Tumor Mutational Burden From Circulating Tumor DNA Predicts Recurrence of Hepatocellular Carcinoma After Resection

Objective: Describe the utility of circulating tumor DNA in the postoperative surveillance of hepatocellular carcinoma (HCC). Background: Current biomarkers for HCC like alpha-fetoprotein (AFP) are lacking. Circulating tumor DNA (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 November 1, 2020, to July 1, 2023, received ctDNA testing using the Guardant360 platform. Tumor mutational burden (TMB) is calculated as the number of somatic mutations-per-megabase of genomic material identified. Results: Forty-seven patients had postoperative ctDNA testing. The mean follow-up was 27 months, and the maximum was 43.2 months. Twelve patients (26%) experienced recurrence. Most (n=41/47, 87.2%) had identifiable ctDNA postoperatively; 55.3% (n=26) were TMB-not detected versus 45.7% (n=21) TMB-detectable. Postoperative identifiable ctDNA was not associated with RFS ( P =0.518). Detectable TMB was associated with reduced RFS (6.9 vs 14.7 mo, 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 for TMB-prediction of recurrence was 0.752 versus 0.550 for AFP. ROC analysis established a TMB cutoff 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 cutoff (<11 ng/mL, P =0.682) or the cutoff established by ROC analysis (≥4.6 ng/mL, P =0.494). TMB-high was associated with poorer RFS on cox-regression analysis (hazard ratio=5.386, 95% CI: 1.109–26.160, P =0.037), while microvascular invasion ( P =0.853) and AFP ( P =0.439) were not. Conclusions: Identifiable TMB on postoperative 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.