about 50% of the patients that were found to be MRD are actually metastatic. So, I think in very particular cases, we can use it to guide clinical decision-making. The place where I’ve used it the most is in low-risk stage 2 [patients], basically universally testing everyone. But I highly recommend that everyone [enroll patients in] the enormous abundance of clinical trials that are ongoing in this space because we really need to understand what these tests mean and how they can inform decision-making.

And then in the recurrence setting, it’s challenging. I still see it potentially as a tool to compliment CT scans, but I don’t necessarily see a future where we’re going to eliminate CT scans. And what a [difficult] conversation it is to have with the patient. If you find a positive test and then your imaging is negative, what do you do?

John L. Marshall, MD: What are you going to do with that? That’s the extension I was going to ask the panel. Everybody’s doing and wanting their [Holy] Grail test, the “do I have cancer?” test. This is where this kind of technology is going, and I think we’re going to see this incredible incidence go up without any way to intervene going forward.

Stacey Cohen, MD: It’s still early in development, though.

John L. Marshall, MD: But people are doing it. And then will insurance cover it, and how we are going to manage that on a global scale is a real challenge. Back to some of this molecular testing that we’re not doing in stage 2 and 3 [patients]. Should we redo some adjuvant trials, Dr Eng? Does EGFR really not work, or has it not worked because we had the wrong patients in the study? You’re cooperative group people. Shouldn’t we spend our good money on something like that that might change the outcome for patients?

Cathy Eng, MD, FACP: Admittedly, we don’t have a lot of new developments in the adjuvant setting, but we are incorporating or looking at the role for testing for circulating tumor DNA for MRD. And you’ve got the phase 3 trial for stage 2 patients, COBRA [NCT05249127]. Then you’ve got CIRCULATE-US [NCT05174169] for stage 3 patients. It’s a great opportunity to still incorporate a new tool. And obviously there are other studies as well.

Tanios Bekaii-Saab, MD, FACP: [Dr Marshall,] that’s a great question. Now we have refined better how we pick patients, say for MSI-high, or for BRAF V600E, and what would bring those early stages.

John L. Marshall, MD: Trastuzumab would’ve been negative in all breast [cancer] patients.

Tanios Bekaii-Saab, MD, FACP: That is absolutely true. Now that we know in the metastatic setting we have targets of relevance, [and] that we can change the natural course and biology of metastatic disease. It makes sense to start bringing a lot of those earlier. [Dr Parikh,] you’re leading that effort in your study, but also more is needed. I don’t know if you want to talk a little bit about your study and how it fits this particular question.

Aparna R. Parikh, MD: We have a study exactly answering that question. [We’re investigating] biomarker selected adjuvant therapy escalation after adjuvant chemotherapy. [We] haven’t felt comfortable yet replacing standard adjuvant chemotherapy for stage 3 patients, but what we’re doing is post–stage 3 adjuvant standard of care, 3 or 6 months [of therapy with] CAPOX [capecitabine, oxaliplatin], FOLFOX [leucovorin calcium, fluorouracil, oxaliplatin], or whatever you want to do if you’re still ctDNA positive and if you have a biomarker. So if you’re MSI-high, you get adjuvant PD-1 therapy. If you’re HER2+, you are getting herceptin-perjeta. This is prior to herceptin-tucatinib.

John L. Marshall, MD: I’ll be impressed if you can enroll that cohort.

Aparna R. Parikh, MD: I don’t think we will.

Tanios Bekaii-Saab, MD, FACP: It’s good to have it.

Aparna R. Parikh, MD: It’s good to have it, but I don’t think we will.

John L. Marshall, MD: We’ll know where to send a patient.

Aparna R. Parikh, MD: Exactly. And then adjuvant BRAF as well.

John L. Marshall, MD: We’re just trying to do a feasibility study across all GI [gastrointestinal] cancers in exactly that space. We not only have a colon cohort, but a pancreatic, a gastric, and a hepatobiliary [cohort], just to see if they’re out there after you’ve done your adjuvant, if you’re still ctDNA-positive.

Aparna R. Parikh, MD: And we can talk about the challenges.

John L. Marshall, MD: We’ve accrued some so far.

Stacey Cohen, MD: We have too.

Cathy Eng, MD, FACP: I want to mention the new Alliance [for Clinical Trials in Oncology] trial that just opened up in the adjuvant setting for BRAF as well. [It] is a national trial that’s available to patients. The Sinicrope trial has completed enrollment, and we’re obviously looking forward to that about the role of IO [immuno-oncology] therapy in the stage 3 setting.

Tanios Bekaii-Saab, MD, FACP: The MSI-high.

John L. Marshall, MD: Dr Cohen, you’re presenting a paper here at ASCO around this topic. Do you want to drill down on that?

Stacey Cohen, MD: At ASCO-GI we presented some information on cell-free DNA and thinking about how that influences our detection of ctDNA. Because as much as we’re talking about the end results, the logistics here are key. I think we’ve all hinted at that with different tissue testing vs blood testing. And it all comes down to when does that person make it into your clinic, and how timely is that in relation to surgery. We’re all looking at that 4- to 8-week window for doing adjuvant therapy. If we’re going to start incorporating ctDNA into our common testing strategies, we need those results as soon as we can.

So what our study did using the Signatera assay, which is a tumor-informed test, was to see when can we actually start sending that. Because we know that that tumor-informed test takes a little bit longer. And what we showed is that you can start testing as early as 2 weeks after surgery. And this is key because if we knew a patient was going to surgery, we could order that tissue profiling to be done even before they went to surgery, and we could get that blood drawn 2 weeks later. [That] could cut down some of the turnaround time for the tumor-informed assays.

When we use the tumor-uninformed [test], as I know you’re using, [Dr Parikh], and COBRA is using in that study, that gives us some more leeway. But the logistics are important here because just because we want to do something, we don’t always see the patient show up in that exact perfect scenario. It’s really helpful to start thinking through some of these processes on an individual institution level.

Transcript edited for clarity.

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