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

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.

• Evaluate overall survival [Time frame: at 24 months]
• Evaluation of the combination of circulating GPC-3 level with other biomarkers (PIVKA, AFP) before, 3 weeks and 3 months after initiation of Atezolizumab/Bevacizumab and/or their variation value could predict treatment response. [Time frame: at inclusion, at 3 weeks and at 3 months of the first infusion of Atezolizumab/Bevacizumab]
• Evaluation of the combination of circulating GPC-3 level with other biomarkers (PIVKA, AFP) before, 3 weeks and 3 months after initiation of Atezolizumab/Bevacizumab and/or their variation value could predict overall Survival. [Time frame: at inclusion, at 3 weeks and at 3 months of the first infusion of Atezolizumab/Bevacizumab, at 24 months]
• Evaluation of the HCC response to treatment on Imaging assessment (CT-scan and MRI) every 3 months according to the miRECIST criteria (combination of mRECIST and iRECIST criteria) [Time frame: at inclusion, at 3,6,9,12,15,18,21 and 24 months of the first infusion of Atezolizumab/Bevacizumab,]