A multianalyte blood test detected more hepatocellular carcinoma (HCC) — including more early-stage tumors — than abdominal ultrasound in adults with cirrhosis, according to a prospective, blinded multicenter trial published in Journal of Hepatology.
“Hepatocellular carcinoma (HCC) incidence is still increasing, and 5-year survival is still very poor, around 20%, and much of this is due to late diagnosis,” the study’s senior author, Mindie H. Nguyen, MD, MAS, AGAF, FAASLD, a hepatologist at Stanford University Medical Center, Palo Alto, California, told GI & Hepatology News. She noted that real-world nationwide US data show that only 9% of patients with a documented diagnosis of cirrhosis undergo liver ultrasound screening every 6-12 months, despite professional society guidelines recommending ultrasound-based HCC surveillance every 6 months for patients with cirrhosis since 2020. She added that a blood-based test “likely will receive better adherence by patients,” potentially increasing early-stage HCC detection and improving survival outcomes.
For the study, Dr. Nguyen and colleagues compared the blood test with ultrasound for detecting liver cancer, using multiphasic magnetic resonance imaging (MRI) performed at the same time as the reference standard. They enrolled 1,556 adults with cirrhosis across 42 US clinical sites in the prospective, blinded CLiMB study. After excluding some participants and completing follow-up evaluations for unclear imaging results, 1,268 patients were included in the final analysis.
Among these patients, 46 (4%) were diagnosed with hepatocellular carcinoma based on magnetic resonance imaging (MRI). Nearly half of the cancers were 2 cm or smaller, and 80% were 4 cm or smaller. Most tumors were diagnosed at an early stage (T1).
All participants underwent blood testing, abdominal ultrasound, and multiphasic MRI. Ultrasound and MRI scans were reviewed centrally by board-certified radiologists who were unaware of the patients' clinical information and test results. The HelioLiver Dx blood test was performed by technicians who were blinded to the imaging findings. The test, which is commercially available but not yet FDA cleared, combines cell-free DNA methylation markers with patient age, sex, and blood levels of alpha-fetoprotein (AFP), AFP-L3, and des-gamma-carboxy prothrombin to determine whether the result is positive or negative.
For detecting hepatocellular carcinoma, HelioLiver Dx identified 48% of cancers, compared with 28% detected by ultrasound. The blood test had a specificity of 88%, versus 94% for ultrasound. Using prespecified statistical criteria, the researchers found that HelioLiver Dx was more sensitive than ultrasound while maintaining a similar level of specificity.
For tumors measuring 2 cm or smaller, HelioLiver Dx detected 29% of cancers, while ultrasound detected none. For tumors larger than 2 cm but no greater than 3 cm, detection rates were 54% for HelioLiver Dx and 31% for ultrasound. The blood test also outperformed ultrasound in patients with early-stage (T1) disease, detecting 40% of tumors compared with 10% for ultrasound alone.
The investigators also compared HelioLiver Dx with alpha-fetoprotein (AFP) alone and with ultrasound-plus-AFP screening strategies. Using the commonly used AFP cutoff of 20 ng/mL, AFP alone detected 22% of cancers, while ultrasound combined with AFP detected 35%. Lowering the AFP cutoff to 10 ng/mL increased the sensitivity of ultrasound plus AFP to 39%. HelioLiver Dx outperformed all of these approaches, detecting 48% of cancers.
“I hope this is the first of many more blood-based test options to come for patients at high risk for liver cancer,” Dr. Nguyen said. “I strongly believe that blood-based testing will be much easier for patients to do, will greatly enhance effectiveness of HCC surveillance via both increased adherence and increased test efficacy. One of the most important factors in the prognosis of HCC patients is early diagnosis, so HCC surveillance is paramount.”
Exploratory analyses showed that HelioLiver Dx consistently detected more cancers than the comparison screening methods across a range of patient groups, including those defined by sex, race, ethnicity, and the underlying cause of cirrhosis. Depending on the cause of liver disease, the blood test's sensitivity was approximately 6 to 67 percentage points higher than that of the comparator strategies. However, the study was not designed to determine whether these subgroup differences were statistically significant.
The authors noted that current guidelines recommend ultrasound every 6 months, with or without AFP, to screen for hepatocellular carcinoma (HCC) in patients with cirrhosis. However, many patients do not receive regular surveillance, and ultrasound accuracy can vary depending on patient factors, tumor size, and the skill of the person performing the test. Because more than 80% of participants in the CLiMB study were enrolled at community-based centers, the findings may reflect real-world screening settings.
Dr. Nguyen and colleagues acknowledged several limitations of the study. The analysis was cross-sectional and did not assess long-term outcomes, patient adherence to surveillance, or effects on mortality. The study also enrolled fewer participants than originally planned, which reduced its statistical power. In addition, it was not designed to evaluate differences within patient subgroups or to directly compare HelioLiver Dx with ultrasound plus AFP. The cohort included a high proportion of patients with obesity, a factor known to reduce the sensitivity of ultrasound, “though this may reflect a real-world situation with the rising epidemic of obesity and metabolic dysfunction-associated steatotic liver disease-related HCC,” Dr. Nguyen said.
“One would want any test to be as sensitive and specific as possible,” she added. “That is the task for future research including Helio Genomics: to develop and test the second-generation test to increase sensitivity and test accuracy even though the current panel is already significantly more sensitive than ultrasound.”
The study was funded by Helio Genomics. Several authors are current or former employees of the company. Dr. Nguyen disclosed that she receives research support from Pfizer, Enanta, AstraZeneca, Delfi Technologies, GSK, Gilead, CurveBio, Exact Sciences, Helio Genomics, Glycotest, Vir Biotech, Roche, National Institutes of Health, and Aligos.