Liquid biopsy tracking during sequential chemo-radiotherapy identifies distinct prognostic phenotypes in nasopharyngeal carcinoma

Abstract

Liquid biopsies have the utility for detecting minimal residual disease in several cancer types. Here, we investigate if liquid biopsy tracking on-treatment informs on tumour phenotypes by longitudinally quantifying circulating Epstein-barr virus (EBV) DNA copy number in 673 nasopharyngeal carcinoma patients undergoing radical induction chemotherapy (IC) and chemo-radiotherapy (CRT). We observe significant inter-patient heterogeneity in viral copy number clearance that is classifiable into eight distinct patterns based on clearance kinetics and bounce occurrence, including a substantial proportion of complete responders (≈30%) to only one IC cycle. Using a supervised statistical clustering of disease relapse risks, we further bin these eight subgroups into four prognostic phenotypes (early responders, intermediate responders, late responders, and treatment resistant) that are correlated with efficacy of chemotherapy intensity. Taken together, we show that real-time monitoring of liquid biopsy response adds prognostic information, and has the potential utility for risk-adapted treatment de-intensification/intensification in nasopharyngeal carcinoma.

Long-Term Monitoring of Dynamic Changes in Plasma EBV DNA For Improved Prognosis Prediction of Nasopharyngeal Carcinoma

“…Based on this dynamic change, we divided 252 patients into 5 subgroups/patterns and performed survival analysis. This was different from the previous reports [20][21][22][23][24][25][26], which mainly focused on the following time points primarily from pre-treatment to 3 months post-treatment.…”

“…Many studies have reported that plasma EBV DNA loads and its dynamic changes could be used as a predictive marker for NPC prognosis at limited time points [20][21][22][23][24][25][26], such as pre-treatment and 3 months post-treatment, however, the prognostic value and dynamic changes of plasma EBV DNA at other time points, such as more than 3 months post-treatment, are not be fully understood yet. Notably, in this study, we enrolled 252 NPC patients who received plasma EBV DNA tests at 4 time points (pre-treatment, 3, 12, and 24 months post-treatment).…”

“…In addition, dynamic changes of plasma EBV DNA pre-and post-treatment may also be useful for prognosis prediction and treatment evaluation. Recently, several studies have reported the potential prognostic value of dynamic changes in plasma EBV DNA in NPC patients at different time points, including during treatment [20,21], pre-and early post-treatment [22,23], and within 3 months posttreatment [24][25][26]. However, long-term monitoring of dynamic changes in plasma EBV DNA after 3 months post-treatment might also provide prognostic value.…”

Diagnostic and prognostic performance of circulating levels of the Epstein-Barr virus microRNAs BART 7-3p and BART 13-3p in nasopharyngeal carcinoma

“…In the present work, pre-treatment plasma levels of miR-BART7-3p were a prognostic marker for NPC, with high expression indicating higher risk of distant metastasis. In contrast, detectable posttreatment miR-BART7-3p levels were a poor predictor of DMFS and OS, as confirmed in multivariate analysis (14)(15)(16)(17)(18). 28.6% (70/245) of patients was still detectable EBV DNA at post-treatment, which…”

“…One study suggested that plasma EBV DNA is useful for screening for early asymptomatic NPC, with 97.1% sensitivity and 98.6% specificity (13). EBV DNA level is also a strong predictor of NPC poor outcomes, especially high-risk of distant metastasis (14)(15)(16)(17)(18). However, current methods for assaying plasma levels of EBV DNA show high variability (19)(20)(21)(22)(23).…”