The use of circulating tumor DNA (ctDNA) to drive adjuvant chemotherapy decisions for patients with colorectal cancer (CRC) could ultimately affect treatment decision-making in clinical practice, according to Stacey A. Cohen, MD, who added that prospective data from larger trials remain a key hurdle to integrating this strategy into real-world use.

She also highlighted that data for neoadjuvant immunotherapy regimens in patients with mismatch repair–deficient (dMMR)/microsatellite instability–high (MSI-H) CRC underscore the need to determine MSI status at diagnosis before patients are sent to surgery.

“Coming out of all this great published data from 2024…are 2 major trends. One is that we are seeing that ctDNA is an exciting factor to help us [better] understand how to treat patients,” Cohen explained in an interview with 

. “[Second,] the data [for neoadjuvant immunotherapy] are exciting. There is more room to grow, but we are making great progress.”

The potential utility of tumor-informed ctDNA as a prognostic tool for guiding chemotherapy decisions in patients with CRC has been underscored by data from the observational CIRCULATE-Japan GALAXY trial (UMIN000039205). Updated findings from the study presented at the 

 showed that ctDNA positivity was associated with significantly worse disease-free survival (DFS) and overall survival (OS), and the findings also demonstrated the potential benefit of administering adjuvant chemotherapy to patients positive for minimal residual disease (MRD).

In the interview, Cohen discussed the updated findings from CIRCULATE-Japan Galaxy and the need to prospectively evaluate the role of ctDNA as a prognostic marker in CRC. She also provided an overview on the current landscape of neoadjuvant immunotherapy in dMMR/MSI-H, highlighting insights from both the phase 2 NICHE-2 and NICHE-3 trials (NCT03026140) in this patient population.

Cohen is a physician and an associate professor in the Clinical Research Division of Fred Hutchinson Cancer Center, as well as an associate professor in the Division of Hematology and Oncology at the University of Washington School of Medicine in Seattle.

findings from the subgroup analysis from the CIRCULATE-Japan GALAXY trial 

reveal about the use of ctDNA to inform adjuvant chemotherapy decisions in patients with resected CRC?

: It is great that we continue to see updates from the CIRCULATE-Japan GALAXY study. When [findings] were first published and presented, there were approximately 1000 patients [included in the trial]. There are [now] over 2000 patients, and [investigators] aim to get closer to 5000 patients. It is great getting updates along the way because it's a large, impressive set of observational data. It helps to get strength in bigger numbers.

We're seeing some different trends in how to interpret the data, but this remains an observational cohort. Therefore, some of the issues that have been present throughout [the study] continue to be an issue in terms of how we [apply] these data [to clinical practice]. We need some strong, prospective studies, and that is not what CIRCULATE-Japan GALAXY is aiming to do. However, it continues to offer us some great direction on where the most fruitful areas of a prospective clinical trial could come.

As we review some of the updates from GALAXY, ctDNA continues to be a very strong prognostic risk factor, meaning that the detection of ctDNA is associated with much worse survival. We're learning about how we can start to use that [information] to help make clinical decisions. Ideally, you want to use the presence of ctDNA to suggest that someone's at a higher risk for recurrence, then escalate therapy or give therapy when you wouldn't otherwise. [Conversely,] in a patient who's ctDNA negative, you want to be able to step back and perhaps avoid the toxicity of therapy or give a less-toxic therapy.

As we see updates in GALAXY, we're still noticing that [patients with] a variety of stages [of CRC] were included. All patients went to surgical resection; however, this is where some of the heterogeneity comes up. For example, some patients had chemotherapy before surgery—perhaps this was more prevalent in patients with stage IV disease. This was all done at the discretion of the clinician who was treating a given patient, but it offers some heterogeneity in the patient population.

We're seeing improvements in DFS and OS for patients who were ctDNA negative. They showed that [trend] both at the up-front time point called the MRD time point, which was after surgery before any chemotherapy was given, and then also in the surveillance time period, which is a more longitudinal dataset for patients who had completed their chemotherapy and beyond.

Some interesting updates included in the ESMO Congress presentation and the 

 publication were that we continued to see that liver metastases are higher-shedding sites of metastasis. Therefore, a patient who had a radiographic recurrence in the liver was more likely to have positive ctDNA, whereas [ctDNA] still can be detected in some patients with lung and the peritoneum [recurrences], but it may occur a little bit less often. We know that approximately 5% of patients who are ctDNA negative will still have recurrences. It may be that these [recurrences] are related to lower-volume sites of disease, or that [patients had metastatic] sites in organs that don't tend to shed as much ctDNA.

