Early HPV ctDNA Kinetics and Imaging Biomarkers Predict Therapeutic Response in p16+ Oropharyngeal Squamous Cell Carcinoma

Abstract Purpose: In locally advanced p16+ oropharyngeal squamous cell carcinoma (OPSCC), (i) to investigate kinetics of human papillomavirus (HPV) circulating tumor DNA (ctDNA) and association with tumor progression after chemoradiation, and (ii) to compare the predictive value of ctDNA to imaging biomarkers of MRI and FDG-PET. Experimental Design: Serial blood samples were collected from patients with AJCC8 stage III OPSCC (n = 34) enrolled on a randomized trial: pretreatment; during chemoradiation at weeks 2, 4, and 7; and posttreatment. All patients also had dynamic-contrast-enhanced and diffusion-weighted MRI, as well as FDG-PET scans pre-chemoradiation and week 2 during chemoradiation. ctDNA values were analyzed for prediction of freedom from progression (FFP), and correlations with aggressive tumor subvolumes with low blood volume (TVLBV) and low apparent diffusion coefficient (TVLADC), and metabolic tumor volume (MTV) using Cox proportional hazards model and Spearman rank correlation. Results: Low pretreatment ctDNA and an early increase in ctDNA at week 2 compared with baseline were significantly associated with superior FFP (P 0.02 and P 0.05, respectively). At week 4 or 7, neither ctDNA counts nor clearance were significantly predictive of progression (P = 0.8). Pretreatment ctDNA values were significantly correlated with nodal TVLBV, TVLADC, and MTV pre-chemoradiation (P 0.03), while the ctDNA values at week 2 were correlated with these imaging metrics in primary tumor. Multivariate analysis showed that ctDNA and the imaging metrics performed comparably to predict FFP. Conclusions: Early ctDNA kinetics during definitive chemoradiation may predict therapy response in stage III OPSCC.