Background: Conventional transarterial chemoembolization (cTACE) is an effective locoregional therapy in hepatocellular carcinoma (HCC). We evaluated variations around cTACE in a-fetoprotein (AFP), circulating cell-free and tumor DNA (cfDNA and ctDNA) as a marker of therapeutic response.Methods: This prospective monocentric study enrolled consecutive patients treated by cTACE with samples collected at baseline (D-1), day 2 (D+2) and at 1 month (M+1). All cTACE were carried out by only one interventional radiologist and according to the same procedure using farmorubicin drug. cfDNA was quantified by fluorometric method and ctDNA by digital Polymerase Chain Reaction designed for two-hotspot TERT mutations. CT-scan or MRI were performed at M+1 following cTACE and independently reviewed. The objective was to identified by ROC curves the thresholds of cfDNA, ctDNA and AFP variations associated with progression.Results: A total of 38 patients was included from March 2018 to March 2019. All except one had cirrhosis and alcohol was the most frequent etiology of HCC (73.7%). A total of 24/38 (63.2%) patients were naïve for TACE. At M+1, 33/38 patients (86.8%) had a controlled disease and 5/38 (13.2%) a progressive disease (PD). ctDNA was detectable in 16/38 (42.1%) patients at D-1, 30/38 (78.9%) at D+2 and 14/35 (40.0%) at M+1 and cfDNA median value was 21.6 ng/mL, 82.3 ng/mL and 17.8 ng/mL, respectively. All markers significantly increased from D-1 to D+2 (p<0.005) and cfDNA and ctDNA significantly decreased from D+2 to M+1, (p<0.0001). The analysis of variations from D-1 to M+1 identified that thresholds at +31.4% for cfDNA and 0% for ctDNA were significantly associated with PD at M+1, 44.4% (>+31.4%) vs. 3.8% (<¼+31.4%) and 50.0% (>0%) vs. 5.0% (<¼0%), respectively. No significant threshold was identified for AFP. Using a score combining both cfDNA and ctDNA (n¼28), patients were classified into high (n¼5) or low-risk (n¼23) of PD at M+1 with a PD rate of 80.0 % vs 4.3% (p¼0.001) and a median progression-free survival of 1.3 vs 10.3 months (p¼0.002), respectively.Conclusions: This study suggests that cfDNA and ctDNA increases around TACE procedure are associated with therapeutic failure.Legal entity responsible for the study: The authors.

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