经治疗后血浆中 EBV DNA 靶向测序提高鼻咽癌危险分层。

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

机构信息

Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, New Territories; Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories; Centre for Novostics, Hong Kong Science Park, New Territories; State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories; Department of Otorhinolaryngology, Head and Neck Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories.

出版信息

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

DOI:10.1016/j.annonc.2022.04.068

PMID:35491007

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.

摘要

背景

实时聚合酶链反应（PCR）定量检测初治结束时的血浆 EBV（Epstein-Barr virus）DNA 是鼻咽癌（nasopharyngeal carcinoma，NPC）患者强有力的预后标志物。然而，多达 40%的治疗后血浆 EBV DNA 检测不到的患者后来出现疾病复发。针对整个 EBV 基因组的靶向测序可能会更全面、更公正地检测血浆 EBV DNA，并使其他参数（如片段大小）可用作生物标志物。因此，我们探讨了血浆 EBV DNA 测序是否能更准确地预测 NPC 患者的预后。

患者和方法

对 769 例接受放化疗后 6-8 周的 IIB-IVB 期 NPC 患者的血浆样本进行靶向 EBV DNA 测序分析。

结果

基于 PCR 的分析（检测到任何水平的血浆 EBV DNA）预测局部和远处复发的敏感性分别为 42.3%和 85.3%。基于测序的分析（涉及定量和大小分析）在预测局部和远处复发方面的性能优于 PCR。基于测序推断的血浆 EBV DNA 比例（0.01%）的截断值，基于测序的分析对局部和远处复发的敏感性分别为 88.5%和 97.1%，相应的阴性预测值分别为 99.1%和 99.4%。在定量 PCR 检测到 EBV DNA 不可检测的患者中，测序可以进一步根据血浆 EBV DNA 的比例定义一个亚组，该亚组的生存结果较好，5 年无进展生存率（progression-free survival，PFS）接近 90%。多变量分析显示，基于测序的血浆 EBV DNA 定量水平是预测总生存和 PFS 的独立预后因素，其风险比最高。