Circulating Tumor DNA Assessment to Predict Risk of Recurrence after Surgery in Patients with Locally Advanced Esophageal Squamous Cell Carcinoma
Takei S., Kotani D., Laliotis G., Sato K., Fujiwara N., Kawazoe A., Hashimoto T., Mishima S., Nakayama I., Nakamura Y., Bando H., Kuboki Y., Sakashita S., Spickard E., George GV., Dutta P., Sharma S., Malhotra M., Sethi H., Jurdi A., Liu MC., Yoshino T., Shitara K., Kojima T., Fujita T.
Objective: To investigate the association between perioperative ctDNA status and prognosis in patients with esophageal squamous cell carcinoma (ESCC). Background: Circulating tumor DNA (ctDNA) has emerged as a promising biomarker for assessing molecular residual disease (MRD) in various malignancies. However, there are limited studies evaluating the utility of ctDNA for predicting recurrence risk in patients with ESCC. Methods: We prospectively enrolled patients with locally advanced ESCC who were scheduled to receive neoadjuvant chemotherapy (NAC) followed by surgery. This report retrospectively analyzed ctDNA with a personalized, tumor-informed 16-plex mPCR-NGS assay at multiple time points: pre-NAC, post-NAC but before surgery, postoperatively, and longitudinally during follow-up. Results: A total of 28 patients who underwent curative surgery, and had successful whole-exome sequencing analysis of tumor tissue samples were included in this report. At the pre-NAC time point, ctDNA was detected in 50% of patients with stage I and 100% of those with stages II, III, and IV. Post-NAC but before surgery, ctDNA was detected in 33.3% of patients. The recurrence rate was 77.8% in ctDNA-positive patients compared to 27.8% in ctDNA-negative patients, with significantly worse recurrence-free survival (RFS) for ctDNA-positive patients vs. ctDNA-negative patients (HR: 4.56, P=0.01). In patients analyzed during the MRD window (2-16 weeks post-surgery), the recurrence rate was 100% in ctDNA-positive patients compared to 30.4% in ctDNA-negative patients, with significantly worse RFS (HR: 30.99, P<0.0001). Similarly, during surveillance (>16 weeks post-surgery), detectable ctDNA was significantly associated with poor RFS (HR: 27.34, P=0.003). Conclusion: This study suggests that ctDNA-based MRD assessment may be valuable for evaluating patients with ESCC, particularly in post-NAC and postsurgical settings.