The Prognostic Value of Circulating Tumor DNA during Post-Radiotherapy Surveillance in Esophageal Squamous Cell Carcinoma

Abstract

<h3>Purpose/Objective(s)</h3> Esophageal squamous cell carcinoma (ESCC) is a common form of esophageal carcinoma in East Asian countries, while there is an unmet need for reliable biomarkers aiding in early detection of relapse/metastasis and prognosis stratification. Here, we investigated whether circulating tumor DNA (ctDNA) tests could detect relapse/metastasis prior to radiological imaging, and explored the prognostic value of ctDNA monitoring after radiotherapy/chemoradiotherapy (RT/CRT) in ESCC. <h3>Materials/Methods</h3> 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 (37.8–50.4Gy to subclinical areas at risk and 44.94–59.92 Gy to the gross tumor and involved lymph nodes). Serial plasma samples were collected at baseline (T₀) and four landmark time-points: week 4 of RT/CRT (T₁), 1–3 months post RT/CRT (T₂), 3–6 months post RT/CRT (T₃), and at least 12 months post RT/CRT (T₄). ctDNA was analyzed using next-generation sequencing of 474 cancer-relevant genes. Kaplan-Meier curves were generated for progression-free survival (PFS), overall survival (OS), locoregional recurrence-free survival (LRFS), as well as distant metastasis-free survival (DMFS), and Cox proportional hazards models were fitted to estimate hazard ratios (HR) with 95% confidence intervals (CI). <h3>Results</h3> A total of 139 plasma samples from 40 eligible patients were analyzed (median age: 64 [range: 40–78], 88% males, 95% stage III/IV, 70% baseline ctDNA shedding), and the median follow-up time was 20.6 months (range: 12.2–33.3). Radiological progression was observed in 17 patients, of whom 13 (77%) had detectable post-RT/CRT ctDNA with a mean lead time of 5.5 months compared to radiological imaging. ctDNA positivity at T₁ or T₂ was associated with inferior PFS (T₁, HR: 3.60, 95% CI: 1.30–10.01; T₂, HR: 5.45, 95% CI: 1.72–17.26) and OS (T₁, HR: 2.70, 95% CI: 0.99–7.36; T₂, HR: 4.02, 95% CI: 1.27–12.75). Patients achieving ctDNA clearance between T₀ and T₁/T₂ had superior PFS compared to those with failure to clear ctDNA (T₁, HR: 0.31, 95% CI: 0.08–1.13; T₂, HR: 0.11; 95% CI: 0.02–0.61). Furthermore, ctDNA positivity at T₁ was identified as a potential indicator of worse LRFS (HR: 4.43, 95% CI: 1.31–15.04), while it was less profoundly associated with DMFS. <h3>Conclusion</h3> 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 in guiding post-RT/CRT treatments for locoregional control.