by Dr. Pierce Chow Kah Hoe
National Cancer Center Singapore
Hepatocellular carcinoma (HCC) is the 6th most common cancer in the world and is diagnosed in more than a million new patients a year. It is however the 2nd most important cause of cancer death  and the 3rd most important cancer in Asia [2-4]. Surgery is potentially curative in early HCC which applies approximately to only 20% of patients  and confers a modest overall survival (OS) of > 60% at 5 years with early cancers defined as those within the Milan criteria. Another 30% may undergo loco-regional therapies such as trans-arterial chemo-embolization (TACE) and Selective Internal Radiation Therapy (SIRT) with median survivals of 18 – 24 months. Untreated patients with intermediate tumour but good liver function survive 6 – 8 months [6,7] and with poor liver function < 3 months [8,9]. Tumour recurrence after surgical resection is > 50% at 5 years even for those with early disease  and is responsible for the poor overall surgical survival. Of the common solid cancers, the distinct absence of efficacious systemic therapies for HCC results in poor outcomes for advanced cancer stages, no meaningful adjuvant therapy for resected cases and poor long-term surgical outcomes [11,12].
HCC is a highly heterogeneous cancer with only one systemic therapy namely sorafenib  in which its randomized clinical trials showed the survival improved by only 2.3 and 2.8 months in Asian and Western patients respectively [7,14]. The underlying mechanism of sorafenib remains unclear and there is no validated predictive biomarker [15-17]. Therefore, there is an urgent and unmet clinical need to adopt new approaches to identify and develop novel therapeutic options for treating HCC.
Previous approaches to characterize the genomic heterogeneity of HCC (and most other solid cancers) have been based on single tumor samples from retrospective cohorts to identify the presence/ absence of driver alterations. This has not lead to many efficacious therapies [18-24]. Between 2002 and 2012, the 71 anti-cancer drugs approved by FDA (including 52 molecular targeted drugs) have only managed to increase median overall survival by 2.1 months [25,26]. Tumour heterogeneity and specifically Intra-tumour heterogeneity (ITH), is increasingly recognised as being important in drug development strategies in precision medicine for cancer . Previous studies in renal , breast [29-31], lung , colorectal [33-35], pancreatic [36,37], and glioblastoma cancers  have established the presence of significant intra-tumour diversity. However, ITH in HCC has been largely understudied and previously published studies on genetic diversity in HCC did not investigate intra-tumour heterogeneity [21,39].
Recent advances in genomic technology have provided an unprecedented opportunity for longitudinal, spatial and in-depth mapping of tumor samples from surgical resections to reveal genetic variations at the whole genome level. A process of branched tumor evolution [40-42] can be clearly represented by a phylogenetic tree where the trunk represents mutations present in all parts of the tumor and the branches are mutations specific to a particular region . This also reflects relative molecular time acquisition i.e. trunk mutations are acquired prior to branch mutations . With regards to HCC, whole genome sequencing of HCC samples would also have the advantage of analysing hepatitis B virus integration in the genome , the hepatitis B virus being one of the most important etiologies in development of HCC.
The inability to identify clonally dominant driver mutations from HCC prevents clinicians from being able to efficaciously select systemic therapy and to personalise therapy to patient. The paucity of efficacious systemic therapy is a main reason for the high case fatality in HCC. Hence there is a compelling need for a more thorough understanding of the genetic heterogeneity of HCC to develop more efficacious therapy. From a therapeutic perspective, targeting clonally dominant driver mutations that are early and constant events on the phylogenetic tree (e.g. KRAS, NRAs, BRAF in colorectal cancer) provides a more effective drug development strategy than considering actionable alterations as being present or absent.
The study of Totoki et al shows similarly significant differences in mutational signatures between ethnicities. These warrant investigations to determine patterns of inter-ethnic heterogeneity which will inform drug development and help stratify therapy in HCC.
Apart from focusing on the genomics characteristic of HCC tumors, alternative treatment targeting the tumor microenvironment (TME) is also another important theme. Of particular interest is targeting the immune microenvironment of HCC which has shown potential prognostic and therapeutic values in several studies [45-47]. The recent introduction and success in immunotherapy in cancer has revolutionized the field of cancer therapy  with approval of anti-CTLA4 and anti-PD-1 for melanoma [49-53]. The effectiveness of various immunotherapies which are currently at various stages of clinical trials in HCC is yet to be determined [54-56]. Cancer immunotherapy has tremendous potential role in treating cancers that are highly heterogeneous at the genomic level and lack of effective systemic therapy like HCC.
Given the paucity of efficacious systemic therapy in HCC, a fresh approach is required for precision medicine in HCC. With that, the impact on healthcare will be significant worldwide especially in countries where HCC is endemic.
Dr. Daniel G. Tenen
Pierce K.H Chow MBBS M.Med (Surgery) FRCSE, FAMS, PhD
Professor, Duke-NUS Graduate Medical School, Singapore
Senior Consultant Surgeon, National Cancer Center Singapore
Senior Consultant Surgeon, Singapore General Hospital
Associate Faculty, Genome Institute of Singapore
Pierce Chow is Senior Consultant Surgical Oncologist and Co-Director (Surgical) of the Comprehensive Liver Cancer Clinic at the National Cancer Centre Singapore. He is concurrently Senior Consultant Surgeon in HPB and Transplant Surgery at the Singapore General Hospital and Professor at the Duke-NUS Graduate Medical School, Singapore.
Professor Chow was the Chapter of Surgeon’s Gold Medalist at the conjoint Royal College of Surgeons of Edinburgh/M.Med (Surgery) examination in 1994 and subsequently completed a clinical fellowship in Liver Transplantation in Australia.
Professor Chow specialises in Hepato-Pancreato-Biliary (HPB) surgery and leads the Program in Translational and Clinical Liver Research at the National Cancer Centre Singapore. This multi-disciplinary and multi-institutional programme of translational and clinical researchers focuses on NAFLD/NASH, the genomics of HCC and applications to precision medicine, and brachytherapy and immunotherapy in HCC.
He co-founded the Asia-Pacific Hepatocellular Carcinoma Trials Group in 1998 and has been the protocol chair of 5 multi-national trials. In 2012 the National Medical Research Council Singapore conferred him the National Outstanding Clinician-Scientist Award for improving clinical outcomes of patients with his research on Liver Cancer.
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