There continue to be some interesting updates. [Investigators] showed data from different molecular subgroups that mimicked patterns that we've seen before in terms of molecular markers that are prognostically better or worse.

My takeaway from GALAXY is that we're continuing to learn how to treat patients [with CRC] by using ctDNA. None of these data are going to truly be practice-changing because it's not a prospective study integrating ctDNA, by which we change our management because of the ctDNA result. However, this continues to add to the breadth of data that encourages us to continue this line of research.

How could prospective data help inform the use of ctDNA for treatment decisions in clinical practice?

I'm hoping that as we have some strong prospective trials, we'll be able to start using ctDNA. The GALAXY study is great because it asks and addresses [questions about] so many different clinical situations. However, we need [prospective data for] a very specific situation, such as stage II colon cancer where we debate whether to give any chemotherapy, where we could use that test to help guide that management.

Beyond just using [results from the ctDNA] test, [we also want to identify] a specific chemotherapy regimen. For example, when we look at the [phase 2] DYNAMIC trial [ACTRN12615000381583] out of Australia, it is an amazing clinical trial, but it [used] an assay that's not commercially available, so we can't necessarily replicate that in our own practice. There was also a lot of physician choice about which chemotherapy regimen to use.

We need to [focus] on a very specific question with a [prospective] ctDNA trial [in CRC], and if that's found to be positive, we can go from there and start to use [ctDNA] in more settings. [There are] more data to come, and even within the CIRCULATE-Japan cohort of studies, there will be [prospective] trials that will come out soon. That's what we're lacking at this point.

How could disease management differ for a patient with sustained vs transient ctDNA clearance?

The hope is that we’ll need to modify our treatment strategies as well as our surveillance strategies. Clearance implies that someone has negative ctDNA. The question is, ‘Is that marker enough to say that a patient [with negative ctDNA] doesn’t need as frequent visits, lab checks, or radiographic studies?’ At this point, we have not scaled back in any way in terms of our surveillance. The idea, more hypothetically, could be that if someone was ctDNA negative for a given number of checks and you were able to show [with prospective data] that recurrences didn't happen [in these types of patients] outside of symptoms or rare instances, maybe you would say that the benefit of doing radiographic annual imaging is not there. You would then potentially not screen them or do as much surveillance. I don't think anybody's willing to go down that pathway just yet because we worry about every lab test having an error and the potential for that.

The idea of ctDNA clearance also gets to the fact that longitudinal testing matters, and it matters how patients respond over time. We think that risk groups determined right after surgery matter based on pathology and MRD testing, but we also need to incorporate their response to subsequent therapy. For example, if a patient got adjuvant treatment and cleared their ctDNA, we know that those patients do better than patients who remain ctDNA positive, and patients who briefly clear their ctDNA do better than those who never clear their ctDNA; that's the idea of transient clearance vs no clearance. However, we haven't yet [established how to use this information in practice].

These [data] make some nice survival curves, but they don’t help us totally answer the question regarding what to do next. We may find that patients who are ctDNA positive, remain positive, or convert back to being positive are the ones in whom we would recommend for closer radiographic surveillance compared with the patients who are ctDNA negative and may continue to be negative. Maybe those are the patients who [are going to require] less-intense surveillance.

, did it surprise you that no patients with dMMR CRC treated with neoadjuvant nivolumab (Opdivo) plus ipilimumab (Yervoy) experienced disease recurrence at 3 years, irrespective of whether they achieved a pathological complete response (pCR)?

This is an exciting time to be using immunotherapy in CRC. We know that [patients with dMMR tumors represent] only a subset of patients with localized CRC or rectal cancer—we are talking about approximately 10% to 15% of patients. However, we're seeing some exciting data that's changing how we treat patients.

In rectal cancer, there have been interesting studies, 

 of dostarlimab-gxly [Jemperli] out of Memorial Sloan Kettering Cancer Center in New York, New York, showing that we can achieve a CR with immunotherapy alone in those patients.

