Prof Pierce Chow: ELEGANCE study explores cutting-edge methods to detect liver cancer early and more accurately
Cara Yap, 5 July 2021
Study start date: 15 April 2021
About the study
Called EarLy DEtection of HCC: miRNA, microbiome and imaGing biomArkers in the evolution of chroNiC livEr Disease in a high-risk prospective cohort (ELEGANCE), the four-year long study launched late last month will enroll 2,000 participants at risk for HCC. These include patients with liver cirrhosis, hepatitis B or C, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). The study involves public and private sector collaboration and has three tracks: 1) to evaluate the efficacy of a miRNA diagnostic kit for HCC with Singapore-headquartered multi-cancer early detection company MiRXES; 2) to develop an AI algorithm for identification of patients at-risk of developing HCC using state-of-the-art quantitative MR imaging, with digital medical technology company, Perspectum, whose Asia Pacific headquarters are in Singapore; and 3) to determine the changes in the microbiome and metabolome that lead to HCC with Southeast Asian precision gut microbiome company AMiLi. The goal of all three tracks is early diagnosis, better and more cost effective methods for improved patient outcomes and the identification of novel therapeutic targets.
How to get enrolled in the study
The multi-centre study is open for recruitment at healthcare institutions including National Cancer Centre Singapore (NCCS), Singapore General Hospital (SGH), National University Hospital (NUH), Changi General Hospital (CGH), Sengkang General Hospital (SKH), Tan Tock Seng Hospital (TTSH) and eight SingHealth Polyclinics (Bedok, Bukit Merah, Marine Parade, Outram, Pasir Ris, Punggol, Sengkang and Tampines). For more information on the study and eligibility, please contact the study’s coordinators at +65 6326 6573 or drop them an email at firstname.lastname@example.org
About the Principal Investigator
Professor Pierce Chow is Senior Consultant and Co-Director (Surgical) of the Comprehensive Liver Cancer Clinic at the NCCS, Senior Consultant Surgeon in Hepato-pancreato-biliary and Transplant Surgery at NCCS and SGH. He is concurrently Professor and Course Director at the Duke-NUS Medical School Singapore and Adjunct Faculty at the Genome Institute of Singapore. In addition to managing a busy HPB surgical oncology service, Prof Chow has conducted extensive research on hepatocellular carcinoma (HCC). He is actively involved in clinical trials on novel therapies and leads collaborative multi-disciplinary research on intra-tumoral genomic, immunomic and metabolomic heterogeneity in HCC and their applications to precision medicine. He co-founded the Asia-Pacific Hepatocellular Carcinoma Trials Group in 1997 and has been the protocol chair of 7 prospective multi-national trials including the SIRveNIB trial which closed in 2016. In 2005 he led the multi-disciplinary research that developed BrachySil® (now OncoSil®) and the subsequent first-in-man trial. 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. Prof Chow was awarded the NMRC Translational-Clinical Research Grant for the Flagship Program in Liver Cancer in 2016 and has commenced the multi-national PLANET study (Precision Medicine in Liver Cancer Asia-Pacific Network). In 2020, Prof Chow was awarded an A*STAR grant to conduct a nation-wide cohort study do develop diagnostics for ELEGANCE.
Why are only 20 per cent of HCC patients diagnosed at an early stage?
It is actually very challenging to diagnose HCC early, with one of the reasons being that the liver is an internal organ. Hence, liver cancer is not something you can see or feel, unlike breast cancer, where you may feel a lump while taking a shower. For you to experience symptoms in liver cancer, essentially means you have not detected it early enough. Patients who are diagnosed early are usually on a surveillance programme, or undergoing some kind of imaging for another related condition. High-risk patients who have conditions such as hepatitis or liver cirrhosis may see their doctors regularly for surveillance. The other reason it is not detected early is because the current modalities of diagnosing very early stage HCC are actually not so sensitive. Ultrasound will only detect large tumours well, but not for early stage liver cancer. Moreover, blood tests are also not so sensitive, so that’s where the challenges lie.
What are the average survival odds for patients who are diagnosed and treated for HCC at an early stage, compared to those at a later stage?
The difference is actually stark - diagnosis at an early stage means the possibility of cure - where we are able to treat the cancer without it returning. Once it reaches the intermediate or advanced stage, however, we are looking at treatment that prolongs your life - unless that treatment can reduce the cancer to an early stage where you can potentially be treated with modalities with the aim to cure. With the best systemic therapy for late-stage liver cancer patients, we are looking at a median survival rate of 20 months or less, while you can potentially be cured and live your natural life span if you detect it at an early stage.
Hence, therapeutic aims are very different. Aside from the chances of survival, there is also the cost factor - if you are diagnosed very early, the cost of treatment is relatively low, while systemic therapy for advanced stage liver cancer patients can be hugely expensive.
What's the disparity in treatment costs are we looking at, in the context of Singapore’s healthcare system?
