Profiling circulating tumor DNA for recurrence prediction and prevention in hepatocellular carcinoma following liver transplantation.

Sensitive biomarkers for recurrence risk stratification, recurrence surveillance and adjuvant therapy guidance are of unmet need for patients with hepatocellular carcinoma (HCC) undergoing liver transplantation (LT). Herein, we explored the potential of profiling circulating tumor DNA (ctDNA) for prediction and prevention of recurrence in HCC after LT. HCC patients (n = 91) who underwent LT were prospectively enrolled. ctDNA was assayed using next-generation sequencing from perioperative plasma (n = 408). Associations between ctDNA status with clinicopathological parameters, tumor recurrence, and adjuvant treatment effect were analyzed. Higher preoperative ctDNA burden correlated with microvascular invasion (median: 45.0 vs 5.1 MTM/mL, P = 0.003) and recurrence (156.2 vs 7.7 MTM/mL, P < 0.001). ctDNA clearance was noted in 87.7% patients after LT and patients who kept positive postoperative ctDNA showed higher recurrence risk (HR = 8.86, P < 0.001), especially early recurrence (within 1 year; 75.0% vs 10.1%, P < 0.001). During follow-up, positive longitudinal ctDNA was similarly predictive of recurrence (HR = 36.50, P < 0.001). The AUC of longitudinal ctDNA for predicting recurrence was 0.930-significantly higher than alpha-fetoprotein (0.655, P < 0.001). Longitudinal ctDNA detected radiologically evidenced recurrence with a median lead time of 5.1 months compared to standard-of-care surveillance. Among patients who received adjuvant therapy, those with positive postoperative ctDNA could benefit (HR = 0.11, P = 0.003) and those with decreased ctDNA burden following treatment experienced longer interval from ctDNA positivity to recurrence (HR = 0.17, P = 0.006). Serial ctDNA analysis demonstrates strong prognostic value, capable of heralding tumor recurrence prior to radiological recurrence and measuring treatment efficacy. Its integration into clinical practice of HCC provides unique opportunities for adjuvant therapy decision-making following LT.