Experts Outline the Evolving Role of ctDNA-Based MRD Testing Across Solid Tumors

Although circulating tumor DNA (ctDNA) testing has emerged as powerful tools for detecting minimal residual disease (MRD) and refining risk stratification across solid tumors, questions remain about how best to integrate these assays into routine clinical practice. During a recent OncLive® Peer Exchange, experts in breast, colorectal (CRC), urothelial, and lung cancers discussed evolving evidence in support of ctDNA-based MRD testing, where these technologies are already influencing treatment decisions, and the clinical trials that could ultimately establish their role in guiding therapy escalation, de-escalation, and surveillance.

“We can all agree that ctDNA and MRD testing fit [into the treatment paradigm] and there's a role for them, but their value at this point is not uniform across every [disease] stage, and it also varies based on tumor type,” Eleonora Teplinsky, MD, said. “The data [with these tests] are different based on which cancer we're looking at, but the strongest signals currently are in the post-treatment setting. After the completion of surgery or curative intent therapy during surveillance, we're trying to think about if we use ctDNA to identify patients at higher risk of recurrence before the disease is visible on imaging. Then we can track patient-specific mutations over time using these tumor-informed assays.”

How have ctDNA and MRD testing performed in breast cancer and CRC?

The panelists dove into tumor-specific data and clinical experience with ctDNA and MRD testing in their disease areas, sharing what key trials have shown, where they personally apply ctDNA testing, and what remains uncertain. “[In breast cancer], we don’t have robust points where we are routinely [utilize ctDNA testing], because we don't necessarily know how to act on the results. I am really in favor of using it in a clinical trial, and I encourage clinical trials for my patients, but I will say I will occasionally use it in a high-risk patient,” Teplinsky said.

In order to further elucidate the role of ctDNA testing in breast cancer treatment and monitoring, investigators have initiated the interventional SURVIVE study (NCT05658172).¹ SURVIVE is a large-scale, multicenter, partially double-blinded randomized controlled trial comparing intensified surveillance with a liquid biopsy–guided surveillance strategy incorporating tumor markers, circulating tumor cells, and ctDNA with standard surveillance in survivors of medium- to high-risk early breast cancer. Patients are being randomly assigned 1:1 to standard or liquid biopsy-guided intensified follow-up. All disease subtypes are eligible; the completion of primary therapy is required and adjuvant endocrine, antibody, or targeted therapy are permitted.

Prior to the initiation of SURVIVE, data from an exploratory analysis of the phase 2 I-SPY 2 trial (NCT01042379), which assessed novel agents in sequence with standard chemotherapy in patients with breast cancer, showed that detectable ctDNA at baseline was associated with cN-positive disease, larger functional tumor volume (FTV), and high baseline Ki67 among those with stage 2 or 3 hormone receptor–positive, HER2-negative disease.² Most patients with evaluable ctDNA information (n = 101) who were ctDNA-positive at baseline were found to be cN-positive (64%) compared with 40% of patients who were ctDNA-negative at the same time point (P = .063). ctDNA positivity was also shown to be associated with higher Ki67 (P = .03) and larger FTV (P = .03).

“A lot of the excitement now around ctDNA [in breast cancer] is that [we may be able to use it] to detect it earlier, and will that make a difference in long-term outcomes for our patients,” Teplinsky said. “We’re not at a point yet where we have that robust data that we can intervene on, but I'm hopeful we'll see more in the next few years.”

Benjamin Weinberg, MD, then discussed the significance of 2 observational datasets that examined ctDNA-guided therapy in CRC: BESPOKE CRC (NCT04264702) and GALAXY, an observational arm of the CIRCULATE-Japan study (UMIN000039205). “We [also] hope to get the prospective results of [the phase 2/3] CIRCULATE-US [trial (NCT05174169)], which is randomly assigning ctDNA-negative patients to either standard doublet chemotherapy or observation with serial ctDNA monitoring. If they flip to ctDNA-positive [status] or are de novo positive, [we are] escalating potentially to 6 months of triplet chemotherapy vs 6 months of doublet chemotherapy. This study hopefully will finally settle whether we can really use ctDNA in the adjuvant setting, especially in stage 3 [disease], where I think most of us are still a little gun shy in terms of de-escalation.”

BESPOKE CRC was the first large, prospective, United States (US)–based trial to report on the utility of tumor-informed ctDNA in patients with CRC following surgery.³ The study enrolled patients across 133 sites in the US and aimed to evaluate the ability of a personalized ctDNA assay to inform adjuvant chemotherapy treatment decisions in patients with stage 2 or 3 disease.

