HPB Cancers Biomarkers
(i) Early diagnosis of HCC
The incidence of hepatocellular carcinoma (HCC) is currently the most rapidly rising of any cancer in the Western world, related to the increasing burden of the major risk factor, chronic liver disease. This is particularly pertinent to the Merseyside region, which has the highest incidence of liver disease in England and Wales (Environmental Health Atlas Map). Mortality approximates incidence indicating the generally lethal nature of this disease and currently the only way to improve outcomes is by early diagnosis. Since the major risk factor for HCC is known, surveillance of patients with chronic liver disease in the form of 6-monthly liver ultrasonography is performed, although its implementation is highly variable across the UK and it is limited by poor sensitivity and specificity and operator variability. We have built statistical models, using clinical parameters and three recognised biomarkers for hepatocellular carcinoma (HCC) (alpha-fetoprotein, AFP-L3 and des gamma carboxy prothrombin) that can accurately determine the risk of HCC presence in the individual patient with chronic liver disease and which can be performed on <20µl serum. Similar models can also very accurately predict survival. The major advantage of these models is that all the variables involved are entirely objective unlike currently available approaches to HCC surveillance. We are currently developing a large multi-centre randomised trial to determine whether this test can support, or supplant, the current standard of surveillance ultrasound examination.
(ii) Biliary cancer biomarkers
Having already accumulated in excess of 100 serum samples from patients with biliary cancers, in collaboration with Dr Chiara Braconi and Prof Jeff Evans at the Beatson Institute and Simon Afford in Birmingham, we are investigating a number of candidate biomarkers, including small non-coding RNAs and full-length and cleaved cytokeratins for improved diagnosis, prognostication and prediction of treatment response in patients with cancers of the biliary tract.
(iii) Biomarkers of drug-induced liver injury
The dose-limiting toxicity for many anti-cancer agents is hepatic. Currently, the occurrence of drug-induced liver injury (DILI) is routinely assessed by monitoring a variety of clinical chemistry markers including serum ALT/AST, bilirubin, alkaline phosphatase and others. Whilst a useful guide, there are specificity and sensitivity issues with these. For example, ALT/AST, which are the primary reference estimate for liver damage, may poorly reflect injury to normal liver tissue in patients with hepatic malignancies for a variety of reasons and have never been fully validated for drug-induced liver injury against histologically characterised biopsies. Thus, there is a need to augment the current safety biomarker repertoire with respect to DILI through the incorporation of additional markers. The MRC CDSS have developed a panel of novel selective and sensitive early serum biomarkers of liver damage. Each of the biomarker assays is established within our labs and has been demonstrated, through peer-reviewed publications, to have sufficient sensitivity for monitoring in human plasma samples from patients with DILI. We are currently undertaking validation against histological changes in patients with chemotherapy-induced liver toxicity following neo-adjuvant chemotherapy prior to liver resection for colorectal liver metastases and the panel is also being applied to a number of early phase clinical trials in the LEDDU portfolio.
