Early Detection of de Novo Cancer in Liver Transplant Recipients - a ScandiaTransplant Collaboration

BACKGROUND Liver transplantation is a complex surgical procedure and the only curative treatment for many patients with chronic end-stage liver disease and acute liver failure. Short-term survival for liver transplant recipients has improved markedly over the past decades with a 1-year survival of 90%[1]. In contrast, over the same time period there has been no improvement in long-term survival, with only 61-74% of liver transplant recipients living 10 years after transplantation [2, 3]. This is despite the median age at time of transplantation being 48 years. De novo cancer after transplantation is one of the leading causes of late death and an independent risk factor for mortality after liver transplantation [3, 4].

The cumulative incidence of de novo cancer after liver transplantation in the Scandinavian population is 1% at 1 year, 3% at 3 years, 4% at 5 years, 9% at 10 years, and 15% at 20 years [5]. Risk of de novo cancer for liver transplant recipients is twice the cancer risk in the general population [5, 6] and even higher for children and adolescents [3]. In addition, cancers present at a more advanced stage [6]. After liver transplantation lifelong immunosuppressive treatment is necessary to prevent organ rejection. Immunosuppression is considered as a primary risk factor for de novo cancer [7-10], likely due to impaired cancer surveillance [8].

While there are no reliable biomarkers reflecting the status of the immune function in liver transplant recipients, opportunistic infections with Cytomegalovirus (CMV) and Torque Teno Virus (TTV), have shown to act as surrogate measures for over-immunosuppression. In contrast to Epstein-Barr virus (EBV) and human herpes virus 8 (HHV8), CMV and TTV have not been directly implicated in the pathogenesis leading to cancer and these viruses may therefore serve as functional markers for the level of immunosuppression [11-13]. The relationship between opportunistic virus infections and non-virus associated de novo cancers after liver transplantation has not been sufficiently investigated.

Due to high incidence of cancer, screening may be relevant in liver transplant recipients [14, 15]. Positron Emission Tomography-Computed Tomography (PET-CT) is the method of choice to detect de novo cancers, but the modality is costly and carries a risk of false positive results [16]. The method genome-wide cell free DNA fragmentation allows differentiation between cell free DNA from healthy individuals and patients with cancer [17]. In a previous study, early detection of various cancers was possible with a high accuracy (area under curve (AUC) of 0.94). Moreover, tissue of origin could be identified from fragmentation profiles. This method has not been investigated in liver transplant recipient and may be used to screen recipients, who could benefit from further investigations such as PET-CT.

In conclusion, to reduce cancer related mortality in liver transplant recipients, new tools are needed to identify recipients with increased risk of developing de novo cancer. In particular, new tools are needed that will allow diagnosis of de novo cancer at an early time-point that allows curative intended intervention. The study has potential to provide information to close important gaps in our knowledge and to improve the prognosis in liver transplant recipients.