Findings from BESPOKE CRC showed that ctDNA-positivity at the MRD time point was predictive of inferior disease-free survival (DFS); the median DFS post-surgery among MRD-negative patients (n = 530) was not reached compared with 15.98 months (95% CI, 13.77-20.22) among those who were MRD-positive (n = 93; HR, 12.1; 95% CI, 8.0-18.3; P < .0001). The 2-year DFS rates after surgery were 91.59% (95% CI, 88.38%-93.94%) and 29.86% (95% CI, 13.26%-48.54%), respectively. ctDNA-positivity during surveillance was also found to be predictive of inferior DFS regardless of treatment with adjuvant therapy (HR, 59.98; 95% CI, 27.3-131.9; P < .0001) or observation (HR, 80.10; 95% CI, 30.0-207.0; P < .0001). Sustained ctDNA clearance was associated with superior DFS vs transient or no clearance; 85% of patients with transient clearance developed molecular recurrence by month 15.

In GALAXY, investigators examined the postsurgical risk stratification and adjuvant chemotherapy decision-making potential of ctDNA in patients with stage 2 to 4 resectable CRC.⁴ At a median follow-up of 16.74 months (range, 0.49-24.83), postsurgical ctDNA positivity at 4-weeks after surgery was associated with a higher recurrence risk (HR, 10.0; 95% CI, 7.7-14.0; P < .0001); the 18-month DFS rates among patients who were ctDNA-positive (n = 187) and negative (n = 852) were 38.4% (95% CI 31.4%-45.5%) and 90.5% (95% CI, 88.3%-92.3%), respectively. ctDNA was also shown to be the most significant prognostic factor associated with recurrence risk in patients with stage II or III disease (HR, 10.82; 95% CI, 7.07-16.6; P < .001). Notably, post-surgical ctDNA-positivity was able to effectively identify patients with stage 2 or 3 disease who derived benefit from adjuvant chemotherapy (adjusted HR 6.59; 95% CI, 3.53-12.3; P < .001).

“We have to be cautious in overinterpreting, overfitting these observational, non-randomized studies,” Weinberg said. “But I would say that, in our clinic, I feel much more comfortable not giving patients with stage 2 disease adjuvant chemotherapy. The vast minority of patients in the stage 2 setting benefit from adjuvant chemotherapy. We're overtreating [many] of them.”

What is the current and future role of ctDNA testing in bladder and lung cancers?

In the bladder cancer space, investigators notably examined ctDNA-guided treatment with adjuvant atezolizumab (Tecentriq) in patients with muscle-invasive bladder cancer (MIBC) in an exploratory analysis of the phase 3 IMvigor011 study (NCT04660344).⁵ In IMvigor011, patients underwent surveillance ctDNA monitoring until 1 year after cystectomy; they underwent repeat testing if ctDNA negative. If patients were ctDNA negative until 1 year, they received no treatment and entered surveillance follow-up. If patients were ctDNA positive at any time and had no confirmed evidence of radiographic disease, they were randomly assigned 2:1 to receive atezolizumab at 1680 mg vs placebo every 4 weeks for up to 1 year.

“Bladder cancer is one of those cancer types in which we have actual clinical utility for ctDNA [testing], specifically in the adjuvant setting for immunotherapy patients,” Petros Grivas, MD, PhD, said. “The interesting finding was that patients who [were] ctDNA positive appear to derive significant benefit from adjuvant of atezolizumab, while the ctDNA-negative subset did not.”

Findings from the exploratory analysis presented during the 2026 Genitourinary Cancers Symposium demonstrated that the timing of ctDNA status offered prognostic information beyond binary ctDNA status in untreated patients, with early ctDNA positivity being associated with inferior DFS and OS. Patients who were ctDNA negative (n = 357) experienced a median DFS that was not evaluable (NE; 95% CI, NE-NE) compared with 11.1 months (95% CI, 9.2-13.5) and 6.0 months (95% CI, 5.1-6.6) among patients who were ctDNA positive at a subsequent test (n = 86) and those who were ctDNA positive at the initial test (n = 126), respectively. The median OS among these respective subgroups was NE (95% CI, NE-NE), 35.1 months (95% CI, 24.9-NE), and 21.9 months (95% CI, 15.0-NE).

