Post-liver transplant (LT) immunosuppression is necessary to prevent rejection; however, a major consequence of this is tumor recurrence. Although recurrence is a concern after LT for patients with HCC, the oncologically optimal tacrolimus (FK) regimen is still unknown. This retrospective study included 1406 patients with HCC who underwent LT (2002-2019) at 4 US institutions using variable post-LT immunosuppression regimens. Receiver operating characteristic analyses were performed to investigate the influences of post-LT time-weighted average FK (TWA-FK) level on HCC recurrence. A competing risk analysis was employed to evaluate the prognostic influence of TWA-FK while adjusting for patient and tumor characteristics. The AUC for TWA-FK was greatest at 2 weeks (0.68), followed by 1 week (0.64) after LT. Importantly, this was consistently observed across the institutions despite immunosuppression regimen variability. In addition, the TWA-FK at 2 weeks was not associated with rejection within 6 months of LT. A competing risk regression analysis showed that TWA-FK at 2 weeks after LT is significantly associated with recurrence (HR: 1.31, 95% CI: 1.21-1.41, p < 0.001). The TWA-FK effect on recurrence varied depending on the exposure level and the individual's risk of recurrence, including vascular invasion and tumor morphology. Although previous studies have explored the influence of FK levels at 1-3 months after LT on HCC recurrence, this current study suggests that earlier time points and exposure levels must be evaluated. Each patient's oncological risk must also be considered in developing an individualized immunosuppression regimen.
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