 If we look at the data, they saw that [the median time to CR was 6.22 months], and only in a few patients [experienced a CR] by 3 months of treatment. We know from other studies—for example, the phase 3 KEYNOTE-177 study [NCT02563002] that compared [pembrolizumab (Keytruda) alone] vs chemotherapy in first-line metastatic dMMR/MSI-H CRC—that the time to response [with immunotherapy] was similar.

Therefore, when we think about the NICHE-2 data, these patients received only 1 month of [neoadjuvant] immunotherapy, and we saw very impressive responses. All patients went to surgery, and they saw very impressive pathologic responses. You may ask the question, ‘Are patients going to still do as well if they don't achieve a pCR?’ My takeaway from these data is we might not have waited long enough. Four weeks is probably insufficient to be able to convert all patients to a pCR if we look at the data in rectal cancer and CRC. What we're seeing [with the NICHE-2 data] is that many patients had a good response, and they were having regression of the tumor that didn't completely get to a pCR.

We also have to remember that all patients were mandated to have surgery in this trial. The next question becomes, ‘Are we ever going to get to a point where we could [use] non-operative management?’ That's much trickier because we don't have the same abilities to do surveillance [in CRC]. A colonoscopy is more complicated, and we don't have MRI.

The data from NICHE-2 are encouraging with this type of DFS, [and this study also included] patients with high-risk cT4 disease. We should be holding surgery until we know the MSI status of patients; even though [the dMMR/MSI-H population] only [accounts for] 10% to 15% [of the overall CRC population], knowing this status can make dramatic improvements in outcomes. We don't have the ability right now to give immunotherapy in the adjuvant setting, so it makes it that much more important to recognize [this status] early on.

Findings from NICHE-3 also showed that neoadjuvant nivolumab plus relatlimab-rmbw (Opdualag) generated pCRs in patients with dMMR colon cancer. How do you weigh these findings with the potential for non-operative management?

NICHE-3 evaluated nivolumab plus relatlimab, the latter of which is a LAG-3 inhibitor, as opposed to ipilimumab, which is a CTLA-4 inhibitor. We know from melanoma that ipilimumab may bring higher toxicity, although with the current doses, it may be more similar to what we see for nivolumab plus relatlimab. Therefore, we would expect that their outcomes would be pretty similar. However, [the combinations] haven't necessarily been tested head-to-head.

It's very exciting to see data coming out for nivolumab plus relatlimab. To me, we’re asking multiple questions in parallel. First, we want to know if we should be doing immunotherapy for these patients [with dMMR/MSI-H disease], and the data are suggesting that we should in the neoadjuvant setting. The next question would be, what's the optimal regimen? We don't have that answer yet because the NICHE-2 and NICHE-3 regimens have not been compared.

We [also have to consider if there are] certain toxicities to worry about. Prior studies have shown concern for grade 5 adverse effects or deaths related to therapy, such as myocarditis with the use of combination immunotherapy and even with single-agent immunotherapy. As we start to get excited about these drugs, we must remember that there are rare but very serious toxicities that can happen. Certainly, we know that patients may die of their disease or have poor outcomes; however, the deaths that have been observed have given everyone a moment of pause, although we continue to move forward.

As we're talking, I don't know that non-operative management is here yet, and we need more trial data to show [if that is a feasible option]. [One reason] is the inability to do adequate surveillance. We want to make sure that if patients don't go to surgery, we have good oversight so you can catch that patient if they start to have any evidence of progression. That's complicated because a colonoscopy is not an easy ask, and a patient’s ability to comply with those types of procedures may be less [likely] if we need to do it more often.

[These data] give us some information for planning future trials. My takeaway from NICHE-3 is that [nivolumab plus relatimab] remains an exciting combination to use, and I look forward to what the next [trial] iteration is going to be. Ideally, at some point, it'll be a head-to-head study.

Given all the ongoing research and emerging data surrounding ctDNA and immunotherapy, how do you see these ultimately affecting the management of CRC in clinical practice?

The presence of ctDNA suggests poor prognosis, which [could identify] patients who may need more aggressive therapies. However, questions remain on how to apply that to an individual patient. I encourage any studies that evaluate [ctDNA] because the [lack of] prospective data is preventing us from making [the use of ctDNA] more standard.

In the CRC world, we absolutely need to know the MSI status before we take someone to surgery. This is because we are seeing much more impressive outcomes with neoadjuvant immunotherapy, even in patients who don't have a PCR. However, a little bit of immunotherapy can go a long way, and we'd love to improve our survival outcomes for patients.

