Commentary: The Emerging Role of Circulating Tumor Cells Beyond Pathological Complete Response in Esophageal Cancer

Abstract

See Article page 71.

Neoadjuvant chemoradiotherapy (nCRT) followed by surgery is the standard of care for locally advanced esophageal cancer (EC). Achieving a pathological complete response (pCR) represents a major prognostic milestone; however, it does not guarantee a cure. Approximately 25% to 33% of patients who achieve pCR still experience disease recurrence, most commonly through distant metastasis [1]. This so-called “pCR paradox” implies that conventional histopathological assessment may fail to detect systemic micrometastases that persist despite effective local tumor control. Although trials such as CheckMate 577 have successfully defined the role of adjuvant therapy for non-pCR patients, individuals with pCR remain in a prognostic “gray zone,” as routine adjuvant therapy is not currently recommended for this group [2]. The study by Hsieh et al. [1] addresses this unmet need by examining whether circulating tumor cells (CTCs) can uncover occult systemic risk in patients who appear “cancer-free” on histological evaluation.

Hsieh et al. [1] evaluated 24 patients with EC who achieved pCR following nCRT and subsequent esophagectomy. Circulating tumor cell counts were assessed in peripheral blood samples obtained immediately prior to surgery. The investigators employed an immunofluorescence-based flow cytometry platform that combined CD45-positive leukocyte depletion with anti-EpCAM labeling, enabling identification of CTCs as a surrogate marker of minimal residual disease (MRD). Notably, despite the absence of viable tumor cells in resected specimens, 75% of patients with pCR exhibited detectable CTCs, with a mean concentration of 5.1 cells/mL. This observation highlights the sensitivity of liquid biopsy approaches in capturing the systemic nature of esophageal malignancy, even in cases where local disease control appears complete.

The primary contribution of this study lies in its re-stratification of risk within the pCR population. Univariable Cox regression analysis identified CTC count as the sole independent predictor of disease-free survival (DFS) (hazard ratio, 1.113; p=0.034). Through time-dependent receiver operating characteristic curve analysis, the authors determined an optimal prognostic cutoff value of 4.5 CTCs per mL, which yielded an area under the curve of 0.72. This level of discrimination reflects moderate to high predictive accuracy and exceeds that of many conventional clinicopathological parameters within this narrowly defined subgroup.

The observed survival differences were clinically substantial. Patients in the low-CTC group (<4.5 cells/mL) demonstrated a 3-year DFS rate of 92.9%, whereas those in the high-CTC group (≥4.5 cells/mL) experienced a marked reduction to 50.0% (p=0.032). Median DFS in the high-risk group was limited to 32.9 months, while it was not reached in the low-risk group. Although the difference in 3-year overall survival between groups (100% vs. 70.0%) did not achieve statistical significance (p=0.235), the direction of the effect suggests a less favorable long-term prognosis among patients with persistent circulating tumor cells. Collectively, these findings support the notion that pCR represents a biologically heterogeneous state and that CTC quantification offers a “molecular lens” for identifying high-risk individuals who may benefit from personalized postoperative management.

From a biological perspective, the detection of CTCs in 75% of patients achieving pCR suggests that nCRT may effectively eradicate the primary tumor mass while failing to eliminate systemic disease. The authors appropriately acknowledge a key limitation of their EpCAM-based detection strategy related to epithelial–mesenchymal transition (EMT). Prior studies have demonstrated that EpCAM expression is dynamic; although primary epithelial tumors often express EpCAM robustly, disseminated tumor cells may downregulate this marker to facilitate migration and invasion [3]. As a result, EpCAM-dependent enrichment approaches may underestimate the true CTC burden. Marker- independent platforms, or strategies incorporating mesenchymal markers, may therefore be required to capture the full spectrum of CTC heterogeneity, particularly given that EMT-associated cells are thought to possess enhanced metastatic potential and therapeutic resistance [4]. Nonetheless, Hsieh et al. [1] demonstrate that, even within these methodological constraints, elevated EpCAM-positive CTC counts remain a strong indicator of systemic disease burden.

An additional limitation of the study is its histological homogeneity, as esophageal squamous cell carcinoma (ESCC) accounted for 95.8% of the study population. Given the distinct molecular and genomic drivers underlying ESCC and esophageal adenocarcinoma (EAC), extrapolation of these findings to EAC should be approached with caution. Prior investigations in EAC have reported substantially lower CTC detection rates when using EpCAM-dependent platforms, such as CellSearch, compared with marker-independent methods, a discrepancy that may reflect greater phenotypic heterogeneity in this subtype [5].

Moreover, the reliance on a single, static post-nCRT CTC measurement represents an important constraint. Such a “snapshot” approach does not adequately reflect the dynamic kinetics of tumor cell dissemination. Future research and clinical practice would benefit from a transition toward longitudinal monitoring strategies. Ko et al. [6] demonstrated that serial CTC assessment, particularly at pre-cycle III of chemotherapy, was independently associated with progression-free survival, and that integrating longitudinal CTC trends with cell-free DNA analysis significantly improved prognostic stratification for overall survival. An optimal risk-assessment framework would incorporate CTC evaluation at multiple clinically relevant time points, including baseline, mid-treatment, and post-nCRT. Assessing patterns such as CTC clearance or temporal trajectories may ultimately prove more informative than reliance on any single measurement [7].

In conclusion, Hsieh et al. [1] present a compelling proof of concept demonstrating that CTC quantification can meaningfully refine prognostic assessment among patients achieving pCR. By moving beyond binary surgical endpoints, this approach aligns with the core principles of precision oncology. Although the current findings represent a significant leap forward in the context of ESCC, validation in more diverse histological cohorts, along with incorporation of dynamic, multi-timepoint monitoring strategies, will be essential to fully optimize post-nCRT management and to ensure that a “complete response” more reliably translates into durable long-term cure.