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. 2022 Aug;33(8):794-803.
doi: 10.1016/j.annonc.2022.04.068. Epub 2022 Apr 29.

Improved risk stratification of nasopharyngeal cancer by targeted sequencing of Epstein-Barr virus DNA in post-treatment plasma

D C T Chan  1 , W K J Lam  2 , E P Hui  3 , B B Y Ma  3 , C M L Chan  1 , V C T Lee  1 , S H Cheng  1 , W Gai  1 , P Jiang  4 , K C W Wong  3 , F Mo  3 , B Zee  5 , A D King  6 , Q T Le  7 , A T C Chan  3 , K C A Chan  4 , Y M D Lo  8
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Free article

Improved risk stratification of nasopharyngeal cancer by targeted sequencing of Epstein-Barr virus DNA in post-treatment plasma

D C T Chan et al. Ann Oncol. 2022 Aug.
Free article

Abstract

Background: Quantitative measurement of plasma Epstein-Barr virus (EBV) DNA by real-time PCR at the end of primary treatment is a robust prognostic marker for nasopharyngeal carcinoma (NPC) patients. However, up to 40% of patients who would later develop disease recurrence had undetectable post-treatment plasma EBV DNA. Targeted sequencing for the entire EBV genome potentially allows a more comprehensive and unbiased detection of plasma EBV DNA and enables the use of other parameters such as fragment size as biomarkers. Hence, we explored if plasma EBV DNA sequencing might allow more accurate prognostication of NPC patients.

Patients and methods: Plasma samples collected from 769 patients with stage IIB-IVB NPC at 6-8 weeks after radiotherapy were analysed using targeted sequencing for EBV DNA.

Results: The sensitivities of the PCR-based analysis, at a cut-off of any detectable levels of plasma EBV DNA, for prediction of local and distant recurrences were 42.3% and 85.3%, respectively. The sequencing-based analysis (involving quantitation and size profiling) achieved better performance for both local and distant recurrences than PCR. Using a cut-off of the proportion of plasma EBV DNA deduced by sequencing at 0.01%, the sensitivities of the sequencing-based analysis for local and distant recurrences were 88.5% and 97.1%, with the resultant negative predictive values of 99.1% and 99.4%, respectively. Among patients with undetectable EBV DNA on quantitative PCR, sequencing could further define a subgroup that enjoyed superior survival outcomes based on the proportion of plasma EBV DNA, with a 5-year progression-free survival (PFS) approaching 90%. On multivariate analysis, sequencing-based quantitative level of plasma EBV DNA was the independent prognostic factor with the highest hazard ratio for prediction of overall survival and PFS.

Conclusion: NPC prognostication using post-treatment plasma EBV DNA could be enhanced through sequencing.

Keywords: cancer surveillance; circulating tumour DNA; liquid biopsy; personalised medicine; precision oncology.

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Conflict of interest statement

Disclosure KCAC and YMDL hold equities in DRA, Take2 and Grail/Illumina; were consultants to Grail and previously received research funding from Grail. YMDL is a scientific cofounder of Grail. WKJL holds equities in Grail/Illumina. PJ holds equities in DRA and Grail/Illumina; is a consultant to Take2; is a Director of KingMed Future. DCTC, WKJL, KCAC and YMDL have filed patent applications based on the data generated from this work. EPH receives speaker’s honoraria from Merck Sharp & Dohme (MSD) and Merck Serono and serves as a consultant or in the advisory board from MSD. BBYM serves in the advisory board and receives speaker’s honorarium from Novartis, Bristol-Myers Squibb and MSD and receives research grant from Novartis and is a consultant to Viracta Therapeutics and Y-Biologics. ATCC receives research funding from Merck Serono, MSD, Novartis, Pfizer and Eli Lily, speaker's honorarium from Beigene, Springer and Pfizer, travel funding from BMS, MSD, Pfizer, Roche, Novartis and AstraZeneca, and is an advisory board member for MSD, Tessa Therapeutics. BZ is the founder and shareholder of Health View Bioanalytic Limited. QTL is a consultant to MSD and serves in the advisory boards of Nanobiotics, Roche and Coherus. Patent royalties are received from Grail, Illumina, Sequenom, DRA, Take2 and Xcelom. All other authors have declared no conflicts of interest.

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