Perioperative circulating tumor DNA profiling for recurrence risk in esophageal squamous cell carcinoma: moving toward a biology-driven surveillance model

Introduction

Esophageal squamous cell carcinoma (ESCC) remains a significant global health burden, particularly in East Asia, where its incidence and mortality are disproportionately high. Despite advancements in multimodality therapy, including neoadjuvant chemotherapy (NAC), chemoradiation, and minimally invasive surgical approaches, nearly half of patients experience relapse after curative-intent resection, revealing the limitations of pathologic staging and tumor regression grade (TRG) as predictors of recurrence (1,2). Traditionally, postoperative surveillance relies on cross-sectional imaging and endoscopic evaluations, which often detect relapse only after macroscopic disease becomes apparent, limiting opportunities for early intervention (3).In this context, circulating tumor DNA (ctDNA) has emerged as a highly sensitive, real-time biomarker capable of identifying molecular residual disease (MRD) and forecasting relapse far earlier than radiologic surveillance (4). The prospective observational study by Takei et al. offers timely and valuable insights into how personalized, tumor-informed ctDNA assessment may refine perioperative decision-making, improve recurrence risk stratification, and potentially reshape management strategies for locally advanced ESCC (5).

ctDNA dynamics after NAC and surgery: identifying high-risk patients early

Takei et al. analyzed serial ctDNA profiles from 28 patients treated with NAC followed by surgery, collecting plasma samples before NAC, after NAC, during the postoperative MRD window, and throughout long-term surveillance. This systematic sampling strategy allowed the investigators to assess how ctDNA fluctuations reflect treatment response and recurrence risk across the entire perioperative continuum (5). Unlike conventional radiologic or pathologic markers, ctDNA provides a dynamic readout of tumor burden, with the added advantage of detecting microscopic disease that may not be visible on imaging.

Post-NAC ctDNA positivity strongly predicted recurrence

One of the study’s most clinically meaningful observations was the strong prognostic value of post-NAC ctDNA status. Among patients with evaluable post-NAC samples, 77.8% of those who remained ctDNA-positive experienced recurrence, compared with only 27.8% of patients who achieved ctDNA clearance. The hazard ratio for recurrence-free survival was 4.56 (P=0.01), and post-NAC ctDNA status emerged as the most significant prognostic factor on multivariate analysis (5). These findings indicate that persistent ctDNA after NAC likely reflects biologically active micrometastatic disease that is not adequately detected by conventional imaging or histopathologic response assessment.

Importantly, post-NAC ctDNA positivity represents a critical inflection point in the perioperative treatment course. Patients with detectable ctDNA following systemic therapy may benefit from treatment augmentation, alternative sequencing strategies, or early consideration of consolidation approaches prior to surgery (6). Such risk-adapted decision-making aligns with evolving paradigms from NAC-focused trials such as Japan Clinical Oncology Group (JCOG) 1109, which emphasize the heterogeneity of treatment response and the need for individualized therapeutic strategies rather than uniform surgical management (7).

In addition, post-NAC ctDNA assessment offers a translational opportunity to evaluate the biological effectiveness of NAC regimens themselves. Persistent ctDNA despite cytoreduction may prompt reconsideration of chemotherapy backbones and support the integration of immunotherapy-based strategies, particularly in light of emerging evidence for perioperative checkpoint blockade in upper gastrointestinal malignancies (8).

Postoperative MRD positivity identifies patients with near-certain relapse

The postoperative MRD window (2–16 weeks after surgery) yielded the most striking prognostic separation. Every patient with detectable ctDNA during this period ultimately experienced recurrence, corresponding to an exceptionally high hazard ratio of 30.99 (P<0.0001) (5). This magnitude of risk far exceeds that conferred by traditional pathologic features, suggesting that postoperative ctDNA is an extremely powerful surrogate for persistent microscopic disease.

Comparable findings have been reported in colorectal (9), urothelial (10), and breast cancers (11), where early postoperative ctDNA positivity consistently identifies patients at the highest risk of relapse even when imaging remains negative. These cross-cancer parallels reinforce the biological principle that MRD detection corresponds to the presence of residual, proliferative tumor clones that will eventually manifest clinically unless intervened upon.

Thus, postoperative ctDNA stands out as a decisive marker to guide adjuvant therapy decisions in ESCC. Patients with detectable ctDNA after surgery may benefit from intensified systemic therapy or early enrollment in MRD-directed clinical trials (12). Conversely, sustained ctDNA negativity could identify patients who can safely avoid overtreatment, an important consideration in a disease where therapeutic morbidity remains substantial (13,14).

Surveillance ctDNA detects recurrence months before imaging

During long-term surveillance, ctDNA positivity predicted recurrence in 85.7% of patients and carried a hazard ratio of 27.34 (P=0.003) (5). Crucially, ctDNA detection preceded radiographic relapse by a median of 7.66 months, providing a substantial lead time. This early warning signal creates an actionable window in which clinicians can intensify monitoring or initiate pre-emptive systemic therapy.

Early molecular relapse detection is particularly valuable in ESCC, where metastatic spread often occurs rapidly, and symptoms may present late (15). A ctDNA-guided surveillance model may enable earlier identification of oligometastatic disease, allow for more effective salvage treatments, and potentially improve survival outcomes.

ctDNA provides biological information beyond TRG and pathologic complete response (pCR)

Although TRG and pCR remain widely used markers of NAC response, their prognostic accuracy is limited. In Takei et al., TRG1 patients were frequently ctDNA-positive (73%), demonstrating that histologic downstaging does not necessarily correlate with elimination of systemic disease (5). Moreover, ctDNA-negative patients had favorable outcomes even in the absence of pCR, highlighting that ctDNA captures biological tumor behavior not reflected by static histopathology.

These observations reaffirm the growing consensus that ctDNA offers a more granular and biologically meaningful assessment of response than morphologic or pathologic surrogates alone.

Translational implications and future directions

The study contributes to a rapidly expanding framework in which ctDNA functions as a versatile biomarker across the perioperative continuum, guiding treatment response, postoperative MRD status, and long-term surveillance strategies (5). Post-NAC ctDNA dynamics may help clinicians identify patients who are unlikely to benefit from standard chemotherapy regimens and who may require earlier escalation or modification of systemic therapy. Similarly, the detection of postoperative MRD offers a biologically precise means of identifying individuals at highest risk for relapse, potentially guiding the use of adjuvant immunotherapies or rational combination approaches that target micrometastatic disease more effectively. Beyond the perioperative setting, integrating ctDNA into surveillance paradigms provides a reliable tool capable of signaling relapse months before radiographic evidence emerges, creating opportunities for timely salvage interventions and personalized follow-up strategies. Despite these promising implications, the study’s modest sample size, retrospective ctDNA processing, and single-center design underscore the need for larger multicenter prospective studies (2,16). Future research may draw from frameworks such as the CIRCULATE-Japan initiative in colorectal cancer, which employs ctDNA-guided risk stratification and MRD-directed therapeutic strategies, offering a potential blueprint for similar precision-based approaches in ESCC.

Conclusions

Takei et al. provide compelling evidence that personalized ctDNA-based MRD monitoring can enhance biological risk stratification in locally advanced ESCC. Their findings support a shift toward perioperative management guided not only by imaging and pathology but also by dynamic molecular signals that reflect true residual disease. As ctDNA-guided frameworks evolve, MRD detection may ultimately become integral to individualized treatment strategies, adjuvant therapy selection, and surveillance paradigms in ESCC.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Translational Medicine. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-2025-1-181/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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