Kataoka K, Mori K, Nakamura Y, et al. Survival benefit of adjuvant chemotherapy based on molecular residual disease detection in resected colorectal liver metastases: Subgroup analysis from CIRCULATE-Japan GALAXY. 

. 2024;35(suppl 2):S459-S460. doi:10.1016/j.annonc.2024.08.627

Chalabi M, van den Dungen LDW, Verschoor YL, et al. Neoadjuvant immunotherapy in locally advanced MMR-deficient colon cancer: 3-year disease-free survival from NICHE-2. 

. 2024;35(suppl 2):S1217-S1218. doi:10.1016/j.annonc.2024.08.2263

De Gooyer P, Verschoor Y, van den Dungen LDW, et al. Neoadjuvant nivolumab plus relatlimab in MMR-deficient colon cancer: results of the NICHE-3 study. 

. 2024;35(suppl 2):S428-S429. doi:10.1016/j.annonc.2024.08.572

Cercek A, Sinopoli JC, Shia J, et al. Durable complete responses to PD-1 blockade alone in mismatch repair deficient locally advanced rectal cancer. 

. 2024;42(suppl 17):LBA3512. doi:10.1200/JCO.2024.42.17_suppl.LBA3512

Articles

Stacey A. Cohen, MD, provides an overview on the current landscape of immunotherapies and prognostic tools in the treatment of colorectal cancer.

ctDNA, Neoadjuvant Immunotherapy Combos Could Help Reshape Management of CRC

Circulating tumor DNA (ctDNA) and mismatch repair (MMR) test results are crucial to inform treatment decision-making for patients with colorectal cancer (CRC), and continued use of these tests may further elucidate the roles of adjuvant chemotherapy and neoadjuvant immunotherapy, according to Benjamin Adam Weinberg, MD.

Updated findings from the CIRCULATE-Japan GALAXY trial (UMIN000039205) presented at the 

showed that post-surgical ctDNA positivity in the minimal residual disease (MRD) surveillance window, which translated to MRD-positive disease (n = 336), correlated with a higher risk of disease recurrence after curative-intent surgery in patients with clinical stage II to IV CRC vs those with MRD-negative disease (n = 1294; HR, 20.50; 95% CI, 11.16-37.66; 

 Furthermore, the 24-month overall survival (OS) rate was 83.70% (95% CI, 77.80%-88.10%) among patients with MRD-positive disease vs 99.50% (95% CI, 98.80%-99.80%) among those with MRD-negative disease. Disparities in OS and disease-free survival (DFS) between the MRD-positive and -negative populations became increasingly pronounced in the months after surgery.

Moreover, findings from the phase 2 NICHE-2 trial (NCT03026140) demonstrated that among 111 efficacy-evaluable patients with nonmetastatic, locally advanced, treatment-naive, MMR-deficient (dMMR) CRC who received neoadjuvant nivolumab (Opdivo) plus ipilimumab (Yervoy), 98% (95% CI, 94%-100%) achieved a pathological response, including major pathological responses (95%) and pathologic complete responses (pCRs; 68%).

“dMMR testing is here to stay, and ctDNA testing is powerful,” Weinberg said in an interview with 

. “Knowledge is power, and [ctDNA testing is] another tool in our toolbox and another data point that needs to be considered.”

In the interview, Weinberg, an associate professor of medicine at the Georgetown Lombardi Cancer Center in Washington, DC, highlighted how findings from CIRCULATE-Japan GALAXY show the prognostic value of adjuvant ctDNA testing in CRC, how long-term data from NICHE-2 support the continued use of neoadjuvant immune checkpoint inhibition in dMMR CRC, and unanswered questions that these trial findings have brought to the surface in the CRC research field.

: Updated findings from the CIRCULATE-Japan GALAXY trial were presented at the 2024 ESMO Congress. What are your thoughts on the data and the ability of ctDNA-based MRD detection to predict adjuvant chemotherapy benefit in patients with resected CRC?

: ctDNA MRD testing is prognostic for patients with resected CRC. With longer-term follow-up, we’re getting a more enriched dataset where we can make more conclusions as we await the results of prospective randomized studies assessing whether we can use ctDNA in the adjuvant setting to make clinical decisions regarding which patients should receive adjuvant chemotherapy. The Japanese [investigational team used] the Signatera [assay], a tumor-informed ctDNA platform. [This large, prospective, observational trial] enrolled 5996 patients with different stages of resected CRC. Stage for stage, this study showed that ctDNA is prognostic.

