Cell-free DNA testing shows promise for early liver cancer detection

Methylation-based cfDNA assays appear particularly promising.

by Doug Brunk

Cell-free DNA (cfDNA) testing is emerging as a potentially powerful tool to improve how clinicians detect, monitor, and risk-stratify hepatocellular carcinoma (HCC), according to a review published in Hepatology.

HCC remains a leading cause of cancer-related death worldwide, in large part because it is often diagnosed at advanced stages. Current guidelines recommend semiannual ultrasound with alpha-fetoprotein (AFP) for surveillance in patients with cirrhosis or chronic hepatitis B. However, the approach has well-recognized limitations, including suboptimal sensitivity for early-stage disease, reduced performance in patients with obesity or metabolic liver disease, and low real-world uptake, noted corresponding author Ju Dong Yang, MD, medical director of the liver cancer program at Cedars-Sinai Medical Center, Los Angeles.

Dr. Yang and colleagues summarized rapidly evolving evidence on cfDNA, small fragments of DNA released into the bloodstream from dying cells, as a noninvasive biomarker that may address several of these gaps. Tumor-derived cfDNA reflects the molecular features of HCC and can be analyzed for genetic mutations, methylation patterns, copy number changes, and fragmentation profiles.

Among the potential clinical applications of cfDNA, early detection appears to be the most advanced. Investigators summarized several cfDNA-based blood tests that combine tumor-derived DNA features with demographic variables and serum markers such as AFP. Multiple assays have progressed to phase 3 validation, with results showing sensitivity for early-stage HCC that is noninferior or superior to ultrasound-based surveillance, while maintaining high specificity, often above 85% to 90% in validation cohorts. The authors noted that cfDNA testing is not operator dependent and may be easier to implement consistently across clinical settings.

Methylation-based cfDNA assays appear particularly promising. Multitarget tests integrating cfDNA methylation markers with AFP and clinical variables achieved areas under the receiver operating characteristic curve exceeding 0.9 in phase 2 studies. Dr. Yang and colleagues noted that the assays maintain performance across viral and nonviral etiologies of liver disease, a key advantage as metabolic dysfunction–associated steatotic liver disease becomes a more common driver of HCC. Large prospective trials directly comparing methylation-based blood tests with ultrasound surveillance are ongoing.

Fragmentation-based approaches represent another emerging strategy. The tests analyze the size and genomic distribution of cfDNA fragments using low-coverage whole-genome sequencing and machine learning. Case–control studies have demonstrated strong diagnostic accuracy and high specificity, but larger cohort-based validation is still needed before clinical adoption, investigators noted.

Beyond surveillance, researchers highlighted the potential role of cfDNA in supporting more personalized management of HCC. Early studies summarized in the review suggest that cfDNA features may identify patients at higher risk of recurrence or aggressive tumor behavior, independent of conventional clinical predictors. In the post-treatment setting, detection of tumor-specific cfDNA after curative-intent therapy has been associated with an increased risk of recurrence, raising the possibility of earlier intervention or intensified follow-up.

The authors noted that many cfDNA applications remain investigational. “Currently, there is a lack of Western cohorts with processing protocols compatible with cfDNA for HCC biomarker evaluation,” they wrote. “In addition, large volumes of plasma samples are usually required for deep sequencing. Fortunately, National Cancer Institute’s Biorepositories and Biospecimen Research Branch has introduced a cfDNA-specific guideline to harmonize the collection and processing steps for future studies. Establishing prospective blood biobanks by following these cfDNA-compatible protocols across multiple institutions would greatly facilitate the validation of emerging cfDNA assays.”

Dr. Yang disclosed that his research is funded by the National Institutes of Health. He also consults for AstraZeneca, Eisai, Exact Sciences, and Fujifilm Medical Sciences.

Summary content

The guidelines emphasize four-hour gastric emptying studies over two-hour testing. How do you see this affecting diagnostic workflows in practice?

Dr. Staller: Moving to a four-hour solid-meal scintigraphy will actually simplify decision-making. The two-hour reads miss a meaningful proportion of delayed emptying; standardizing on four hours reduces false negatives and the “maybe gastroparesis” purgatory that leads to repeat testing. Practically, it means closer coordination with nuclear medicine (longer slots, consistent standardized meal), updating order sets to default to a four-hour protocol, and educating front-line teams so patients arrive appropriately prepped. The payoff is fewer equivocal studies and more confident treatment plans.

