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

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          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.

          Abstract

          Liquid biopsies are emerging as a useful method for diagnosis and prognosis in cancer. Here, the authors show the prognostic value of monitoring the level of circulating Epstein-barr virus DNA throughout induction chemotherapy and chemo-radiotherapy and its potential utility for risk-adapted individualised therapy in nasopharyngeal carcinomapatients.

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          Most cited references 21

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          Plasma Epstein-Barr virus DNA and residual disease after radiotherapy for undifferentiated nasopharyngeal carcinoma.

          Epstein-Barr virus (EBV) DNA can be detected and quantified in the plasma of patients with EBV-related tumors, such as nasopharyngeal carcinoma (NPC). Although NPC at early stages can be cured by radical radiotherapy, there is a high recurrence rate in patients with advanced NPC. The pretreatment level of circulating EBV DNA is a prognostic factor for NPC, but the prognostic value of post-treatment EBV DNA has not been studied. We designed a prospective study in Hong Kong, China, to investigate the value of plasma EBV DNA as a prognostic factor for NPC. One hundred seventy NPC patients, without metastatic disease at presentation, were treated with a uniform radiotherapy protocol. Circulating EBV DNA was measured by real-time quantitative polymerase chain reaction before treatment and 6-8 weeks after radiotherapy was completed. Risk ratios (RRs) were determined with a Cox regression model, and associations of various factors with progression-free and overall survival and recurrence rates were determined with a stepwise Cox proportional hazards model. All statistical tests were two-sided. Ninety-nine percent of patients achieved complete clinical remission. Levels of post-treatment EBV DNA dominated the effect of levels of pretreatment EBV DNA for progression-free survival. The RR for NPC recurrence was 11.9 (95% confidence interval [CI] = 5.53 to 25.43) for patients with higher post-treatment EBV DNA and 2.5 (95% CI = 1.14 to 5.70) for patients with higher pretreatment EBV DNA. Higher levels of post-treatment EBV DNA were statistically significantly associated with overall survival (P<.001; RR for NPC recurrence = 8.6, 95% CI = 3.69 to 19.97). The positive and negative predictive values for NPC recurrence for a higher level of post-treatment EBV DNA were 87% (95% CI = 58% to 98%) and 83% (95% CI = 76% to 89%), respectively. Levels of post-treatment plasma EBV DNA in patients with NPC appear to strongly predict progression-free and overall survival and to accurately reflect the post-treatment residual tumor load.
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            Survival probabilities (the Kaplan-Meier method).

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              Establishment and Validation of Prognostic Nomograms for Endemic Nasopharyngeal Carcinoma

              This study aimed to establish an effective prognostic nomogram with or without plasma Epstein-Barr virus DNA (EBV DNA) for nondisseminated nasopharyngeal carcinoma (NPC).
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                Author and article information

                Contributors
                melvin.chua.l.k@singhealth.com.sg
                sunying@sysucc.org.cn
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                2 September 2019
                2 September 2019
                2019
                : 10
                Affiliations
                [1 ]Department of Radiation Oncology, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, People’s Republic of China
                [2 ]ISNI 0000 0004 0385 0924, GRID grid.428397.3, Division of Radiation Oncology, National Cancer Centre Singapore; Division of Medical Sciences, National Cancer Centre Singapore, , Duke-NUS Medical School, ; 11 Hospital Drive, Singapore, 169857 Singapore
                Article
                11853
                10.1038/s41467-019-11853-y
                6718666
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);
                Award ID: 81802707
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100001349, MOH | National Medical Research Council (NMRC);
                Award ID: Clinician-Scientist Award - #NMRC/CSA/0027/2018
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100001381, National Research Foundation Singapore (National Research Foundation-Prime Minister's office, Republic of Singapore);
                Award ID: NRF-CRP17-2017-05)
                Award Recipient :
                Funded by: the Pearl River Scholar Funded Scheme, the Special Support Program of Sun Yat-sen University Cancer Center (16zxtzlc06), the Health & Medical Collaborative Innovation Project of Guangzhou City, China (201604020003), the Natural Science Foundation of Guang Dong Province (No. 2017A030312003), Health & Medical Collaborative Innovation Project of Guangzhou City, China (201803040003), the Innovation Team Development Plan of the Ministry of Education (No. IRT_17R110), the Overseas Expertise Introduction Project for Discipline Innovation (111 Project, B14035), the Duke-NUS Oncology Academic Program Proton Research Program.
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                © The Author(s) 2019

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                head and neck cancer, tumour biomarkers

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