Relationship Between 18FDG PET/MRI Patterns and ctDNA to Predict HCC Recurrence After Liver Transplantation

Hepatocellular Carcinoma (HCC) is the third leading cause of death by cancer worldwide, being responsible for nearly 700,000 deaths in 2012. Liver transplantation (LT) provides the best results as a curative treatment for patients with early-stage HCC. Other curative treatment strategies for early stages HCC include resection and ablation. However, the recurrence rates are higher than LT. Due to organ shortage, better criteria for recipient selection are necessary. The first widely accepted criteria for graft allocation in HCC patients is the so-called Milan Criteria (MC): single HCC nodule ≤ 5 cm or 3 nodules all ≤ 3 cm, achieving a 4-y survival of 85%. Recently, MC is seen as too restrictive, its inclusion preventing patients who might have better survival following LT when compared to other therapies. Reluctant to have sizing-only criteria, the University of Toronto, since 2004, has applied the so-called Extended Toronto Criteria (ETC) to LT, which offers transplant to patients with any size and any number of tumors provide they do not have systemic cancer-related symptoms, extrahepatic disease, vascular invasion or poorly differentiated tumors. A recent prospective study conducted at University Health Network (UHN) has shown 5-years survival rates of 68% when ECT are applied. Recent studies have demonstrated the need to use, besides the lesion size, variables which can predict the biological behavior of the tumor.

Currently, important treatment decisions, like the selection of patients for transplantation, are made on crude, static tumour characteristics such as the size and number of lesions, but do not reflect other aspects of tumour biology. To date, pre-transplantation percutaneous biopsy is the best strategy to assess tumor differentiation and, consequently, tumor biological behavior. However, HCC is a very complex disease. Microscopic and molecular analyses have demonstrated a highly heterogeneous degree of cell differentiation. Patients with more than one tumor may have two or three degrees of cell differentiation between the tumors. Even within a single HCC nodule, more than one clonal mutations can be present. To date, there is not a precise method to determinate the degree of differentiation of each patient's disease and percutaneous core biopsy, an invasive method, is the best estimative the investigators can reach.

Since it is impossible to precisely determine the degree of differentiation of HCC with one single tissue sample, the use of imaging becomes necessary. Magnetic resonance imaging (MRI) and enhanced computed tomography (CT) are extensively validated as staging methods for HCC. The use of 18F-Fluorodeoxyglucose (18F-FDG) Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) is still underevaluated in the field of HCC. However, previous studies have demonstrated that 18F-FDG PET/CT may have role in assessing the HCC tumoral differentiation and predict survival after LT. There is no investigation on use of 18F-FDG PET/MRI as a tool to predict biological behavior in HCC.

Recently, the Pugh Lab has developed a circulating tumor DNA (ctDNA) sequencing assay that combines a hybrid-capture method with a novel bioinformatics algorithm to enable full-length sequence analysis of all exons in genes of interest or any other arbitrary genomic region, rather than mutation hotspots13. With the availability of these technologies in our group, the investigators next sought to determine whether these methods were applicable to HCC patients, gathering two innovative tools in transplant patients' care.