The evolving role of ctDNA in colorectal cancer: guidance of adjuvant therapy or surveillance strategies?

Over the past decade the emergence of circulating tumor DNA (ctDNA) platforms has greatly impacted the field of oncology. In colorectal cancer (CRC), ctDNA has gained recognition as a prognostic biomarker and a potential decision support tool to guide treatment decisions after surgical resection (1). Several recent studies have investigated the utility of this platform to inform clinical decision making at additional points of care, including detection of minimal residual disease (MRD) and surveillance in the postoperative setting (2-4).

The assays commonly used are tumor-agnostic (plasma-only) or tumor-informed. Plasma-only assays, which do not require tumor tissue, offer faster turnaround and broader scalability. Tumor-informed assays require individualized tumor tissue to identify patient-specific mutations and to design corresponding probes. Tumor-informed assays have historically demonstrated high analytical sensitivity and specificity (e.g., 88% and 98%, respectively, with serial testing) for relapse detection (4). However, recent plasma-only platforms incorporating methylation and multi-omic features now report specificities ≥95–98% and longitudinal sensitivities ranging from ~60% to >80% in stage II–III CRC) narrowing the sensitivity gap in certain clinical contexts (5,6).

Several prospective and retrospective studies have shown that ctDNA can be used as a reliable prognostic biomarker (2,3). Detection of ctDNA strongly correlates with recurrence risk after surgical management. In the GALAXY study, a prospective multicenter cohort study, investigators showed that ctDNA positivity during the MRD window was associated with a markedly increased risk of recurrence with a disease-free survival (DFS) hazard ratio (HR) of 11.99 and overall survival (OS) HR of 9.68 respectively (2). Moreover, sustained ctDNA clearance after adjuvant chemotherapy (ACT) was correlated with markedly improved 2-year DFS compared to persistent ctDNA positivity (89% vs. 3%, respectively). Nearly all patients with persistent ctDNA positivity relapsed during follow-up, with true sustained clearance and no recurrence observed in only 1.9% of cases (2). These findings were consistent with a prior study that showed that ctDNA positivity in stages I–III CRC after surgery was associated with a sevenfold increase in risk of recurrence (4). Similarly, the BESPOKE study, a prospective cohort study of tumor-informed ctDNA MRD assay in stage I–III colon cancer, revealed strong prognostic associations for negative ctDNA-MRD and prolonged DFS (3).

While ctDNA can be a powerful prognostic tool its role in surveillance in clinical practice is less encouraging. In an earlier prospective multicenter cohort study, Reinert et al. showed that ctDNA was able to detect 14 of 16 relapses (88%) with a mean lead time of 8.7 months compared to standard radiographic surveillance methods (4). Conversely, a retrospective cohort study of 48 patients with stage II–IV resected CRC directly compared ctDNA positivity with carcinoembryonic antigen (CEA) and standard imaging showed significantly lower sensitivity (53%) compared to imaging (60%) and imaging plus CEA (73%) in detecting recurrence. Results also translated to no overall survival or salvage therapy benefit from earlier detection with ctDNA (7). The differences in results observed between these studies could be accounted for by the more frequent imaging schedule in the Fakih study that followed the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines^®), which recommend imaging every 6–12 months for the first 2 years, then annually for 5 years (8). In contrast, Reinert et al. followed the Danish Colorectal Cancer Group (DCCG) guidelines that recommend computed tomography (CT) imaging at 1 and 3 years after surgical resection (4).

In the oligometastatic setting findings appear more favorable. A recent study reported that serial plasma-only ctDNA monitoring after curative-intent therapy detected molecular recurrence with a sensitivity of 83% and specificity of 85%, preceding radiographic recurrence by a median of 6.7 months (9). At a single post-treatment time point, sensitivity was more modest (58%), underscoring the value of longitudinal monitoring (9). The observed differences in outcomes may stem from the oligometastatic cohort harboring higher overall tumor burden and higher likelihood of micrometastatic disease, whereas patients with earlier stage disease could present with lower baseline ctDNA shedding or a more indolent growth course. Given that this study was blinded to physicians and management was not altered based on ctDNA findings, further studies will need to establish whether there is clinical utility of earlier salvage therapy in this patient population.

