Development and validation of a risk model integrating plasma Epstein-Barr virus DNA (EBV DNA) level and TNM stage for stratification of nasopharyngeal cancer (NPC) to adjuvant therapy

Abstract

Abstract Background Clinical guidelines for treatment decision in NPC are mainly based on the anatomical classification by UICC TNM staging. The concentration of plasma EBV DNA measured after radiotherapy (RT) or chemoradiation (CRT) is highly prognostic and independent of UICC stage, which may be useful in risk stratification of NPC patients to adjuvant therapy. Methods For model development, we used the prospective multi-center 0502 EBV DNA screening cohort (recruitment period 2006 - 2015; n\u2009=\u2009745). Eligible patients had histologically confirmed NPC of stage II-IVB (UICC 7th Edition) and post-RT EBV DNA measured in plasma, no loco-regional disease or distant metastasis after RT/CRT and received no adjuvant therapy. Primary endpoint was overall survival (OS). We used recursive-partitioning analysis (RPA) to classify patients into groups of low-, intermediate- and high-risk of death. For internal validation, we pooled independent patient cohorts from previous published biomarker studies (1997-2006; n\u2009=\u2009340). For external validation, we used external cohort of NPC patients treated at Sun Yat-sen University Cancer Center (2009 - 2012; n\u2009=\u2009837) using SYSU EBV DNA test. Results RPA classified NPC patients based on the post-RT plasma EBV DNA level and UICC stage into three distinct prognostic groups (Table). RPA low risk group shared similar 5-yr OS (89.4%; 95% CI\u2009=\u200986.4-92.5%) as UICC stage II (88.5%; 84.0-93.1%) but included 2.3x number of patients that could be potentially spared of adjuvant therapy toxicity. The overall C-index of OS was 0.7118 for RPA risk group, compared to 0.6042 for TNM stage and 0.6747 for EBV DNA (both p\u2009 Table . 287O Patient No. (%) 5-yr OS HR (95% C.I.) P UICC TNM stage (7th Ed) 1) Stage II 209 (28.1) 88.5 - 2) Stage III 368 (49.4) 81.0 1.50 (0.99-2.25) 0.054 3) Stage IVAB 168 (22.6) 69.4 3.01 (1.97-4.59) Post-RT plasma EBV DNA (copies/ml) 1) 0 573 (76.9) 87.3 - 2) 1-49 74 (9.9) 83.2 1.32 (0.76-2.27) 0.3259 3) 50-499 59 (7.9) 50.5 3.85 (2.55-5.81) 4)\u2009>\u2009=500 39 (5.2) 28.3 11.59 (7.60-17.67) RPA risk group 1) Low risk EBV DNA 0 and stage II/III 1-49 and stage II 483 (64.8) 89.4 - 2) Intermediate risk EBV DNA 0 and stage IVAB 1-49 and stage III/IVAB 50-499 and stage II 176 (23.6) 78.5 2.40 (1.65-3.50) 3) High risk EBV DNA 50-499 and stage III/IVAB >500 and any stage 86 (11.5) 37.2 8.54 (5.93-12.29) Conclusions Incorporation of post-RT plasma EBV DNA level into UICC TNM stage improved risk stratification of NPC patients to adjuvant therapy. Clinical trial identification Identifier: NCT00370890. Legal entity responsible for the study Comprehensive Cancer Trials Unit, Department of Clinical Oncology, The Chinese University of Hong Kong. Funding Has not received any funding. Disclosure E.P. Hui: Advisory / Consultancy, Research grant / Funding (institution): Merck Sharp & Dohme; Speaker Bureau / Expert testimony: Merck Serono; Research grant / Funding (institution): Pfizer. W.K.J. Lam: Shareholder / Stockholder / Stock options: Grail. K.C.A. Chan: Advisory / Consultancy, Shareholder / Stockholder / Stock options: Grail; Leadership role, Shareholder / Stockholder / Stock options: Take2; Leadership role, Shareholder / Stockholder / Stock options: DRA. Y.M.D. Lo: Advisory / Consultancy, Leadership role, Shareholder / Stockholder / Stock options: Grail; Leadership role, Shareholder / Stockholder / Stock options: Take2 Health; Leadership role, Shareholder / Stockholder / Stock options: DRA. A.T.C. Chan: Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Merck Sharp & Dohme. All other authors have declared no conflicts of interest.