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Circulating Tumor DNA and Tumor Mutational Burden in Hepatocellular Carcinoma: Analysis of an Emerging Biomarker for Disease Monitoring
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Chase J. Wehrle1, *Hanna Hong
1, *Sami Fares
1, *Bassam Estfan
2, *Suneel Kamath
2, *Smitha Krishnamurthi
2, *Wen Wee Ma
2, *Andrea Schlegel
1, *Jaekeun Kim
1, *Koji Hashimoto
1, R. Matthew Walsh
1, *David C. Kwon
1, *Federico Aucejo
11Digestive Diseases and Surgery Institute, Cleveland Clinic, Cleveland, OH; 2Taussig Cancer Institute, Department of Gastrointestinal Oncology, Cleveland Clinic, Cleveland, OH
AbstractObjectives: Current biomarkers for hepatocellular carcinoma (HCC) like Alpha-fetoprotein (AFP) are lacking in sensitivity and specificity. 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 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: Fifty-five patients were included, most (n=47, 85.5%) of whom had post-operative ctDNA. 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 (<11ng/mL, p=0.682) or the cut-off established by ROC-analysis (
>4.6ng/mL, p=0.494).
Conclusions: Identifiable TMB on post-operative ctDNA predicts HCC recurrence, and outperformed AFP in this cohort. Perioperative ctDNA may be considered as a useful surveillance tool following curative-intent hepatectomy for HCC. Further, 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.
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