Glypican-3 as a Prognostic Factor in Patients With Hepatocellular Carcinoma Treated by Immunotherapy

Recently, the positive results of the Imbrave 150 study (randomized study comparing Atezolizumab+Bevacizumab versus Sorafenib) prompted investigators to redefine their management strategy for advanced HCC by proposing the combination Atezolizumab+ Bevacizumab as first-line treatment in these patients. Identifying new predictive biomarkers of response is essential to optimize the identification of patients who will benefit from immunotherapy. Glypican-3 (GPC-3) is a cell surface glycoprotein that belongs to the family of heparan sulfate chain proteoglycan that is directly implicated in several cancers and more particularly in HCC. GPC-3 overexpression in serum predicts a poor prognosis for patients with HCC and is associated with early tumor recurrence. Through this study, the investigators want to determine whether the concentration of circulating GPC-3 alone, or in combination with other biomarkers used in current practice (PIVKA, AFP) could predict the response to treatment with Atezolizumab/Bevacizumab and OS.

When hepatocellular carcinoma (HCC) is diagnosed, only 25% of patients will be able to have a curative treatment such as liver transplantation, treatment by ablation or surgical resection. In the majority of cases, patients will only have access to so-called palliative treatment. For many years, the only treatment available for patients with advanced HCC was sorafenib, a tyrosine kinase inhibitor with an average overall survival of 10.6 months. Recently, the positive results of the Imbrave 150 study (randomized study comparing Atezolizumab + Bevacizumab versus Sorafenib) prompted investigators to redefine their management strategy for advanced HCC by proposing the combination Atezolizumab+Bevacizumab as first-line treatment in these patients. Indeed, the overall survival (OS) and progression-free survival rates (PFS) were significantly higher in the Atezolizumab+Bevacizumab arm (OS: 67.2% at 12 months and PFS: 6.8 months) versus Sorafenib (OS: 54.6% at 12 months, PFS 4.3 months). The recent approval of the treatment in France is a unique opportunity to carry out a pilot study on clinical, biological, histological, molecular and immune prognostic and predictive factors in patients treated with the Atezolizumab+Bevacizumab combination. Identifying new predictive biomarkers of response is essential to optimize the identification of patients who will benefit from immunotherapy. HCCs are characterized by multiple genomic alterations and the abnormal expression of numerous pro- and anti-oncogenic genes. Glypican-3 (GPC-3) is a cell surface glycoprotein that belongs to the family of heparan sulfate chain proteoglycans. As a co-receptor, GPC-3 is involved in the control of several major signaling pathways (IGF2, Wnt/beta-catenin, etc.) and plays an important role in cell proliferation and tissue growth. At the tumoral level, GPC-3 is directly implicated in several cancers and more particularly in HCC. GPC-3 is overexpressed in 72% of HCCs and its expression is absent in normal liver tissues and benign liver lesions. GPC-3 overexpression is associated with the state of cell tumor differentiation and proliferation in HCC, tumor aggressiveness, as well as poor prognosis and shorter OS. GPC-3 overexpression in serum also predicts a poor prognosis for patients with HCC and is associated with early tumor recurrence. Through this study, the investigators want to determine whether the concentration of circulating GPC-3 alone, or in combination with other biomarkers used in current practice (PIVKA, AFP) could predict the response to treatment with Atezolizumab/Bevacizumab and OS.

Eligibility Criteria:
Inclusion Criteria:

* 18 years ≤ age \< 90 years
* Diagnosed with HCC developed on a cirrhotic liver or on chronic liver disease that has not reached the stage of cirrhosis regardless of the etiology diagnosed according to the diagnostic criteria for TNCD updated in June 2021 (1)
* Having an indication for systemic therapy with Atezolizumab+Bevacizumab validated in multidisciplinary meeting according to the current recommendations of cancer societies.
* Understanding the French language.
* Having been informed and accepted to participate to the study.

Exclusion Criteria:

* HIV or known immune deficiency or immunosuppressive treatment
* Autoimmune diseases or other immunotherapies
* History of portosystemic shunt or liver transplantation
* Sepsis, vasoconstrictor drugs.
* Pregnant or breastfeeding women
* Protected populations: under guardianship or curators