Pre-operative lymph node staging in localized esophageal cancer using a high-sensitivity ctDNA assay.
Year: 2026
Type: article
Abstract: e16111 Background: Accurate lymph node (LN) staging remains essential in esophageal cancer (EC) treated with neoadjuvant chemoradiotherapy (CRT) followed by surgery. Circulating tumor DNA (ctDNA) offers a non-invasive measure of tumor burden and may complement imaging-based staging. We evaluated whether an ultrasensitive, tumor-informed ctDNA assay at diagnosis and its dynamics during CRT correlate with clinical and pathological nodal status, and whether ctDNA predicts recurrence-free survival (RFS). Methods: This retrospective analysis includes the first 32 patients from a multicenter prospective observational study (target n = 250). Patients had localized EC (ESCC n = 8; EAC n = 24), received CRT and were staged with PET-CT and, when indicated, laparoscopy. Plasma was collected at baseline, after CRT, and post-operatively. ctDNA was quantified using NeXT Personal, a whole-genome, tumor-informed assay leveraging up to ~1,800 patient-specific variants (limit of detection ~1 PPM). ctDNA dynamics were assessed using the post-CRT/baseline ratio. Associations with clinical staging (cT/cN), pathological outcomes (ypT/ypN), and RFS were evaluated using non-parametric tests and landmark Kaplan–Meier analyses. Results: ctDNA was detectable at diagnosis in all evaluable patients (100% pre-treatment sensitivity). Baseline ctDNA levels were significantly higher in cN-positive vs. cN-negative patients (median 1,580 vs. 58 ppM; p = 0.034). The ctDNA post-CRT/baseline ratio correlated with both pathological tumor stage (ypT; ρ = 0.38, p = 0.046) and pathological nodal stage (ypN; ρ = 0.45, p = 0.015), indicating that limited ctDNA decrease during CRT is associated with persistent nodal disease at surgery. Among ctDNA-negative patients after CRT (n = 18) who proceeded to surgery, only 1 patient harbored ypN+ disease (6%). 6/12 patients with persistently detectable ctDNA after CRT were ypN+ (50%). Notably, ctDNA negativity after CRT and before surgery was significantly prognostic of RFS (HR: 3.9, log-rank P = 0.04), and stratified patients by RFS more effectively compared with pathological complete response (pCR, HR: 2.5, log-rank P = 0.2). Furthermore, persistent ctDNA detection after surgery was also associated with inferior RFS (HR: 10.9, log-rank p≈2.2×10⁻⁶) with a median follow-up of 25.1 months. Conclusions: In this cohort of esophageal cancer patients treated with CRT and surgery, ctDNA PPM quantity at diagnosis correlated with clinical LN involvement and persistent ctDNA after CRT. CRT indicated a high likelihood of residual nodal involvement in the resection specimen. Conversly, ctDNA clearance after CRT was associated with a very low likelihood of ypN-positive disease and a limited residual primary tumor burden, which—if confirmed in larger cohorts—may open opportunities for organ-preserving strategies, addressing a current unmet need in esophageal cancer.
Source: Journal of Clinical Oncology
Authors: Filip Van Herpe, Stijn Vanstraelen, Scott Lemmens, Mieke De Wit, Gabriela Chiritescu, Lieven Depypere, Hans Van Veer, Gertjan Rasschaert, Siddharth Chhajlani, Michiel De Maat, Timon Vandamme, Eduard Callebout, Elke Van Daele, Pieter Vandecandelaere, Yannick Mandeville, Philippe Nafteux, Sabine Tejpar, Jeroen Dekervel
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W7162625726