Longitudinal assessment of plasma EBV-DNA in non-endemic EBV-related nasopharyngeal cancer (NPC): the LEA study

Background: Plasma Epstein Barr Virus (EBV)-DNA is an established biomarker for endemic EBV-related nasopharyngeal carcinoma (NPC). Its relevance in non-endemic regions is less understood. This study longitudinally assessed plasma EBV-DNA (LEA study) throughout the curative management of non-endemic EBV-related NPC to evaluate its prognostic value. Materials and methods: Between 2012 and 2023, patients with non-endemic, non-metastatic, histologically confirmed EBER+ NPC treated at a tertiary center were retrospectively analyzed. Plasma EBV-DNA levels were measured at pre-treatment (T1), early (T2a, ≤6 weeks) and late (T2b, ≤14 weeks) post-treatment, during follow-up (T3), and after induction chemotherapy (T4), when applicable. EBV-DNA was analyzed for its association with recurrence-free survival (RFS). Results: At a median follow-up of 60 months (range: 9–134), 167 patients were included. Median age was 50 years (range: 22–75), with 72 % male; 84 % had stage III-IV disease (TNM VIII Edition). Pre-treatment EBV-DNA was detected in 96 % of patients, with no predictive cut-off (median RFS: 43 vs. 62 months for detectable vs. undetectable EBV-DNA). Post-treatment undetectable EBV-DNA correlated with better RFS, also with no cut-off. Follow-up EBV-DNA anticipated recurrence in 71 % of cases by a median of 38 days (range: 11–365). Persistently negative follow-up EBV-DNA was observed in 91 % of non-recurrent patients; isolated positive spikes lacked prognostic significance. Post-induction chemotherapy EBV-DNA demonstrated a 92 % negative predictive value for recurrence. Conclusions: Plasma EBV-DNA is a valuable prognostic biomarker for non-endemic NPC. Pre- and post-treatment undetectable EBV-DNA holds a positive prognostic value. Post-induction EBV-DNA is the most informative timepoint. Longitudinal EBV-DNA monitoring is warranted in clinical practice.