For patients with primary liver cancer, liver transplantation can offer an opportunity for long-term survival. However, cancer recurrence remains a critical concern. Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) can recur after transplantation, and recurrence is associated with poor outcomes.

Today, surveillance after liver transplantation relies primarily on imaging and blood-based tumor markers, including alpha-fetoprotein and carbohydrate antigen 19-9. While these tools are important, their sensitivity and specificity are limited, creating an opportunity for additional methods to help clinicians identify or confirm recurrence.

In a study published in the Journal of Gastrointestinal Oncology, Dr. Maen Abdelrahim, Professor of Medicine at Houston Methodist, evaluated whether a personalized tumor-informed circulating tumor DNA (ctDNA) assay could complement existing surveillance methods after liver transplantation. This assay demonstrated 75% sensitivity and 100% specificity for recurrence detection.

Personalized ctDNA assays show promise for recurrence surveillance in liver transplantation recipients

CtDNA consists of small fragments of genetic material released by cancer cells into the bloodstream. Because ctDNA can be detected from a blood sample, it can indicate the presence of cancer without requiring an invasive tissue biopsy.

Dr. Abdelrahim used a personalized, tumor-informed assay designed around the individual patient's primary tumor. The goal was to determine whether serial ctDNA testing could identify recurrent HCC or CCA following liver transplantation.

Evaluating ctDNA after liver transplantation

The prospective study followed 38 liver transplant recipients with HCC or CCA. Patients underwent serial peripheral blood ctDNA testing alongside standard surveillance with imaging and conventional tumor markers. Imaging detected cancer recurrence in six patients. Of those six, three had positive ctDNA results, while three had negative or insufficient-to-process ctDNA results.

Among the 31 patients whose ctDNA tests could be evaluated, the assay demonstrated 75% sensitivity and 100% specificity. By comparison, standard tumor biomarkers demonstrated 75% sensitivity and 93% specificity. The findings demonstrate that personalized ctDNA testing is feasible in the post-transplant setting and may provide particularly useful information when conventional surveillance results are uncertain.

ctDNA as a confirmatory diagnostic tool

The study does not demonstrate that ctDNA should replace imaging or conventional tumor markers. In fact, imaging detected recurrence earlier than ctDNA in five of the six patients who experienced recurrence. Only one patient had a positive ctDNA result before imaging identified recurrence, and the result still required confirmatory imaging. Instead, Dr. Abdelrahim identified a potentially vital role for ctDNA as a confirmatory diagnostic tool.

Its high specificity means that a positive result could provide additional evidence of recurrence when imaging or conventional blood tests raise concerns. In some situations, this could potentially reduce the need for an invasive solid-tissue biopsy. This distinction is particularly important for liver transplant recipients, who may face additional clinical considerations because of immunosuppression and limited treatment options following recurrence.

“The high specificity and low sensitivity of ctDNA assays suggest a confirmatory or diagnostic role may supplant invasive solid tissue biopsy when abnormal conventional modalities suggest recurrence and show the need for more investigations in the surveillance setting.”

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Maen Abdelrahim, MD, PhD, PharmD

Building the next generation of transplant surveillance

The study represents the first prospective evaluation of serial tumor-informed ctDNA testing for recurrence surveillance after liver transplantation in patients with primary liver cancers. The results provide important proof of feasibility while also highlighting challenges that must be addressed before routine clinical adoption.

Approximately 10% of ctDNA assays in the study were insufficient to process, often because there was not enough primary tumor tissue available to develop the personalized assay. This was associated with patients who had received locoregional treatment before transplantation. Patient compliance with repeated blood collection also emerged as a consideration for long-term surveillance.

Larger prospective studies are needed to determine the optimal testing frequency, improve assay success rates and clarify how ctDNA should be integrated with imaging and conventional biomarkers.

The long-term opportunity is to develop a more personalized surveillance strategy that combines multiple information sources to identify recurrence and guide clinical decision-making. For patients who have undergone liver transplantation for HCC or CCA, ctDNA may become an important additional tool — not as a replacement for established surveillance, but as a highly specific, minimally invasive way to help clinicians determine when further investigation is warranted.