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Liquid biopsy a valuable tool for detecting, monitoring HCC

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Overcoming difficulties of tissue biopsy

Detection and characterization of circulating tumor DNA (ctDNA) is one of the major forms of liquid biopsy. Because ctDNA can reflect molecular features of cancer tissues, it is considered an ideal alternative to tissue biopsy. Furthermore, it can overcome the limitation of tumor tissue biopsies such as bleeding, needle tract seeding, and sampling error.

Ju Dong Yang, MD, is with the Karsh Division of Digestive and Liver Diseases in the department of medicine, with the Comprehensive Transplant Center, and with the Samuel Oschin Comprehensive Cancer Institute at Cedars Sinai Medical Center, Los Angeles. He

Dr. Ju Dong Yang

In the current article, the authors reviewed the molecular characteristics of ctDNA and their detection technologies, as well as the molecular landscapes of ctDNA in hepatocellular carcinoma (HCC) covering single-nucleotide variation, copy number variations, DNA methylation aberrations, preferred end motifs or coordinates, and hepatitis B virus integration. They also discussed the clinical utility of ctDNA for the management of HCC.

Currently, several large biomarker trials of ctDNA for early HCC detection are underway. Once its accuracy is established in phase 3-4 biomarker studies, the role of ctDNA in the context of the existing surveillance program should be further defined. As the combination of ctDNA and other orthogonal circulating biomarkers was shown to enhance the performance, future research should explore biomarker panels that include ctDNA and other promising markers to maximize performance. Predictive biomarkers for treatment response is an unmet need in HCC. Investigating the role of a specific ctDNA marker panel as a predictor of immunotherapy responsiveness would be of great interest and is under active investigation.

Ju Dong Yang, MD, is with the Karsh Division of Digestive and Liver Diseases in the department of medicine, with the Comprehensive Transplant Center, and with the Samuel Oschin Comprehensive Cancer Institute at Cedars Sinai Medical Center, Los Angeles. He disclosed providing consulting services for Exact Sciences and Exelixis and Eisai.



Liquid biopsy using circulating tumor (ctDNA) detection and profiling is a valuable tool for clinicians in monitoring hepatocellular carcinoma (HCC), particularly in monitoring progression, researchers wrote in a recent review.

Details of the review, led by co–first authors Xueying Lyu and Yu-Man Tsui, both of the department of pathology and State Key Laboratory of Liver Research at the University of Hong Kong, were published in Cellular and Molecular Gastroenterology and Hepatology.

Because there are few treatment options for advanced-stage liver cancer, scientists are searching for noninvasive ways to detect liver cancer before is progresses. Liver resection is the primary treatment for HCC, but the recurrence rate is high. Early detection increases the ability to identify relevant molecular-targeted drugs and helps predict patient response.

There is growing interest in noninvasive circulating cell-free DNA (cfDNA) as well as in ctDNA – both are part of promising strategies to test circulating DNA in the bloodstream. Together with other circulating biomarkers, they are called liquid biopsy.

HCC can be detected noninvasively by detecting plasma ctDNA released from dying cancer cells. Detection depends on determining whether the circulating tumor DNA has the same molecular alterations as its tumor source. cfDNA contains genomic DNA from different tumor clones or tumors from different sites within a patient to help real-time monitoring of tumor progression.

Barriers to widespread clinical use of liquid biopsy include lack of standardization of the collection process. Procedures differ across health systems on how much blood should be collected, which tubes should be used for collection and how samples should be stored and shipped. The study authors suggested that “specialized tubes can be used for blood sample collection to reduce the chance of white blood cell rupture and genomic DNA contamination from the damaged white blood cells.”

Further research is needed

The study findings indicated that some aspects of liquid biopsy with cfDNA/ctDNA still need further exploration. For example, the effects of tumor vascularization, tumor aggressiveness, metabolic activity, and cell death mechanism on the dynamics of ctDNA in the bloodstream need to be identified.

It’s not yet clear how cfDNA is released into the bloodstream. Actively released cfDNA from the tumor may convey a different message from cfDNA released passively from dying cells upon treatment. The first represents treatment-resistant cells/subclones while the second represents treatment-responsive cells/subclones. Moreover, it is difficult to detect ctDNA mutation in early stage cancers that have lower tumor burden.

The investigators wrote: “The contributions of cfDNA from apoptosis, necrosis, autophagic cell death, and active release at different time points during disease progression, treatment response, and resistance appearance are poorly understood and will affect interpretation of the clinical observation in cfDNA assays.” A lower limit of detection needs to be determined and a standard curve set so that researchers can quantify the allelic frequencies of the mutants in cfDNA and avoid false-negative detection.

They urged establishing external quality assurance to verify laboratory performance, the proficiency in the cfDNA diagnostic test, and interpretation of results to identify errors in sampling, procedures, and decision making. Legal liability and cost effectiveness of using plasma cfDNA in treatment decisions also need to be considered.

The researchers wrote that, to better understand how ctDNA/cfDNA can be used to complement precision medicine in liver cancer, large multicenter cohorts and long-term follow-up are needed to compare ctDNA-guided decision-making against standard treatment without guidance from ctDNA profiling.

The authors disclosed having no conflicts of interest.

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