The focus [of this trial was] on the window period of MRD positivity or negativity at the 4-week post-operative time point, which is typically prior to [the start] of adjuvant chemotherapy. [If a patient has] positive [ctDNA results] at that time point, [their prognosis is worse], but that group seems to derive the most benefit from adjuvant chemotherapy. With longer follow-up, we’re now seeing a third group of [patients with] transient ctDNA clearance. Approximately one-third of patients with ctDNA-positive results clear [their ctDNA test] and stay sustained. They do well, and virtually none recur.

Slightly less than one-third of patients have transient clearance, whereby on chemotherapy, their ctDNA levels clear, but then recur or become positive early, usually by 6 to 12 months. By 2 years, [most patients] in that population have recurred. Then, there’s a group [of patients with ctDNA levels] that do not clear at all, approximately one-third of patients. They have by far the worst DFS and OS outcomes.

We’ve gotten a lot more data [showing that ctDNA] is a worthwhile test. However, we await the results of prospective, randomized studies investigating treating these populations differently [from each other], knowing that the ctDNA-positive group derives the most significant benefit from adjuvant chemotherapy, and the ctDNA-negative group derives little to no benefit, depending on stage. Hopefully, we can use this test in the clinic to decide which patients need adjuvant chemotherapy.

What prospective, randomized trials are ongoing to confirm the benefit of ctDNA testing in patients with CRC?

The [phase 3] CIRCULATE-NORTH AMERICA trial [NCT05174169] is a large trial being conducted throughout the United States and Canada. It’s enrolling patients with stage III or stage II/ctDNA-positive disease. Additionally, in 1 side of the trial, patients with negative or undetectable ctDNA are randomly assigned to undergo observation with serial ctDNA testing vs the standard 3 months of adjuvant doublet chemotherapy with CAPOX [capecitabine and oxaliplatin] or FOLFOX [folinic acid, fluorouracil, and oxaliplatin]. If these patients convert to ctDNA positivity, there’s a second randomization to 6 months of CAPOX or FOLFOX vs 6 months of FOLFIRINOX [folinic acid, fluorouracil, oxaliplatin, and irinotecan], adding irinotecan in an intensified chemotherapy strategy, because we know the ctDNA-positive group is at high risk of recurrence.

This is a nice study because on the one hand, [it is asking]: Can we get away with observing, especially in the [patients with] low-risk, stage III, T1, N1 [disease] who [derive little] benefit from chemotherapy? Most of those patients are probably cured by surgery, and we’re probably overtreating them with adjuvant chemotherapy. On the other hand, if a patient is ctDNA positive, regardless of stage, should we be intensifying chemotherapy?

This trial has been open, but it’s going to take years to enroll and read out. As we’ve seen with the CIRCULATE-Japan GALAXY data, with longer-term follow-up, we’re getting a lot more useful information. The hope is that CIRCULATE-NORTH AMERICA will allow us to potentially observe patients who may not derive benefit from adjuvant chemotherapy.

What is the value of serial ctDNA testing and the importance of sustained vs transient ctDNA clearance?

The real power of ctDNA testing comes in repeating the testing serially in a longitudinal fashion. One negative or undetectable test is good. However, there are patients who have residual disease that is just below the level of detection of the test. Repeating the test at various time points adds to the strength and reliability of the test. I can tell patients [that they if have] been ctDNA negative not just at 1 time point, but at 3 or 4 time points over a year, their odds of recurrence drop and are eventually close to 0.

As this technology was first being used, we do not know what we’re doing with these data, but we know that if [a patient has] persistently undetectable ctDNA, that is good. Historically, we still surveilled these patients for up to 5 years following completion of therapy. That’s a long time, and [patients developed] a lot of scan anxiety and now, a lot of ctDNA anxiety, related to those results. However, persistently undetectable [ctDNA results are] good, and fortunately, we see a lot of patients who are persistently undetectable. We’re comfortable [saying], especially years out, that their odds of recurrence are basically 0.

How did the 3-year DFS data from NICHE-2 add to the current knowledge on the benefits of checkpoint inhibitors in patients with dMMR CRC?

