Minimization of tacrolimus in patients with HCC undergoing liver transplant: It is never too early

Hepatocellular carcinoma (HCC) is one of the leading indications for liver transplantation (LT) worldwide and with a growing prevalence due to broader inclusion criteria and more successful downstaging strategies. HCC recurrence may occur in 15%–20% of patients, mostly within the first 2–3 years after LT, although some cases are reported beyond 10 years.1 The prognosis of these patients is hampered by a frequently more aggressive biological behavior of HCC than that observed in the primary tumor and by more restricted therapeutic options, including limitations for using checkpoint inhibitors.2 It is paramount to reduce the risk of HCC recurrence after LT by implementing strategies to modulate immunosuppression. In this issue of Liver Transplantation, Kojima et al3 analyzed a cohort of 1406 patients with HCC who received an LT in 4 widely experienced centers from the United States from 2002 to 2019. After a median follow-up of 5 years after transplant, HCC recurrence occurred in 14.7% of patients. The most relevant finding of the study was the association between increased trough concentrations of tacrolimus and a higher risk of tumor recurrence, aligning with previous observations.4–6 Although there was a cumulative effect of exposure to tacrolimus over time, the most influential period was the first 2 weeks after LT. Despite a potential bias derived from higher doses of tacrolimus and trough levels used in the postoperative period, including more frequent assessments of trough concentrations (ie, more granular and precise data on tacrolimus exposure), the results claim for implementing tacrolimus minimization as early as possible in patients with HCC. The benefit was more pronounced for patients showing trough levels <4.2 ng/mL within the first 2 weeks after LT, which is a very low threshold that not all patients may safely achieve. The strategy to reduce tacrolimus in the postoperative period could also be relevant since induction therapies, despite resulting in lower tacrolimus levels, were associated with increased HCC recurrence rates. This finding is unprecedented, but it should be taken seriously since this is the first study sufficiently powered to analyze the role of induction therapies in HCC recurrence. Regarding inhibitors of the mammalian target of rapamycin, these were implemented at variable time points after LT, usually after the third month, and mainly in patients with a priori higher risk of tumor recurrence, making data on the mammalian target of rapamycin use difficult to interpret. One interesting and novel analysis of this study was the combination of HCC pathological data, serum alpha-fetoprotein, and tacrolimus exposure to predict tumor recurrence after LT. Particularly, the authors performed sensitivity analyses according to the fulfillment of Milan criteria, the presence of vascular invasion, and validated prognostic scores such as RETREAT and HALT-HCC. Although the combination of adverse pathological factors and high tacrolimus exposure was synergistic beyond that of either factor standing alone, the effect of tacrolimus overexposure was more prominent in patients with biologically aggressive tumors.3 Taken as a whole, the evidence suggests a triple-hit hypothesis for HCC recurrence after LT. The first hit implies an aggressive HCC with a meaningful number of cells that have completed the epithelial-to-mesenchymal transition and show capabilities to access the bloodstream before LT or even during hepatectomy. These circulating tumor cells have shown capacities for aggregating in numbers from 2 to 20, which may allow them to persist in the bloodstream for long time intervals.7 However, the immune system may be able to detect and destroy circulating tumor cells, thus preventing the invasion of extrahepatic organs.8 Therefore, the second hit requires an impaired immune surveillance mechanism facilitated by increased tacrolimus trough concentrations early after LT, particularly when immunosuppression potency is boosted with induction agents.3 The question remains regarding how these perioperative events could result in tumor recurrence occurring much later, sometimes beyond 5 years after LT. This requires a third hit, much less understood, that may be related to immune exhaustion, which implies that T cells chronically exposed to certain stimuli, in this case, to HCC-related antigens, become dysfunctional and fail to halt circulating tumor cells.9 While awaiting therapies to reverse immune exhaustion, our efforts should be driven to target the first 2 hits by avoiding transplant or optimizing pre-LT treatment in patients with highly aggressive biological tumors, and by implementing tacrolimus minimization strategies immediately after LT.