ctDNA Informs Adjuvant Chemotherapy Decision in Patients With Stage II Colon Cancer

Cristian Tomasetti, PhD

Using a circulating tumor-DNA (ctDNA) approach in patients with stage II colon cancer, a reduction in the use of adjuvant chemotherapy was achieved without compromising recurrence-free survival (RFS), according to findings from the phase II DYNAMIC study (ACTRN12615000381583).

DYANAMIC is a multi-center randomized controlled trial. Investigators of the study explored the primary end point of non-inferiority in the RFS rate at 2 years. The study’s secondary end point was adjuvant chemotherapy use.

Out of 455 patients who were followed for a median of 37 months, there were fewer patients in the ctDNA-guided arm who were treated with adjuvant chemotherapy (15.3%) vs 27.9% in the standard management arm (Odds ratio [OR], 2.14; P = 0.002). Notably, the largest difference between the ctDNA-guided and standard management arms was seen among patients with T4 or poorly differentiated tumors (6.22 vs 6.31, respectively). Overall, ctDNA-guided management was found to be non-inferior to standard management for 2-year RFS at 93.5% in the ctDNA-guided arm vs 92.4% in the standard management arm, achieving a difference of 1.1% (95% CI, -4.1%-6.2%).

After receiving adjuvant chemotherapy, the 3-year RFS rate was 86.4% in the ctDNA-positive population vs 92.5% in the ctDNA-negative population. In the clinical low-risk subgroup, the 3-year RFS was 96.7%.

In an interview with Targeted Oncology™, Cristian Tomasetti, PhD, associate professor at the John Hopkins University School of Medicine, discussed the role of ctDNA in understanding the need for adjuvant chemotherapy in patients with stage II colon cancer. He explained how ctDNA can signal a patient’s risk of disease recurrence after surgery.

TARGETED ONCOLOGY: What is the ongoing debate about the role of adjuvant chemotherapy for the treatment of stage II colon cancer?

Tomasetti: There are many questions about how to treat a patient after surgery. In the setting of chemotherapy, as you can imagine, questions range from who should we give to, and do we know if all patients need adjuvant chemotherapy afterwards or not? Those are important questions. Then, if a patient gets it, when should the treatment stop? Do we have ways to understand which of the patients that just had surgery are going to relapse? Can we distinguish the group of patients that need adjuvant chemotherapy?

There are several more questions. For example, once a patient is under treatment, can we determine if or how the patient is responding to the treatment? There may be the potential with new technologies to determine whether the patient is responding well to a given treatment or not. And, when should we switch a patient to a different treatment, for example, if there is development or resistance? There are many questions related to what to do after a patient had surgery for stage II colon cancer.

In terms of predictive biomarkers, can you explain what ctDNA after surgery tells us about the disease?

It's been known now for some time that the normal cells as well as cancer cells shed some of their DNA into the bloodstream. By measuring the levels of cell-free DNA, we may be able to detect some of these DNA fragments that don't come from regular healthy cells but come from cancer cells. The idea in this specific setting with colon cancer is that if the surgery was a success, and the cancer was fully removed, then after a few weeks, in theory, we shouldn't find any cell-free DNA coming from cancer cells, because the cancers the cancer has been fully removed in theory.

If instead, we do [find cell-free DNA from cancer cells] then that is a sign that there is still some cancer in the body of that patient. We can use this information to determine who we think are patients that will at some point relapse, because cancer cells are still present. They will proliferate and grow back to produce it and we call that a clonal expansion. Based on this information,we can think about who may need adjuvant chemotherapy or not.

What questions still exist about the use of ctDNA for patients with stage II colon cancer?

As I mentioned, the major question is, can we still find a signal from cancer cells after surgery? Currently if we find any signal, the idea will be that it is better to be safe and to have adjuvant chemotherapy. But one questionis in biology, things are always more complicated than you would imagine.

Today, we have new methodologies and technology to determine whether we still see a signal. Whether we find the presence of cancer cells through circulating tumor DNA after surgery, the question is, how sure are we about that? These are great technologies, but people’s bodies are full of mutations. When we look at a mutation or fragmentation patterns, depending on what we look for, the body normally produces some signal that does not look right.

For example, if I were to look for a KRAS or TP53 mutation, patients with colorectal cancer are not the only ones producing that. There are cells in my body right now that contain that mutation. When I measure in the blood and I look for cell-free DNA, if I were to be looking for that mutation, some of that just naturally presents in my body independent to the cancer. Another important question is, how do we decide how much is normal, and what is the threshold we are going to use to decide a patient has too much of the syndrome versus not a normal amount.

How did you and your co-investigators approach answering some of these questions in the DYNAMIC study?

We decided to look at the question of whether we could compare guided management of stage 2 colon cancer patients using ctDNA with this technology where we can test for the presence of cancer of ctDNA versus the standard management of those patients. What we did is we had 455 patients who were randomized in a ratio of 2:1. About 303 received ctDNA-guided management, and 153 had the standard management.

We followed them for median follow-up of 37 months. Essentially, what we did was we measured at about 4 to 7 weeks after surgery. We looked for the presence of specific mutations that were present in the actual cancer of each patient. After surgery, we had the sample of the cancer of an individual patient, so we can go ahead and sequence that cancer, see what mutations are present specifically present in that cancer patient,and then based on those mutations, we could look in the blood to see if we find the same mutations in ctDNA.

We do that about 4 to 7 weeks afterwards because it takes some time for ctDNA to clear up, even in the case where the surgeon was able to fully remove all cancer cells. After 4 to 7 weeks, if the methodology decided that we could find ctDNA in the patient, then the patient was assigned to adjuvant chemotherapy. If instead, we didn't find any cDNA, then the patient would not receive adjuvant chemotherapy.

What is your key takeaway from the results of the DYNAMIC study? What do the findings suggest about positive/negative ctDNA in these patients?

What I think is very exciting here is that, essentially, we were able to avoid chemotherapy for an important number of these patients thanks to ctDNA and checking in their blood a few weeks after surgery. It didn't really show signs of having a higher risk of recurrence. We determined that they could go without chemotherapy. I think this is very exciting because as you know, chemotherapy is something that no one wants to have to go through, if possible. The idea that you can avoid it in half of the patients is exciting.

On top of that, let's remember, there is also a major financial burden of these treatments. These treatments are expensive whether insurance is covering or not. Looking forward, as I mentioned, there are many questions still to be answered, but what is very exciting, is that these technologies are ready for primetime. What I see in the near future is that these technologies will scale up so that rather than just a first study like this one in general colon cancer patients, there will be studies in other cancer types. We will be able in many cases to avoid chemotherapy, if ctDNA shows that a patient does not have signs of recurrence in the blood.

_REFERENCE:

_{Tie J. Cohen J, Lahouel K, et al. Adjuvant chemotherapy guided by circulating tumor DNA analysis in stage II colon cancer: The randomized DYNAMIC Trial. J Clin Oncol. 2022; 40 (suppl 17). doi: 10.1200/JCO.2022.40.17_suppl.LBA100}