Metoclopramide and erythromycin are the only agents conditionally recommended for initial therapy. How does this align with what is being currently prescribed?

Dr. Staller: This largely mirrors real-world practice. Metoclopramide remains the only FDA-approved prokinetic for gastroparesis, and short “pulsed” erythromycin courses are familiar to many of us—recognizing tachyphylaxis limits durability. Our recommendation is “conditional” because the underlying evidence is modest and patient responses are heterogeneous, but it formalizes what many clinicians already do: start with metoclopramide (lowest effective dose, limited duration, counsel on neurologic adverse effects) and reserve erythromycin for targeted use (exacerbations, bridging).

Several agents, including domperidone and prucalopride, received recommendations against first-line use. How will that influence discussions with patients who ask about these therapies?

Dr. Staller: Two points I share with patients: evidence and access/safety. For domperidone, the data quality is mixed, and US access is through an FDA IND mechanism; you’re committing patients to EKG monitoring and a non-trivial administrative lift. For prucalopride, the gastroparesis-specific evidence isn’t strong enough yet to justify first-line use. So, our stance is not “never,” it’s just “not first.” If someone fails or cannot tolerate initial therapy, we can revisit these options through shared decision-making, setting expectations about benefit, monitoring, and off-label use. The guideline language helps clinicians have a transparent, evidence-based conversation at the first visit.

The guidelines suggest reserving procedures like G-POEM and gastric electrical stimulation for refractory cases. In your practice, how do you decide when a patient is “refractory” to medical therapy?

Dr. Staller: I define “refractory” with three anchors.

1. Adequate trials of foundational care: dietary optimization and glycemic control; an antiemetic; and at least one prokinetic at appropriate dose/duration (with intolerance documented if stopped early).

2. Persistent, function-limiting symptoms: ongoing nausea/vomiting, weight loss, dehydration, ER visits/hospitalizations, or malnutrition despite the above—ideally tracked with a validated instrument (e.g., GCSI) plus nutritional metrics.

3. Objective correlation: delayed emptying on a standardized 4-hour solid-meal study that aligns with the clinical picture (and medications that slow emptying addressed).
At that point, referral to a center with procedural expertise for G-POEM or consideration of gastric electrical stimulation becomes appropriate, with multidisciplinary evaluation (GI, nutrition, psychology, and, when needed, surgery).

What role do you see dietary modification and glycemic control playing alongside pharmacologic therapy in light of these recommendations?

Dr. Staller: They’re the bedrock. A small-particle, lower-fat, calorie-dense diet—often leaning on nutrient-rich liquids—can meaningfully reduce symptom burden. Partnering with dietitians early pays dividends. For diabetes, tighter glycemic control can improve gastric emptying and symptoms; I explicitly review medications that can slow emptying (e.g., opioids; consider timing/necessity of GLP-1 receptor agonists) and encourage continuous glucose monitor-informed adjustments. Pharmacotherapy sits on top of those pillars; without them, medications will likely underperform.

The guideline notes “considerable unmet need” in gastroparesis treatment. Where do you think future therapies or research are most urgently needed?

Dr. Staller: I see three major areas.

1. Truly durable prokinetics: agents that improve emptying and symptoms over months, with better safety than legacy options (e.g., next-gen motilin/ghrelin agonists, better-studied 5-HT4 strategies).

2. Endotyping and biomarkers: we need to stop treating all gastroparesis as one disease. Clinical, physiologic, and microbiome/omic signatures that predict who benefits from which therapy (drug vs G-POEM vs GES) would transform care.

3. Patient-centered trials: larger, longer RCTs that prioritize validated symptom and quality-of-life outcomes, include nutritional endpoints, and reflect real-world medication confounders.

Our guideline intentionally highlights these gaps to hopefully catalyze better trials and smarter referral pathways.

Dr. Staller is with the Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston.

Cell-free DNA testing shows promise for early liver cancer detection

Methylation-based cfDNA assays appear particularly promising.

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