Patients with dMMR rectal and colon cancer benefit from immunotherapy, especially in the neoadjuvant setting. This has changed the paradigm of how we treat these patients. It’s imperative to know MMR status at diagnosis.

In rectal cancer, this is even more paramount because [findings with] single-agent PD-1 inhibition with dostarlimab-gxly [Jemperli] have shown that these patients do not need chemoradiation or surgery. They can get by with just immunotherapy. That has improved the outcomes and quality of life for those patients.

Then, the question was: does this [benefit with neoadjuvant immunotherapy] also translate into colon cancer, where typically the surgery and long-term adverse effects are better than in rectal cancer, where [patients often receive] radiation and surgery in the pelvis? [NICHE-2 showed that] by giving 2 doses of nivolumab and 1 dose of ipilimumab, almost all patients had a pCR, where there was no tumor left at the time of surgery. Some patients had residual disease, but most had some degree of tumor shrinkage, which is impressive. We see these impressive [findings] where each patient has almost a CR, if not a CR.

Where the DFS data add to this and are compelling, is that none of these patients went on to recur, even the ones who didn’t get a pCR. We’re now 3 years out, and none of these patients have occurred, which is impressive and shows that this is the way we should be treating these patients. There’s no benefit from adjuvant therapy, especially adjuvant chemotherapy [in this population], and most of these patients did not go on to receive that.

The traditional paradigm was surgery first followed by adjuvant chemotherapy, so we’re sparing these patients chemotherapy. The question is: do these patients even need surgery? That’s more complicated because [colon] surgery is easier than rectal surgery, but at the same time, would patients need more than 2 doses of nivolumab and 1 dose of ipilimumab?

Anecdotally, in my practice, I’ve treated a couple of these patients who did not get surgery; we’ve treated them for up to 2 years with immunotherapy and then observed them. However, the [neoadjuvant] standard nowadays is 2 doses of nivolumab and 1 dose of ipilimumab. Some patients develop toxicity even from 2 doses of nivolumab and 1 dose of ipilimumab. Some patients need to receive long-term hormone supplementation for low thyroid or adrenal function. That needs to be factored in.

However, there is a more complicated question. Should these patients go straight to surgery? Should they not get surgery at all? Those are answers we still need to sort out.

Without definitive level 1 data to guide neoadjuvant therapy and surgical decision-making, how are patients with dMMR CRC currently treated in these settings?

This is a case-by-case basis because these patients often present differently, with different symptomatology and different goals and objectives about surgery, for example. We deal with this frequently now. The default would be to start doublet immunotherapy and then see what happens.

One of the reasons I use ctDNA testing frequently in the dMMR population is because [these patients’ ctDNA levels] should decrease and often clear as early as after 1 dose of immunotherapy. [ctDNA is] a confirmatory test that we’re on the right track. If these levels remain at 0, do we need to do surgery? Some of these patients are symptomatic and receive surgery one way or another. However, for other patients, whose symptoms resolve on immunotherapy, do they need surgery, and, if not, how much immunotherapy do they need? We don’t know the answer to that question.

Extrapolating from the metastatic realm, after 2 years—some oncologists would say 1 year—we don’t think there’s a benefit from adjuvant or definitive immunotherapy. We often see how it goes and if toxicities develop, because some patients develop no toxicity at all, even from doublet immune checkpoint inhibition. I give ipilimumab at 1 mg/kg every 6 weeks, which seems to be tolerable, and then I give nivolumab every 2 weeks. With that strategy, in a small number of patients, I’ve had success in sometimes avoiding surgery and significant toxicity.

Do you believe a trial will be done to determine whether asymptomatic patients with ctDNA clearance require surgery?

We have a lot of small trials. The problem with this population, even though it can comprise 15% of earlier-stage CRCs, is it’s still not a large population. Now that these drugs are approved and used, we will see more patients treated in the community with immunotherapy and then surgery. [Academic oncologists] need to make sure these data are disseminated throughout the community, so community oncologists are aware of these data and are doing MMR testing, because [MMR testing rates are] not at 100% unfortunately. It would be difficult to do a study. There is the potential to do a study using ctDNA [and enrolling patients with] ctDNA clearance [to undergo] observation vs surgery.

The other issue is financial. If we’re continuing immunotherapy, that’s expensive. A surgery is not inexpensive, but it’s a one-off proposition. Those are the types of higher-level health policy–type arguments that need to be sorted out as well.

