Longitudinal circulating Epstein–Barr virus DNA response to induction chemotherapy and chemo-radiotherapy to identify biological phenotypes in EBV-associated nasopharynx of head and neck cancer.

Abstract

6021 Background: Liquid biopsies have the utility for detecting minimal residual disease in several cancers, but its clinical utility for real-time treatment adaptation remains limited. We adopted Epstein-barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) as a model to investigate its potential. We characterize longitudinal response of circulating EBV DNA to induction chemotherapy (IC) and concurrent chemoradiotherapy (CCRT) in locally advanced NPC (LA-NPC), and investigate the association of complete biological response (cBR, undetectable cfEBV DNA) during treatment to prognoses. Methods: The medical records of 673 LA-NPC cases with serial EBV DNA measurements (pre-treatment, after each IC cycle, post-CCRT) were extracted. Cox regression and landmark analysis were used for survival analyses. Results: Four distinct phenotypes were identified based on their longitudinal cfEBV DNA response: 1) Early responders (200/673[29.7%]) achieved cBR post-IC1; 2) Intermediate responders (332/673[49.3%]) included patients with cBR post-IC2-4, and cBR post-CCRT after two IC cycles or following a temporary bounce (detectable reading following initial cBR); 3) Late responders (75/673[11.2%]) achieved cBR only post-CCRT after 3-4 IC cycles; 4) Treatment-resistant (66/673[9.8%]) patients demonstrated non-cBR post-IC+CCRT. These phenotypes were significantly correlated with prognoses, adjusted for pre-treatment EBV DNA load, N-category and chemotherapy intensity (AHRDFS = 3.46[2.01–6.25], intermediate; 7.50[4.24–14.77], late; 17.33[10.06–33.38], treatment-resistant vs. early responders, Pall < 0.01). Interestingly, intermediate and late responders without cBR post-IC2 had inferior survival despite more IC (HRDFS = 1.83[1.17–2.84], > 2 vs. >2 IC cycles, P < 0.01). For treatment-resistant patients, adjuvant chemotherapy following IC+CCRT reduced risk of distant metastasis (HRDMFS = 0.42[0.24–0.74], P < 0.01). Conclusions: We propose investigate risk-adapted chemotherapy de-intensification and intensification strategies based on the four novel phenotypes, which could shape the individualized treatment of LA-NPC. Our study highlights the feasibility of liquid biopsy for real-time therapeutic adaptation.