A more recent retrospective cohort study of 184 patients with stage II–IV CRC observed little measured clinical benefit from ctDNA as a surveillance tool, with only 44% of patients (20/45) harboring ctDNA positivity before radiographic recurrence (10). Further, only 15% (3/20) achieved durable remission following ctDNA-prompted salvage therapy, versus 28% (7/25) identified by imaging as first evidence of recurrence, irrespective of ctDNA positivity, achieved durable response after salvage therapy (10). In this study the majority of ctDNA positive patients that were identified before standard imaging were not candidates for curative salvage therapy, indicating that detection alone is not sufficient to improve outcomes.

Novel clinical trial designs investigating how best to manage ctDNA positive CRC patients during the surveillance setting are emerging—the first of which is the ALTAIR trial, an offshoot of the Japan-GALAXY study. In ALTAIR, resected stage II–IV CRC patients developing positive MRD by the tumor-informed ctDNA assay used in GALAXY were randomized trifluridine/tipiracil (FTD/TPI) or placebo (11). Overall, differences in DFS were not significant between the two groups. Interestingly, in the subset of (resected) stage IV patients DFS was significantly improved with FTD/TPI compared to placebo (HR 0.53; P=0.012), with 2-year DFS of 34% versus 6.6% respectively (11). These results highlight the potential for ctDNA-guided strategies to improve outcomes in selected patient subgroups during the surveillance period. Recent studies have shown greater promise with the role of ctDNA as a tool to guide treatment decisions in the postoperative setting. The DYNAMIC trial is the first randomized clinical trial to provide evidence regarding the efficacy of using ctDNA to guide ACT in stage II colon cancer (12). Participants were randomized in a 2:1 ratio to treatment decisions informed by ctDNA status vs. standard clinical and pathologic features. This study used a tumor informed assay to identify ctDNA positivity and the primary endpoint was recurrence free survival. In the ctDNA arm, patients who were ctDNA positive received ACT while ctDNA negative patients were observed without chemotherapy. The 5-year recurrence free survival (RFS) was similar in both groups (88% vs. 87%). These differences were consistent across patient subgroups, including those defined by traditional risk factors such as patients with T4 tumors or deficient mismatch repair (dMMR) genes (12). These results show that ctDNA guided ACT could be utilized to safely reduce overtreatment in patients with stage II colon cancer.

The DYNAMIC trial shows promise of use of ctDNA for de-escalation strategies, however the recent COBRA trial puts into question whether ctDNA positivity can be used to guide escalation of treatment decisions in low-risk stage II colon cancer patients (13). The study primarily focused on ctDNA clearance at 6 months of ACT in ctDNA positive patients as the primary endpoint and was halted early for futility as there was no significant difference in clearance between the observation arm and ACT arm. Interestingly, the results were the opposite of what was anticipated, with no benefit for ACT escalation in ctDNA-positive patients. This disappointing result could be explained by several factors including the use of an older generation tumor-agnostic assay, the small number of ctDNA positive cases (n=16), as well as the low-risk nature of the population studied. This highlights that the utility of ctDNA should not be applied universally, particularly in low-risk patients, and that the type of assay used can impact the interpretability of the results.