ctDNA reduction or clearance was associated with improved DFS in the atezolizumab arm and ctDNA clearance was associated with improved DFS in the placebo arm. The median DFS in patients who received atezolizumab and had ctDNA clearance (n = 56) or at least a 2-fold decrease (n = 23) was NE (95% CI, 35.7-NE) vs 14.5 months (95% CI, 8.3-25.1), respectively; comparatively, the median DFS among those who had no change in ctDNA and received the agent (n = 33) was 8.2 months (95% CI, 6.1-10.3). In the placebo group, patients who experienced ctDNA clearance (n = 17) had a median DFS of 27.4 months (95% CI, 13.4-NE); in comparison, the median DFS was 4.5 months (95% CI, 3.7-8.1) among those with no change in ctDNA (n = 23), 3.9 months (95% CI, 2.2-6.2) in patients with a minimum of a 2-fold increase (n = 29), and 7.4 months (95% CI, 2.0-18.4) in those with a minimum of a 2-fold decrease (n = 8).

“We have to sort out the clinical utility, sensitivity, [and] specificity of the assay in the urine, [in terms of] what it means [regarding] lesions and how related they are to the original tumor vs new tumor,” Grivas added. “This will be sorted with larger studies and longer follow-up, but overall, I believe the datasets point towards the increasing use of ctDNA. [It’s] clearly a prognostic [marker with] predictive value in the adjuvant setting, but I think there are many scenarios now, especially patients trying to keep their bladder, [where the] addition of ctDNA [testing] may help us make more individualized decisions.”

The panelists concluded their discussion by highlighting the current role of ctDNA in lung cancer. “There are unique challenges with using ctDNA in patients with lung cancer, specifically, there’s a phenomenon called CHIP [clonal hematopoiesis of indeterminate potential],” John Strickler, MD, commented. “This is essentially contamination of the ctDNA result by some other alteration, maybe in the white blood cells or somewhere else in the body that gets mixed in with your result.”

During the International Association for the Study of Lung Cancer (IASLC) 2025 World Conference on Lung Cancer, investigators presented data from a study that assessed the clinical performance of the Signatera Genome assay to determine its prognostic value for risk stratification in patients with early-stage, resectablenon–small cell lung cancer (NSCLC).⁶ The study included 216 patients with available ctDNA data; 197 were included in the final analysis due to exclusions for incomplete clinical information, lack of a ctDNA test prior to a relapse-free survival (RFS) event and/or inclusion criteria not being met, multiple primary tumors, or less than 3 months of follow-up post-operation.

Findings from the study demonstrated a strong correlation between ctDNA negativity during the post-surgical MRD window with improved RFS and OS (P < .0001). The HRs for RFS in the overall population and in those with extracranial relapse were 10.0 (95% CI, 3.9-28.0; P < .001) and 17.0 (95% CI, 5.4-57.0; P < .001), respectively. Post-definitive treatment ctDNA positivity was also associated with reduced RFS across disease subtypes (HR, 88.3; 95% CI, 34.8-224.0; P < .0001), including in patients with adenocarcinoma (P = .004).

“We are a little bit behind in MRD research, compared with gastrointestinal and genitourinary [cancers],” Luis Raez, MD, said. “This study is very important because it's one of the few studies that we have results for in lung cancer for whole genome sequencing. In this landmark analysis, if a patient was ctDNA-negative after surgery, there was a significant improvement in DFS and in OS. [Additionally], when [chemoimmunotherapy] was finished, patients were again evaluated for MRD. Those that remained positive after adjuvant therapy with the standard of care had a bad prognosis; they have inferior RFS and OS. We are getting much better with whole genome sequencing and the other technologies. Hopefully we can perform more guided-therapy studies.”

John Strickler, MD, is a professor of medicine in the Division of Medical Oncology and a member of the Duke Cancer Institute in Durham, North Carolina.

Petros Grivas, MD, PhD, is the medical director of Local/Regional Outreach and the International Program, as well as a professor in the Clinical Research Division at Fred Hutch Cancer Center in Seattle, Washington.

Luis Raez, MD, is the medical director and chief scientific officer at Memorial Cancer Institute in Pembroke Pines, Florida.

Eleonora Teplinsky, MD, is the head of breast and gynecologic medical oncology, at Valley-Mount Sinai Comprehensive Cancer Care in Paramus, New Jersey, as well as a clinical assistant professor of medicine at the Mount Sinai Icahn School of Medicine.

Benjamin Weinberg, MD, is an associate professor of medicine in the Division of Hematology and Oncology at the Lombardi Comprehensive Cancer Center of Georgetown University in Washington, DC.

References

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