Tumor Mutational Burden from Circulating Tumor DNA Predicts Recurrence of Hepatocellular Carcinoma After Resection: An Emerging Biomarker for Surveillance

Objective: Describe the utility of circulating tumor DNA in the post-operative surveillance of hepatocellular carcinoma (HCC). Summary Background Data: Current biomarkers for HCC like Alpha-fetoprotein (AFP) are lacking. ctDNA has shown promise in colorectal and lung cancers, but its utility in HCC remains relatively unknown. Methods: Patients with HCC undergoing curative-intent resection from 11/1/2020-7/1/2023 received ctDNA testing using the Guardant360 platform. TMB is calculated as the number of somatic mutations-per-megabase of genomic material identified. Results: Forty seven patients had post-operative ctDNA testing. Mean follow-up was 27 months and maximum was 43.2 months. Twelve patients (26%) experienced recurrence. Most (n=41/47, 87.2%) had identifiable ctDNA post-operatively; 55.3%(n=26) were TMB-not detected versus 45.7% (n=21) TMB-detectable. Post-operative identifiable ctDNA was not associated with RFS ( P =0.518). Detectable TMB was associated with reduced RFS (6.9 vs. 14.7months, P =0.049). There was a higher rate of recurrence in patients with TMB (n=9/21, 42.9%, vs. n=3/26, 11.5%, P =0.02). Area-Under the Curve (AUC) for TMB-prediction of recurrence was 0.752 versus 0.550 for AFP. ROC-analysis established a TMB cut-off of 4.8mut/mB for predicting post-operative recurrence ( P =0.002) and RFS ( P =0.025). AFP was not correlated with RFS using the lab-normal cut-off (<11 ng/mL, P =0.682) or the cut-off established by ROC-analysis ( > 4.6 ng/mL, P =0.494). TMB-high was associated with poorer RFS on cox-regression analysis (HR=5.386, 95%CI1.109-26.160, P =0.037) while micro-vascular invasion ( P =0.853) and AFP ( P =0.439) were not. Conclusions: Identifiable TMB on post-operative ctDNA predicts HCC recurrence, and outperformed AFP in this cohort. Perioperative ctDNA may be a useful surveillance tool following curative-intent hepatectomy. Larger-scale studies are needed to confirm this utility and investigate additional applications in HCC patients, including the potential for prophylactic treatment in patients with residual TMB after resection.