Editor's Note: Traditional screening methods in the field of liver cancer prevention and treatment face numerous challenges. At the 2024 European Association for the Study of the Liver (EASL) Annual Meeting, the CLiMB trial, led by Professor Richard Van Etten, Director of the UCI Chao Family Comprehensive Cancer Center in the United States, achieved significant results in the early diagnosis of hepatocellular carcinoma (HCC) in cirrhotic patients using the innovative HelioLiver Dx testing technology. This research was recognized as a breakthrough and was presented orally (Abstract No. LBO-006). HelioLiver Dx testing technology, which detects multiple epigenetic methylation markers on circulating cell-free DNA (cfDNA) and combines the analysis of various protein markers, successfully overcomes the limitations of ultrasound screening in terms of popularity and sensitivity. The study results show that HelioLiver Dx testing significantly surpasses ultrasound in sensitivity, especially in detecting small liver lesions less than 2 cm. We had an in-depth interview with Professor Van Etten and present the content for our readers.Hepatology Digest: At this year’s EASL Annual Meeting, you presented a clinical study on liver cancer. Could you please introduce the main background and objectives of this study?
Professor Van Etten: In the United States, the traditional screening method for at-risk patients—whether they have cirrhosis or chronic hepatitis B infection—is an ultrasound examination every six months, with or without the measurement of alpha-fetoprotein (AFP). However, ultrasound has numerous limitations, including a low uptake rate (in reality, only about 10% of the high-risk population in the U.S. regularly undergoes ultrasound screening) and poor performance in detecting minor liver damage. Early detection of such damage is crucial because the timing of detection is clearly linked to clinical outcomes and survival rates.
HelioLiver Dx is an innovative blood test that observes multiple epigenetic methylation markers on circulating cell-free DNA (cfDNA) and combines this with the analysis of protein markers such as AFP, AFP-L3, and DCP. This test has been validated in a population of patients with cirrhosis.
The CLiMB trial is a prospective, blinded, multi-center study and the first trial using epigenetic markers for early HCC diagnosis in a high-risk population. The unique aspect of this study is that it addresses the urgent need for early HCC detection through HelioLiver Dx testing.
Hepatology Digest: What are the unique advantages or limitations of this multi-analyte blood test in detecting HCC among cirrhotic patients?
Professor Van Etten: HelioLiver Dx testing offers several advantages over ultrasound screening. Firstly, in many areas of the U.S., especially remote regions, ultrasound is not widely available, resulting in less than 10% uptake among cirrhotic patients. Secondly, ultrasound is expensive, highly dependent on the operator’s skills, and less sensitive in detecting small lesions. HelioLiver Dx was designed to overcome these limitations. It not only improves sensitivity in detecting small lesions but also aims to increase the screening uptake rate among high-risk populations. We believe this will enhance screening adherence, enable early disease detection, positively impact survival rates, and potentially reduce healthcare costs.
Hepatology Digest: What are the preliminary results of this study? What is the potential clinical application value of these results for the early diagnosis of HCC in cirrhotic patients?
Professor Van Etten: In the CLiMB trial, we recruited over 1,200 cirrhotic patients. All participants underwent ultrasound and HelioLiver Dx testing, followed by MRI to determine the clinical truth. The results showed that HelioLiver Dx achieved all primary, secondary, and exploratory endpoints, including higher sensitivity than ultrasound and equivalent specificity.
Let me explain these endpoints further. The primary endpoint was to verify if HelioLiver testing had higher sensitivity in detecting HCC compared to ultrasound. Our goal was to increase sensitivity by at least 5%, and the actual results showed an approximately 20% increase. Moreover, based on a non-inferiority margin of -10%, the test’s specificity was comparable to ultrasound. In secondary analyses for lesions smaller than 4 cm, HelioLiver also outperformed ultrasound in sensitivity. Lastly, in exploratory analyses for extremely small lesions (less than 2 cm), HelioLiver’s sensitivity improved by over 29%, while ultrasound failed to detect any of these lesions. Thus, HelioLiver Dx testing has the potential to become the new standard for HCC screening in the U.S. We hope this technology will soon gain FDA approval, allowing more patients to benefit from screening and positively impacting their health and healthcare costs.
Hepatology Digest: Based on the results of this study, what are the future research directions? Is there a possibility to further optimize this multi-analyte blood test to enhance its sensitivity and specificity?
Professor Van Etten: As mentioned earlier, we expect HelioLiver Dx testing to receive FDA approval later this year. Once approved, we will focus on promoting its use among high-risk HCC patients to aid in early treatment. Additionally, we have planned more studies to follow up on patients who undergo this testing. We are also planning a cross-benefit analysis in collaboration with Professor Mindie Nguyen at Stanford University. It’s worth noting that the methylation state detection technology for cell-free DNA that we developed is also applicable to other types of tumors. Therefore, we are preparing feasibility studies for screening other cancers, such as lung cancer, pancreatic cancer, and ovarian cancer.
