• Jiawei Lv, Chenfei Wu, Junyan Li, Foping Chen, Shiwei He, Qingmei He, Guanqun Zhou, Jun Ma, Ying Sun, Denghui Wei, and Li Lin.
• Department of Radiation Oncology, Sun Yat-sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Center for Precision Medicine of Sun Yat-sen University, Guangzhou, 510060, People's Republic of China. lvjw@sysucc.org.cn.
• Bmc Med. 2022 Aug 23; 20 (1): 268.

BackgroundSignificant intertumoral heterogeneity exists as antitumor treatment is introduced. Heterogeneous therapeutic responses are conventionally evaluated by imaging examinations based on Response Evaluation Criteria in Solid Tumors (RECIST); nevertheless, there are increasing recognitions that they do not fully capture patient clinical benefits. Currently, there is a paucity of data regarding the clinical implication of biological responses assessed by liquid biopsy of on-treatment circulating tumor DNA (ctDNA). Here, we investigated whether biological response evaluated by ctDNA kinetics added critical information to the RECIST, and whether integrating on-treatment biological response information refined risk stratification of cancer patients.MethodsIn this population-based cohort study, we included 821 patients with Epstein-Barr virus (EBV)-associated nasopharynx of head and neck cancer (NPC) receiving sequential neoadjuvant chemotherapy (NAC) and chemoradiotherapy (CRT), who had pretreatment and on-treatment cfEBV DNA and magnetic resonance imaging (MRI) surveillance. Biological responses evaluated by cfEBV DNA were profiled and compared with conventional MRI-based RECIST evaluation. The inverse probability weighting (IPW)-adjusted survival analysis was performed for major survival endpoints. The Cox proportional hazard regression [CpH]-based model was developed to predict the on-treatment ctDNA-based individualized survival.ResultsOf 821 patients, 71.4% achieved complete biological response (cBR) upon NAC completion. RECIST-based response evaluations had 25.3% discordance with ctDNA-based evaluations. IPW-adjusted survival analysis revealed that cfEBV DNApost-NAC was a preferential prognosticator for all endpoints, especially for distant metastasis. In contrast, radiological response was more preferentially associated with locoregional recurrence. Intriguingly, cfEBV DNApost-NAC further stratified RECIST-responsive and non-responsive patients; RECIST-based non-responsive patients with cBR still derived substantial clinical benefits. Moreover, detectable cfEBV DNApost-NAC had 83.6% prediction sensitivity for detectable post-treatment ctDNA, which conferred early determination of treatment benefits. Finally, we established individualized risk prediction models and demonstrated that introducing on-treatment ctDNA significantly refined risk stratification.ConclusionsOur study helps advance the implementation of ctDNA-based testing in therapeutic response evaluation for a refined risk stratification. The dynamic and refined risk profiling would tailor future liquid biopsy-based risk-adapted personalized therapy.© 2022. The Author(s).

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