If you are diagnosed at an early stage of the disease - where we, for instance, pick up a 2cm tumour - and you are quite fit physically, we can have it surgically removed. If you aren’t fussed about staying in a single room, you could actually pay the entire fee through Medisave. To undergo the best systemic therapy for advanced-stage liver cancer, we are looking at monthly costs in the region of $10,000 or more. If you are lucky and respond to the therapy, you may undergo the therapy for the rest of your life. So you can imagine how expensive it is, either for the patient or the state.
Tell us more about the groups at high risk of developing HCC. How often are they typically screened for the disease?
The risk groups are very specific. Take for example, a patient with chronic Hepatitis B, of which we have quite a few in Singapore. He has more than 100 times the risk of developing liver cancer, compared to the non-Hep B carrier. Many of these at risk individuals don’t undergo regular surveillance because it can be troublesome. You have to show up at the hospital’s radiology department for the ultrasound scan, which is followed by a blood test. This has to be done every six months, which includes a doctor’s consultation after the tests. As this isn’t something that can be done at the GP, many people who know they are at high risk don’t avail themselves to surveillance. Hence, we have a huge unmet need here, and if we are able to fill this gap then patients should ideally all be diagnosed at a much earlier stage, with many more coming forward for surveillance.
Why is this study so significant?
It is very significant because we actually enrol patients who are known to be at high risk of developing liver cancer. If you really want to know what works in diagnosing them early, you have to follow this group of patients along a longitudinal study. Our study calls for a three-year follow up, with plans to follow up for at least 10 years. We want to know if there is any way to predict who will develop liver cancer, and how early we can detect it.
Most studies that compare diagnostic modalities look at patients who already have liver cancer to gauge their accuracy. This study is very important because it explores what happens to patients as they develop liver cancer, so can we detect it earlier, and in a more accurate manner. Can we do something to prevent it from developing in the first place? It is currently accepted by most doctors that stool (microbiome) changes as people’s bodies change, along with metabolism. But we don’t know the specific components of such changes, which can only be unveiled in a prospective study such as this. We are trying to look for metabolic processes in the body, stool (microbiome) and urine (metabolome) that change as we develop liver cancer, and if we can identify these changes we might actually be able to prevent them. This is quite a unique study, because I don’t think there are any in the world that uses so much cutting-edge technology to look at microbiome and metabolome.
How will this study benefit the patients enrolled, considering they won’t undergo therapy?
At the end of the study most of the 2,000 patients enrolled will probably not have developed liver cancer. However, all of these patients will undergo surveillance for the rest of their lives. While we hope the individual does not really develop liver cancer, they can potentially be cured if we detect it early. Even those who do not develop it will benefit from the scientific data that we derive from the study, because we will apply that to their future consultations.
How exactly does the miRNA diagnostic test work? Why was it chosen as a method to detect HCC?
An ideal diagnosis for cancer should be based on something that the cancer actually shares, which means something involved in the molecular process of the cancer. Today, we use alpha-fetoprotein, which is not that good, as it is actually a by product - some cancers have the alpha-fetoprotein while others don’t. However, we have seen that for liver cancer, micro RNA (miRNA) is something shared by cancer cells themselves, and many are actually involved in the process of the cancer developing.
In very early stage tumours, we have to look at something like miRNA, because it is actually involved in the process of the cancer developing, as opposed to something that is happening in the advanced stage. And there is a precedent for this - the miRNA diagnostic kit was developed by MiRXES and National University Hospital Singapore for cancer of the stomach, and the same technology is now utilised to develop a diagnostic for liver cancer. The other reason is that miRNA is very stable in the blood; some of the other biomarkers are relatively less unstable and therefore not very useful for diagnostics.
How much more accurate will the new miRNA diagnostic kit be?
Using ultrasound scans and alpha-fetoprotein to detect early HCC is about 60 per cent accurate, while we are looking at an accuracy of more than 80 per cent for our new diagnostic tool in our pilot study.
If the study is successful, what kind of new diagnostics solutions will be applied in the clinical setting? How soon can we expect that, after the trial ends?
With this study, we will test out the MiRXES prototype’s efficacy in detecting liver cancer, while at the same time continuing to conduct research - we will collect samples from patients to see whether other combinations of miRNA can be more useful. So in the best case scenario that their prototype works, we are talking about a new diagnostic tool in the market within three years. Instead of having to visit the hospital for an ultrasound scan and blood test every six months, you can drop by your GP after work in the evening, have your blood test done and get your results the next week. This is what we term as disruptive technology, because it will change the way we work and patient outcomes in a very significant way. With early diagnosis, the overall survival rate for liver cancer will improve significantly.
What else should patients who are interested in enrolling in the study be aware of?
In this study, we are enrolling patients who should be on surveillance. All expenses from the tests in the study are covered, and there are potential future benefits to participating in the study. We hope patients who know they are at high risk but don’t undergo surveillance because of the cost can change their minds and take advantage of this study.