Circulating Tumor DNA (ctDNA) as a Prognostic Biomarker in Esophageal Cancer

Reviewed by Dr. Reza Lankarani, General SurgeonFounder | Surgical Pioneering Newsletter and Podcast Series Editorial Board Member | Genesis Journal of Surgery and MedicineInternational Journal of Surgery (2025)DOI: 10.1097/JS9.0000000000003017This systematic review and meta-analysis evaluates the prognostic utility of circulating tumor DNA (ctDNA) in patients with esophageal cancer (EC) who have undergone neoadjuvant therapy (NAT) and esophagectomy. The study, published in the International Journal of Surgery, synthesizes findings from ten observational studies and randomized clinical trials to understand if ctDNA detection correlates with patient outcomes like progression-free survival (PFS), overall survival (OS), and pathological complete response (pCR). Key findings indicate that while baseline ctDNA detection isn't a significant predictor, its presence after NAT and surgery strongly predicts worse survival outcomes and lower rates of pCR. The authors emphasize the need for standardized ctDNA detection methods to enhance its clinical applicability for personalized treatment strategies in EC.Main Themes1. Prognostic Significance of ctDNA Post-Neoadjuvant Therapy (NAT) and Post-SurgeryThe most significant finding of this meta-analysis is the strong association between ctDNA detection after NAT and after surgery with poor survival outcomes and lower rates of pathological complete response (pCR).Post-NAT ctDNA Detection:Significantly associated with worse PFS: "ctDNA after completion of NAT was detected in 16/121 (13%) patients and associated with a statistically significant worse PFS (HR 3.81, 95% CI: 2.19-6.64...)" (Results, ctDNA after NAT). This indicates a nearly 4-fold increased risk of progression.Significantly associated with worse OS: "ctDNA was found in 26/133 (20%) patients after NAT and associated with worse OS (HR 3.00, 95% CI: 1.64-5.50...)" (Results, ctDNA after NAT). This suggests a 3-fold increased risk of death.Associated with lower odds of pCR: "estimation showed the presence of ctDNA status after NAT led to a worse pCR outcome (OR = 0.11, 95% CI: 0.04-0.33...)" (Secondary endpoint: Association of ctDNA with pCR). This indicates a significantly lower likelihood of achieving a complete pathological response.Post-Surgery ctDNA Detection:Significantly associated with worse PFS: "ctDNA after completion of NAT and surgery was associated with a statistically significant worse PFS (HR 4.17, 95% CI: 2.17-8.04...)" (Results, ctDNA after Surgery). This reflects over a 4-fold increased risk of progression.Significantly associated with worse OS: "...and OS (HR 4.00, 95% CI: 1.90–8.42)" (Results, ctDNA after Surgery). This shows a 4-fold increased risk of death.Associated with lower odds of pCR: "Results showed the presence of ctDNA status after surgery led to a worse pathological outcome (OR = 0.26; 95% CI: 0.09–0.073...)" (Secondary endpoint: Association of ctDNA with pCR).2. Lack of Prognostic Value for Baseline ctDNAIn contrast to post-treatment detection, the presence of ctDNA at baseline (before NAT) was not found to be a significant predictor of outcomes.No association with PFS or OS at baseline: "Baseline ctDNA detection was not significantly associated with PFS, OS, or pCR (P > 0.05)." Specifically, "Positive results of ctDNA were not associated with a statistically significant worse PFS or OS (P>0.05)." No association with pCR at baseline: "Estimation with the fixed effects model showed no association between ctDNA status at baseline and pCR outcome (OR = 0.94; 95% CI: 0.43–2.06)." (Secondary endpoint: Association of ctDNA with pCR).This contrasts with some other cancer types (e.g., breast cancer) where baseline ctDNA levels correlate with outcomes, suggesting "the unique tumor biology and heterogeneity of EC, suggesting that the therapeutic effect of NAT on esophageal tumors is optimistic and the timing of ctDNA assessment plays a crucial role in its prognostic utility." 3. Clinical Implications and Potential for Personalized TreatmentThe findings underscore ctDNA's potential as a valuable tool for guiding clinical decisions in EC.Risk Stratification: "These findings underscore ctDNA’s potential as a biomarker for risk stratification and personalized treatment planning in EC patients."Intensified Surveillance/Adjuvant Therapy: "Post-treatment ctDNA positivity (detected in 13–20% of patients) should trigger intensified surveillance/adjuvant therapy due to 3- to 4-fold higher progression/death risk."Guiding Treatment Strategies: "From a clinical perspective, the detection of ctDNA after NAT and surgery may provide relevant information for ameliorating treatment strategies." Patients who are ctDNA-positive post-NAT "could be at a higher risk of recurrence and may benefit from additional therapeutic interventions." "The persistence of ctDNA in the postoperative period could indica