What is your main message for your community and academic colleagues based on this discussion?

We should all do MMR testing regardless of stage, to see which patients could benefit from immunotherapy and as a screen to see which patients may have Lynch syndrome, which should be figured out early. It’s not being used universally, for understandable reasons. We don’t know the proper way to use it in the prospective setting, especially for guiding patient treatment.

In my practice, [ctDNA test results] change how I approach patient treatment, even on adjuvant therapy. [Currently], I’m not comfortable observing a patient with stage III CRC who has undetectable ctDNA levels, but [these ctDNA results] might tailor how aggressively we treat patients in the adjuvant setting. In the stage II realm, [ctDNA test results do] factor into how I treat those patients because most of them are overtreated. I hope these data, especially now with the longer-term CIRCULATE-Japan GALAXY follow-up, are available and discussed amongst community oncologists.

Nagata J, Nakamura Y, Watanabe N, et al. Association of ctDNA-based MRD detection and MRD clearance with short-term overall survival in patients with resectable colorectal cancer: updated analysis of CIRCULATE-Japan GALAXY. 

. 2024;35(suppl_2):S428-S481. doi:10.1016/annonc/annonc1588

Chalabi M, Verschoor YL, Tan PB, et al. Neoadjuvant immunotherapy in locally advanced mismatch repair-deficient colon cancer. 

. 2024;390(21):1949-1958. doi:10.1056/NEJMoa2400634

Benjamin Adam Weinberg, MD, discusses the prognostic value of adjuvant ctDNA testing in CRC and the role of immune checkpoint inhibition in dMMR CRC.

Increased ctDNA and MMR Testing May Alter Adjuvant and Neoadjuvant CRC Management 

Dr Weinberg on the Prognostic Use of ctDNA Testing in Resected CRC

Benjamin Adam Weinberg, MD, associate professor, medicine, Georgetown Lombardi Comprehensive Cancer Center, discusses the ability of circulating tumor DNA (ctDNA)–based minimal residual disease (MRD) detection to predict the benefit of adjuvant chemotherapy in patients with resected colorectal cancer (CRC).

ctDNA-based MRD testing has shown prognostic value for patients with resected CRC, Weinberg begins. With extended follow-up, an enriched dataset is emerging from the CIRCULATE-Japan GALAXY trial (UMIN000039205), aiding in more concrete conclusions regarding the role of ctDNA testing in this patient population, he says. CIRCULATE-Japan GALAXY was a large, prospective, observational trial conducted in Japan that used the Signatera ctDNA platform. This trial enrolled 5996 patients with various stages of CRC and showed that ctDNA status was prognostic across stages, according to Weinberg. 

CIRCULATE-Japan GALAXY focused on ctDNA MRD status at the 4-week post-operative window, prior to the receipt of adjuvant chemotherapy. Patients with positive ctDNA results at this point have a poor prognosis but seem to derive the most benefit from adjuvant chemotherapy, Weinberg explains. In the extended follow-up analysis, 3 distinct patient groups emerged. One group consisted of patients with ctDNA-positive results, one-third of whom cleared ctDNA and maintained clearance, experiencing excellent outcomes with minimal instances of recurrence, he reports. The second group, slightly less than one-third of patients, achieved transient ctDNA clearance with chemotherapy, but their ctDNA levels later became positive, typically within 6 to 12 months of surgery. By 2 years, most patients in this group had disease recurrence, Weinberg says. The final group comprised patients whose ctDNA levels never cleared; approximately one-third of patients fall into this category and have the least favorable disease-free survival and overall survival outcomes, he notes.

A growing body of evidence underscores the value of ctDNA testing as a prognostic tool, Weinberg reiterates. However, results from prospective randomized trials are still needed to refine treatment strategies for these distinct patient populations, he emphasizes. The ctDNA-positive population derives the most substantial benefit from adjuvant chemotherapy, whereas ctDNA-negative patients derive little to no benefit from this treatment approach depending on their disease stage, he notes. The increased clinical use of ctDNA testing may help oncologists tailor adjuvant CRC therapy more effectively, he concludes.

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Benjamin Adam Weinberg, MD, discusses the ability of ctDNA-based MRD detection to predict the benefit of adjuvant chemotherapy in resected CRC.

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