METabolic PROFILE of Hepatocarcinoma and Pancreatic Tumors

Primary liver tumours (hepatocellular carcinoma (HCC)) and pancreatic tumours (pancreatic adenocarcinoma (ADKP); pancreatic neuroendocrine tumours (NETs)) are the most frequent malignant tumours of the hepatobiliopancreatic system and represent a major public health issue. One of the main lines of research for these tumors consists in the early identification of prognostic and theranostic factors to adapt the management of patients as closely as possible to the specificities of their pathology. This identification is currently sorely lacking in daily clinical practice. Thus, unlike what is done for other types of neoplastic pathologies such as breast cancer, the management of primary liver and pancreatic tumors is still often based on recommendations based on the existence of rudimentary prognostic and theranostic markers that do not reflect sufficiently faithfully the heterogeneity of tumor biology. It is therefore essential to identify new, more relevant markers in order to optimize the management of these patients in daily practice.

Metabolic reprogramming is now recognized as an essential characteristic of cancer cells, allowing them to fuel and maintain their proliferation and tumor growth. Such metabolic reprogramming requires modification of several energy pathways, the most commonly recognized being the shift from energy metabolism based on oxidative phosphorylation to energy metabolism based on glycolysis, even under aerobic conditions (Warburg effect). Other metabolic pathways such as increased glutaminolysis have recently been identified. In this context, we hypothesized that the consumption of nutrients by the tumor cell differs significantly from that of the normal cell in order to support its increased energy needs, and that this important and specific metabolic reprogramming would be correlated with the histo-prognostic and theranostic factors of these tumors. Within ADKPs, 2 molecular subtypes have been described: a very aggressive, "basal-like" subtype with increased glycolytic metabolism and metastatic properties and a "classical" subtype, better differentiated with better prognosis. The identification of these subtypes is currently only possible by RNA-seq, a technology not practiced routinely. Similarly, metabolism appears to define a subgroup of aggressive NETs. Indeed, NETs with high glucose uptake, visible on 18FDG PET-CT scan, have a worse prognosis. This type of examination also showed that there was spatial metabolic heterogeneity (primary tumor vs. metastasis) and temporal metabolic heterogeneity in these tumors and that the latter was correlated with prognosis.

Preliminary analyses conducted by the various partners in 2019 made it possible to characterize the metabolic signatures of a series of resected HCC and ADKP using Metafora biosystems' technological platform.

These signatures reflect a metabolic program characteristic of these tumors, which reveal strong specificities. Similarly, a candidate signature correlating with the presence of microscopic vascular invasion has been identified in HCC, and the level of activation of glycolysis and glutaminolysis by some ADKP cells also appears as a trait of interest vis-à-vis the aggressiveness of this cancer.

As these results were obtained on surgical resection parts, the current project will therefore aim to confirm the feasibility of identifying specific prognostic and theranostic metabolic signatures early, on biopsy sampling or circulating blood cells.

This multicenter study includes 300 patients (100 patients for each tumor type) and aims to identify a prognostic metabolic signature from tumor tissue samples of HCC, ADKP and pancreatic NETs.

Inclusion criteria

Common criteria:

• Patient aged 18 or over
• Informed and having signed the consent to participate
• Affiliated with a social security scheme or entitled

1- Patients with hepatocellular carcinoma

• Having a HCC eligible for surgical treatment (liver resection or liver transplantation) not requiring preoperative anti-tumor treatment as validated by the multidisciplinary consultation meeting for primary hepatic tumors
• OR having a HCC not eligible for curative treatment (liver resection, liver transplantation, tumor ablation), as validated by the multidisciplinary consultation meeting for primary hepatic tumors 2- Patients with pancreatic adenocarcinoma or pancreatic neuroendocrine tumor
• Having ADKP or NET eligible for surgical treatment (duodenopancreatectomy, left pancreatectomy, enucleation, central pancreatectomy, hepatic metastasectomy) with or without preoperative anti-tumor treatment as validated by the multidisciplinary consultation meeting.
• OR with an unresectable ADKP or TNEP, with only medical treatment plan as validated by the multidisciplinary consultation meeting

Exclusion criteria

Criteria common to all patients:

• Pregnancy and lactation
• Lack of informed, written and signed consent
• Adult person subject to a legal protection measure or unable to express consent
• Patient under State Medical Aid (AME)
• Person deprived of liberty by a judicial or administrative decision
• Person undergoing psychiatric care

1- Patients with hepatocellular carcinoma

• Suspicion of mixed tumor (hepatocholangiocarcinoma) or intrahepatic cholangiocarcinoma
• History of systemic or locoregional anti-tumor treatment in the target tumor
• Contraindication to a liver biopsy
• Decompensated cirrhosis 2- Patients with pancreatic adenocarcinoma or pancreatic neuroendocrine tumor
• Suspicion of mixed tumor (MINEN) or intra-pancreatic cholangiocarcinoma
• Contraindication to a pancreatic / hepatic biopsy