The BILLIONSTARS study is a prospective, single arm observational study inviting patients diagnosed with hepatocellular carcinoma (HCC) or cholangiocarcinoma (CCC) who are to be recommended locoregional intervention by surgery, ablation or transarterial chemoembolization and/or antitumoral medical treatment. The aim is to investigate how tumor- and individual-related factors affect response to treatment. To this end, circulating tumor DNA, immune cells and various proteins will be analyzed in repeated blood samples taken before, during and after completion of systemic treatment. When applicable, analyses will also be performed on tumor tissue from resected tumors and biopsies, and in some cases also from autopsies

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 or transarterial chemoembolization and/or antitumoral medical treatment will be included. A total enrolment of 150 patients is planned.

Before start of treatment, the patients will receive information about the study by a physician and give their written informed consent. Tumor tissue will be obtained from surgical specimens, predominantly from formalin-fixed paraffin embedded (FFPE) tissue, but in some cases, fresh tissue will be obtained at surgery for cryopreservation to enable future preclinical studies. All blood samples will be taken by a dedicated research nurse in conjunction with the treatment visits. Plasma, serum and buffy coat will be isolated from blood samples, following standard fractionation, to enable analyses of circulating tumor DNA (ctDNA), and other biomarkers. Participants will be asked to fill in quality of life questionnaires (EORTC QLQ-C30 and EORTC-QLQ-HCC18/BIL21) at study start, and after three and six months, respectively.

Treatment regimen will follow national guidelines and will not be affected by participation in the study. Radiological and clinical follow ups will be conducted according to clinical protocols or when deemed necessary by the clinician. Primary endpoint is OS, secondary endpoints are progression free survival and change in quality of life (EORTC QLQ-C30+EORTC-QLQ-HCC18/BIL21).

The study will also include research autopsies. Patients are informed and provide their consent for inclusion in this part of the study when they are in a late palliative phase.

Inclusion Criteria:

• > 18 years of age
• Clinically diagnosed intrahepatic Cholangiocarcinoma (iCCC), perihilar Cholangiocarcinoma (pCCC), distal Cholangiocarcinoma (dCCC), gall bladder carcinoma (GBC) or mixed Hepatocellular carcinoma/Cholangiocarcinoma planned to undergo surgery
• Histologically or cytologically confirmed Cholangiocarcinoma (iCCC, pCCC, dCCC, GBC, mixed HCC/CCC) for patients planned to receive palliative systemic treatment or
• Clinically diagnosed Hepatocellular carcinoma (HCC) planned for surgery, ablation or transarterial chemo-embolization. For patients planned to receive systemic treatment histological or cytological confirmation is required except for patients with LI-RADS 5 lesions.

Exclusion Criteria:

• < 18 years of age
• Severe comorbidities
• Inability to comprehend study information

Adult patients diagnosed with Cholangiocarcinoma or Hepatocellular carcinoma at Skåne University Hospital in Malmö/Lund , Sweden, and at Central Hospital in Kristianstad, Sweden.