The anticipated DYNAMIC-III trial recently published data aimed to evaluate whether postoperative ctDNA positivity could guide ACT escalation in stage III colon cancer (14). Among 961 patients, 259 (27%) were ctDNA-positive and randomized to ctDNA-informed or standard-of-care management. In the ctDNA-informed arm, 89% received treatment escalation, including FOLFOXIRI in 56%. After a median 42 months of follow-up, 2-year RFS was 52% for ctDNA-guided patients versus 61% for standard care (HR 1.11; P=0.6), indicating no benefit from chemotherapy intensification, even with triplet therapy (FOLFOXIRI 47% vs. FOLFOX/CAPOX 51%). However, within the ctDNA-informed arm of DYNAMIC-III, only 65 patients (≈56%) received FOLFOXIRI and 112 patients received standard of care therapy making the analysis statistically constrained as the small sample size yields insufficient power to detect any realistic survival difference. The overall ctDNA-positive cohort of roughly 250 patients provides only about 37% power to detect a HR of 0.75, far below the 80% theoretical power cited in the study design. These limitations underscore that while DYNAMIC-III was a pivotal proof-of-concept trial its regimen-specific and escalation analyses were underpowered, precluding definitive conclusions about the efficacy of chemotherapy intensification in ctDNA-positive stage III colon cancer.

Looking forward, several studies are underway. One of the most anticipated trials, CIRCULATE-US NRG-GI008, will evaluate whether ctDNA can guide both escalation and de-escalation of adjuvant therapy in primarily stage III colon cancer, using DFS as a definitive clinical endpoint (15). The trial’s dual approach—testing non-inferiority in MRD negative patients and superiority of treatment escalation in MRD positive patients looks to provide evidence on whether ctDNA can safely guide personalized treatment strategies in early-stage colon cancer. The VEGA study, another randomized controlled trial in the CIRCULATE-JAPAN platform (16), is currently ongoing and aims to investigate whether observation alone is non-inferior to standard ACT in patients who are ctDNA negative four weeks after surgery in patients with high-risk stage II or low risk stage III colon cancer.

ctDNA has emerged as a valuable prognostic biomarker for risk stratification in CRC. However, its predictive value remains unproven, and mixed results in the CRC surveillance setting indicate that the field is still emerging. Novel prospective trials, such as the IMPROVE-IT2 study, are underway to determine whether ctDNA guided surveillance and earlier intervention can improve DFS compared to standard imaging based follow up (17). Furthermore, emerging large-scale randomized trials are expected to clarify the clinical utility of ctDNA in treatment decision making by establishing standardized frameworks for its interpretation and application. As the field evolves, integration of ctDNA-guided strategies into precision oncology is anticipated to enhance therapeutic decision-making and to improve outcomes in CRC.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Editorial Office, Translational Gastroenterology and Hepatology. The article has undergone external peer review.

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-75/prf

Funding: Funding to support this manuscript was provided, in part, by a 2022 ASCO Conquer Cancer Foundation Career Development Award awarded to J.G. and USA NIH/NCIgrant R01CA252042 to M.P.H.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-75/coif). K.A. reports grant – Varian Medical Systems (to institution) and honoraria – OncLive. Y.N. has served and been paid as a speaker for Natera (last payment received was longer than 36 months ago). J.A.Z. reports existing or prior grants from NCI, speaker’s bureau for HMP, and consulting fees from Agenus and Cardinal Health. M.P.H. is a co-holder of a patent that described a method for the detection of methylation-based ctDNA biomarkers of CRC; and is a member of the scientific advisory board for Asima Health, Inc, Vancouver Canada, a company developing a ctDNA-based liquid biopsy test for cancer detection. She has received no royalties or any other funds from either the patent or company, to this date. J.G. serves as an unpaid editorial board member of Translational Gastroenterology and Hepatology from August 2024 to December 2026. Funding for this manuscript was supported by a 2022 ASCO Conquer Cancer Foundation Award awarded to J.G. J.G. has received consulting fees/honoraria from Agenus, AstraZeneca, Bayer, BeiGene/BeOne, Caper Labs, Eisai, Exelixis, Genentech, Incyte, Natera, Seagen, Taiho Pharmaceutical. J.G. has filed a patent (patent No. WO2023/168345 A2) entitled “METHYLATED DNA MARKERS AND ASSAYS THEREOF FOR USE IN DETECTING COLORECTAL CANCER” on 9/7/2023. The other authors have no conflicts of interest to declare.

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