|Project outline

HERMES – Hepatocellular Carcinoma Recognition by Metabolomics Analysis of Serum

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

“A diagnostic screening test for early detection of hepatocellular cancer to supplement abdominal sonography in HCC surveillance.“
Dr. Eric Schiffer, Head of Clinical Development, numares AG

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 metabolic 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.