The bile duct and liver cancer: ON-treatment surveillance of tumor evolution and response to systemic treatment (BILLIONSTARS) study.

Abstract

Background: Malignancies of the liver and bile ducts are associated with high recurrence rates after surgery and poor prognosis when disseminated. Medical treatment has been improved in recent years, with chemotherapy, targeted therapy and checkpoint inhibitors offering opportunities to influence the course of the diseases. Many patients do not benefit from treatment, however, and predictive and prognostic markers are lacking. The BILe duct and LIver cancer: ON-treatment Surveillance of Tumor evolution And Response to Systemic treatment (BILLIONSTARS) study aims to map how molecular tumor characteristics and pathways of genetic evolution align with treatment response trajectories.

Methods: The BILLIONSTARS study is a prospective, single arm observational study. Patients at Skåne University Hospital in Malmö/Lund and Central Hospital in Kristianstad diagnosed with hepatocellular carcinoma (HCC) or cholangiocarcinoma (CCC) who are to be recommended locoregional intervention by surgery, ablation, transarterial chemoembolization or selective internal radiation therapy and/or antitumoral medical treatment will be included. Tissue obtained in the clinical setting through surgery or biopsy along with tissue from research autopsies will be evaluated with targeted deep sequencing. Circulating tumor DNA (ctDNA) and other relevant biomarkers will be analyzed in blood samples obtained at different timepoints, depending on the type of treatment; before surgery or the start of systemic treatment, prior to each course of systemic treatment, if applicable, and at end of treatment.

Discussion: The treatment field for HCC and CCC is evolving, thus improving outcomes for patients in the palliative setting. The efficacy of targeted therapy and checkpoint inhibition is however highly variable, and no predictive biomarkers have yet been established. The clinical course of the diseases is also highly variable and unpredictable. With this study, we hope to gain an increased insight into the various biological characteristics of these tumors, including novel potential treatment targets, as well as their spatial and temporal heterogeneity. By conducting research autopsies with comprehensive post-mortem sampling, we expect to further expand our understanding of the molecular events leading to terminal disease. The ultimate goal is to design better individualized and adaptive treatment strategies, thereby improving the outlook for patients with HCC or CCC.

Trial registration: This study has been registered in clinicaltrials.gov as NCT06877637 Protocol version 1 March 2025.