Prognostic value of circulating tumour DNA during post‐radiotherapy surveillance in locally advanced esophageal squamous cell carcinoma

BACKGROUND: The potential of circulating tumour DNA (ctDNA) as a reliable biomarker for relapse/metastasis early detection and prognosis in esophageal squamous cell carcinoma (ESCC) after radiotherapy/chemoradiotherapy (RT/CRT) initiation requires comprehensive investigation. METHODS: Treatment‐naive locally advanced ESCC patients with available baseline plasma samples were prospectively enrolled from November 2018 to January 2020. RT/CRT was delivered with a simultaneous integrated boost of radiation dose. Serial plasma samples were collected at baseline (T(0)), week 4 of RT/CRT (T(1)), 1‐3 (T(2)) and 3‐6 months post‐RT/CRT (T(3)). ctDNA was analysed using next‐generation sequencing of 474 cancer‐relevant genes. RESULTS: A total of 128 plasma samples from 40 eligible patients were analysed (median age: 64 [range: 40‐78], 88% males, 95% stage III/IV), and the median follow‐up time was 20.6 months (range: 12.2‐33.3). During the post‐RT/CRT surveillance including 36 patients, radiological progression was observed in 16 patients, and 69% (11/16) had detectable post‐RT/CRT ctDNA prior to radiological progression, with a median lead time of 4.4 months compared with radiological imaging. ctDNA positivity at T(1) (hazard ratio, HR: 3.60, 95% confidence interval, CI: 1.30‐10.01) or T(2) (HR: 5.45, 95% CI: 1.72‐17.26) indicated inferior progression‐free survival (PFS). ctDNA clearance between T(0)‐T(1) (HR: 0.31, 95% CI: 0.08‐1.13) or T(0)‐T(2) (HR: 0.11; 95% CI: 0.02‐0.61) was associated with relatively favourable PFS. Similar results were obtained when focusing on patients without esophagectomy after RT/CRT. Notably, detectable ctDNA at T(1) was a potential indicator of high local recurrence risks (HR: 4.43, 95% CI: 1.31‐15.04). CONCLUSIONS: ctDNA was identified as a robust biomarker for early detection of disease progression and post‐RT/CRT prognosis stratification in ESCC. Detectable ctDNA at week 4 of RT/CRT might indicate higher local recurrence risks, implying the potential clinical utility of ctDNA tests in guiding post‐RT/CRT treatments for locoregional control in ESCC.