Modelling Clinical Issues By Using Patient-Derived Xenografts: Evaluation Of Partial Hepatectomy On Hepatoblastoma Intrahepatic And Distant Growth

Abstract Hepatoblastoma (HB) is a rare disease that represents the most frequent liver malignancy during childhood. HB incidence is approximately 1.5 cases per million children less than 15-years old in Western countries. HB is histologically classified as epithelial or mixed depending on the presence of mesenchymal component. The most common epithelial components are the embryonal and fetal phenotype, reminiscent of at early or late stages of liver development. The improvement of the clinical management in the last 30 years has allowed 5-year survival rate to pass from 35 to 80%,due to the introduction of cisplatin-based chemotherapy. More than 50% of tumors are either inoperable or are metastatic at diagnosis. Neoadjuvant chemotherapy allows tumor size reduction and sometimes leads to complete regression of pulmonary metastasis. In Europe, the SIOPEL (International Childhood Liver Tumors Strategy Group) protocols recommend the use of cisplatinum-based neoadjuvant chemotherapy followed by surgery and adjuvant chemotherapy. All international studies recommend resecting all the metastases remaining after neoadjuvant chemotherapy, however, to date no indication is provided that defines whether metatases removal must take place before or after primary tumor resection by partial or total hepatectomy. As liver regeneration is a complex process that involves the expression and release of numerous factors that induce cell hypertrophy and proliferation, the risk that hepatectomy-induced release of regenerating factors might help the survival and proliferation of microscopic intrahepatic or distant tumor cells leads several clinicians to perform hepatectomy only after the removal of all detectable metastases. To challenge this paradigm, we used a panel of HB patient-derived xenograft and evaluated the impact of partial hepatectomy on intrahepatic and extrahepatic tumor growth. Partial hepatectomy performed either concomitantly with interscapular implantation of HB-217 xenograft, a model established from a patient with intrahepatic recurrence, or at the time of tumor appearance in mice failed to increase tumor growth. When hepatectomy was realized on several HB models concomitantly with either intrahepatic injection of bioluminescent HB cells derived from HB PDXs or by tumor fragments’ direct implantation, one of these models, HB-243, also a model established from a patient with intrahepatic recurrence, showed increased tumor growth in mice concomitantly subjected to partial hepatectomy. These results suggest that increased tumor growth induced by hepatectomy can occur in HB, albeit heterogeneously. We are now evaluating the molecular features of this hepatectomy-sensitive model and the impact of different cytokines on HB-243 PDX-derived tumor cells. The aim of this study will be to identify molecular markers and drivers of tumor sensitivity to hepatectomy. Citation Format: Marianna Cornet, Anais Delaitre Delattre, Laura Brulle Soumare, Victorine Boissay, Thierry Tordjmann, Antoinette Lemoine, Olivier Deas, Jean-Gabriel Judde, Sophie Branchereau, Stefano Cairo. Modelling clinical issues by using patient-derived xenografts: Evaluation of partial hepatectomy on hepatoblastoma intrahepatic and distant growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4936. doi:10.1158/1538-7445.AM2017-4936