Research in primary liver cancer calls for novel strategies targeting dynamic landscape of heterogeneous tumors

SingHealth

Singapore, 13 December 2021 – Clinician scientists and scientists from the National Cancer Centre Singapore (NCCS) and A*STAR’s Genome Institute of Singapore (GIS), in collaboration with Singapore General Hospital (SGH), the National University Health System, Duke-NUS Medical School, Nanyang Technological University, and collaborators from China, Malaysia, Thailand and the Philippines, have described a dynamic genomic landscape of tumour heterogeneity in hepatocellular carcinoma (HCC). This research comes from one of the largest prospective cohorts for HCC known as the Precision Medicine in Liver Cancer across Asia-Pacific Network (PLANet) study. These novel findings from PLANet were recently published in the journal National Science Review (NSR)[1].

Figure 1: Hepatocellular carcinomas (HCC) diversify during tumour evolution, leading to multiple co-existing subtypes in a significant proportion of HCC that will require combination systemic therapies to treat the disease.

Credit: A*STAR’s Genome Institute of Singapore

HCC is the seventh most common cancer worldwide, but the fourth leading cause of cancer death globally due to its high mortality rate[2]. Strikingly, a disproportionate 80% of the disease burden is shouldered by Asian populations. Despite much effort, there is currently no validated predictive biomarker for systemic therapies in HCC and treatment efficacy remains poor. To address this unmet clinical need, a collaborative multi-disciplinary and multi-institutional team was awarded funding to establish the Translational and Clinical Research (TCR) Flagship Programme in Liver Cancer, which is supported with funding from the National Research Foundation Singapore and administered by the Singapore Ministry of Health’s National Medical Research Council (NMRC)[3]. In this programme, the PLANet study was initiated to enrol a prospective HCC patient cohort working with the Asia-Pacific Hepatocellular Carcinoma (AHCC) Trials Group across multiple Asian countries. Specifically, PLANet aims to understand molecular diversities within a tumour known as intra-tumour heterogeneity (ITH), as well as how we can use such understanding to guide patient stratification and treatment in HCC. In 2017, the group discovered that HCC has a wide range of genetic ITH across patients[4].

The study and its findings

The current study is based on a cohort of 67 patients from four Asian countries from the PLANet study and is the first study of ITH across multi-omic data layers (genome, transcriptome, immunome) in HCC. Researchers found variations in different regions of the same tumour for both genetic (DNA mutation) and transcriptomic (RNA expression) profiles. In particular, they found that the level of such variations differs across patients and over 30% of patients show a high transcriptomic ITH where a single tumour could contain multiple transcriptomic subtypes.

Such dynamic, evolutionary process in HCC helps to explain the poor response to systemic therapy in HCC, where therapies addressing only a single group of molecular targets is not sufficient. Using the PLANet cohort, the authors demonstrated how combination therapies can potentially address the high ITH to increase treatment response rates for HCC. Discoveries from this research provide novel scientific rationale for the development of innovative therapies for HCC. In the next phase, the group will focus on how to improve liver cancer treatment outcome by targeting this dynamically evolving heterogeneity.

The PLANet study has also provided researchers and clinicians an atlas to assess the evolutionary history of liver cancer. Such genomic information will provide a solid basis for understanding how individual patients might respond differently to drug treatments, thus enabling a precision medicine approach to treat patients differently in the future. Data from this study is now publicly available via the Singapore Oncology Data Portal (OncoSG)[5] which allows integration, visualisation, analyses, and sharing of cancer genomics datasets generated in Singapore.

Dr Zhai Weiwei, a former principal investigator at GIS who co-led this work, noted, “This study depicted the first full landscape of tumour heterogeneity in HCC, providing a solid basis harnessing tumour evolution for patient prognosis and treatment”.

Professor Pierce Chow, senior author of the study, the overall principal investigator of PLANet and Senior Consultant, Department of Hepato-Pancreato-Biliary/Transplant Surgery, Division of Surgery and Surgical Oncology at SGH and NCCS said, “I have been treating HCC for more than 20 years and have conducted multi-national clinical trials in this cancer, but HCC remains a very challenging malignancy. Significant scientific breakthroughs are required to further improve patient outcomes and our current findings provide an important step in this direction.”

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