Objective: 
Development and validation of a metabolite constellation in serum for early detection of hepatocellular cancer.

Hepatocellular carcinoma (HCC) is an aggressive tumor of the liver with annual incidence of 1-6% in at risk patients with liver cirrhosis [1, 2]). Most patients have symptoms only in advanced stage HCC, impeding early detection of the tumor. The 5-year survival rate is <10% if HCC is diagnosed after symptoms occur in advanced stage [3].However, 5-year survival rates of 50 – 70% are possible when the tumor is diagnosed at an early stage [4]. Therefore, current guidelines recommend to enroll patients with liver cirrhosis in HCC surveillance programs using semiannual abdominal sonography [4,5]. Unfortunately, the sensitivity of sonography for detecting early stage HCC in liver cirrhosis is less than 50% according to a recent meta-analysis [6]. Addition of the widely used serum biomarker AFP (alpha-feto protein) to sonography only marginally improved sensitivity for early HCC and is not recommended in HCC surveillance due to its low sensitivity and specificity. Thus, there is a strong clinical need for a non-invasive test to supplement abdominal sonography in HCC surveillance to improve detection of early stage HCC.

Study design: 
HERMES follows a two-step approach with development and initial testing of the metabolite constellation in retrospective case-control cohorts and a subsequent validation including transfer to the target population in a prospective multicenter study**.

Material: 

Serum samples of cirrhotic patients with and without HCC

Reference standard: 
High-resolution imaging with liver biopsy if necessary

Approach: 
Metabolomics studies allow the analysis of the entire metabolite spectrum (metabolome) of a biospecimen to detect rising and falling concentrations of endogenous substances and to associate them with pathological processes. numares uses its precise, fast and flexible analytical AXINON^® System, which allows simultaneous detection of metabolites in a highly reproducible single analytical step without predefined selection criteria. Using this untargeted metabolic analysis, numares has identified a metabolite constellation in serum for detection of early HCC using a retrospective case-control data set. In an independent sample set not used for biomarker discovery, the metabolite constellation was able to detect early HCC in high-risk patients with liver cirrhosis. Moreover, preliminary work suggests that this metabolite constellation, in combination with abdominal sonography, can provide significant added value over sonography alone. In a first step, the metabolite constellation will be tested in additional retrospective case/control cohorts. In a second step, these results will be validated further and transferred to the actual surveillance setting in a prospective multicentre study**. 

_{**The prospective multicentre study is sponsored by the German Federal Ministry of Education and Research, field of action “Gesundheitswirtschaft im Rahmenprogramm Gesundheitsforschung”, contract number 13GW0307.}

Success: 
numares successfully identified a metabolite constellation in serum for detection of early stage HCC*. 

_{References:
1.    Forner, A., M. Reig, and J. Bruix, Hepatocellular carcinoma. Lancet, 2018. 391(10127): p. 1301-1314.
2.    Ioannou, G.N., et al., Incidence and predictors of hepatocellular carcinoma in patients with cirrhosis. Clin Gastroenterol Hepatol, 2007. 5(8): p. 938-45, 945 e1-4.
3.    Llovet, J.M., A. Burroughs, and J. Bruix, Hepatocellular carcinoma. Lancet, 2003. 362(9399): p. 1907-17.
4.    European Association for the Study of the Liver. Electronic address, e.e.e. and L. European Association for the Study of the, EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol, 2018.
5.    Heimbach, J.K., et al., AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology, 2018. 67(1): p. 358-380.
6.    Tzartzeva, K., et al., Surveillance Imaging and Alpha Fetoprotein for Early Detection of Hepatocellular Carcinoma in Patients With Cirrhosis: A Meta-analysis. Gastroenterology, 2018. 154(6): p. 1706-1718 e1.}

_{*numares’ products are not yet available for sale within the United States; they have not yet been approved or cleared by the U.S. Food and Drug Administration.}