The goal of this prospective clinical trial is to identify a predictive biomarker in patients with advanced HCC (stage B and C) using a combinatorial approach of the liquid biopsy.

The main questions it aims to answer are:

• Is multi-omic liquid biopsy approach able to identify a strong predictive biomarker of immunotherapy efficiency?
• Is there a correlation between tissue biopsy (PD-L1 tissue level of expression) and liquid biopsy (detection of CTC expressing PD-L1) in HCC patients?

Participants blood will be collected at several time points.

In solid cancers, some more aggressive tumor cells actively detach from the primary lesion and then travel through the circulating compartment to reach distant organs and form micro-metastases. Detecting CTCs in the blood is also relevant for assessing tumor progression, prognosis and therapeutic follow-up. The non-invasive, highly sensitive for CTCs analysis is called "liquid biopsy". Over the past few years, a multi-analyses approach (CTCs, circulating tumor DNA, extracellular vesicles, miRNA...) of liquid biopsy has been developed.

Hepatocellular carcinoma (HCC) is the predominant pathological type of primary liver cancer. It represents the sixth most common incidence worldwide and the third most common cause of cancer mortality.

Since 2021, the gold standard treatment for patients with advanced and/or unresectable HCC is the combination of atezolizumab (anti-PD-L1) and bevacizumab (VEGF inhibitor) in cases where chemoembolization is not indicated (patients with lymph node invasion and/or distant lesions or patients with portal flow abnormality). Indeed, this therapy offers a significant benefit in overall survival (19.2 vs 13.4 months, HR 0.66, p<0.0009) as well as in progression-free survival (6.9 vs 4.3 months, HR 0.65, p=0.0001). However, to date, there is no predictive biomarker for the efficacy of immune checkpoint inhibitors (ICI)

The purpose of this research project is to identify a predictive biomarker in patients with advanced HCC (stage B and C) using a combinatorial approach of the liquid biopsy (CTC, CTC expressing PD-L1, immune cell profiling).

Inclusion Criteria:

• Patients of at least 18 years old,
• Patients with advanced hepatocellular carcinoma or HCC with indication for first-line PD-1 or PD-L1 immunotherapy in MDT, without prior systemic therapy,
• The diagnosis of HCC is established according to imaging criteria (LI-RADSv2018 criteria) or after histological evidence,
• Advanced HCC defined by BCLC stages B and C,
• Patients with oral consent.

Exclusion Criteria:

• Administration of a previous systemic anti-tumor treatment (immunotherapy or chemotherapy or targeted therapy)
• No personal history of neoplasia in the previous 5 years
• No personal history of systemic inflammatory diseases
• No immunosuppressive treatment or treatment that could modify immunity (anti-TNF...)
• No affiliation or non-beneficiary of a Social Security system;
• Vulnerable persons according to article L1121-6 of the CSP ;
• Persons of full age who are protected or unable to give their consent according to article L1121-8 of the CSP;
• Pregnant or breastfeeding women according to article L1121-5 of the CSP.
• Non-inclusion due to follow-up difficulties (transfer, insufficient motivation, poor compliance, priority associated pathology in care, etc.)