Currently, there are no highly accurate methods for early detection of HCC and no biomarkers to identify patients who will benefit from combination therapy.
In a report in Gut, Dr. Johann von Felden of Universitaetsklinikum Hamburg-Eppendorf, in Hamburg, Germany and colleagues summarize recent developments in liquid biopsy and its potential application in the clinical management of HCC.
The usefulness of liquid biopsy relies on the release and molecular analysis of tumor components in the bloodstream or other body fluids. These components include nucleic acids, circulating tumor cells (CTCs), and extracellular vesicles (EVs), which are membrane-embedded nanovesicles actively released by all cell types that function in cell-to-cell communication.
Methylation profiling from plasmid DNA has been shown to discriminate patients with early-stage HCC from other at-risk patients, the authors say, and clinical trials comparing this approach against standard surveillance (ultrasound and serum alpha fetoprotein, or AFP, surveillance) are ongoing.
Other early studies suggest that composite biomarkers of mutations in circulating tumor DNA (ctDNA) and tumor markers might be able to identify HCC.
These approaches might also be useful for prognostication, as ctDNA methylation profiling, CTCs and EV RNA have been shown to correlate with HCC stage and/or outcomes.
In other cancers, ctDNA has been useful for detecting minimal residual disease, and this approach might also prove useful in patients with HCC who have undergone tumor resection, Dr. von Felden and his colleagues say.
Preliminary studies have shown that CTCs and EVs might be useful for assessing risk of recurrence after resection of HCC and for predicting the response to immune checkpoint blockade.
ctDNA mutation profiling has also shown promise for identifying the emergence of treatment-resistant HCC, according to the review.
"To date, the most promising approach for early clinical take-up is DNA methylation profiling of ctDNA for the early detection of HCC in patients at risk," the authors conclude. "This may soon challenge the long-standing paradigm of AFP and ultrasound for HCC surveillance."
"Funding initiatives for investigator-initiated trials or large collaborative efforts would help well-designed studies and power adequate sample size," they note. "This cannot overcome biological disadvantages of HCC compared with other tumor entities, such as paucity of hotspot mutations and druggable mutations in HCC, but it would allow to stratify subgroups of patients by patterns of molecular alterations, who are potentially associated with beneficiary outcome."
Dr. Xiao Xu of Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, in Hangzhou, China, who recently reviewed the clinical applications of CTCs and ctDNA as key components of liquid biopsy in HCC patients, told Reuters Health by email, "In principle, I conservatively predict that it will take at least 5-10 years for liquid biopsy to become a standard tool. However, the application of liquid biopsy to HCC seems delayed compared with other malignancies that routinely incorporate liquid-biopsy analysis in clinical trials."
"For example," said Dr. Xu, who was not involved in the review, "in 2016, the (U.S. Food and Drug Administration) approved the first diagnostic tool to detect druggable EGFR mutations in plasma of lung-cancer patients. Therefore, it may take less time in other malignancies to establish a standardized platform for liquid biopsy."
Dr. Irun Bhan of Massachusetts General Hospital and Harvard Medical School, in Boston, who recently reviewed liquid biopsy in HCC, told Reuters Health by email, "It is true that the combination AFP and ultrasound lacks sensitivity for HCC surveillance but an equal or greater roadblock to the early detection of HCC may be identifying at-risk patients and providing them with access to appropriate clinical care including HCC surveillance. Accurate blood-based biomarker tests could increase access to screening for individuals who do not readily have access to subspecialist care or high-quality ultrasound, provided the technology can be disseminated and is affordable."
"The question of cost will be an important factor in how useful future potential biomarkers will be," said Dr. Bhan, who also did not participate in the new review. "This is especially true for early detection biomarkers, which will need to be sent serially for many years."
He added, "Consideration should also be given to newer applications of protein-based biomarkers, such as the GALAD score, which are less exciting in terms of novel technology but are promising biomarkers at a potentially lower cost with increased accessibility."
The review did not have specific funding.
Dr. von Felden did not respond to a request for comments.
By Will Boggs MD
SOURCE: https://bit.ly/3ilGkn7 Gut, online September 3, 2020.
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