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Review
. 2023 Jan;78(1):207-216.
doi: 10.1016/j.jhep.2022.08.036. Epub 2022 Sep 8.

Blood-based biomarkers for hepatocellular carcinoma screening: Approaching the end of the ultrasound era?

Neehar D Parikh  1 , Nabihah Tayob  2 , Amit G Singal  3
Affiliations
Review

Blood-based biomarkers for hepatocellular carcinoma screening: Approaching the end of the ultrasound era?

Neehar D Parikh et al. J Hepatol. 2023 Jan.

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, in part because of inadequate early detection strategies. Current recommendations for screening consist of semi-annual abdominal ultrasound with or without serum alpha-fetoprotein in patients with cirrhosis and in demographic subgroups with chronic hepatitis B infection. However, this screening strategy has several deficiencies, including suboptimal early-stage sensitivity, false positives with subsequent harms, inter-operator variability in ultrasound performance, and poor adherence. A blood-based biomarker with sufficient performance characteristics for early-stage disease could overcome several of these barriers to improving early-stage detection. However, prior to use of a biomarker for screening in clinical practice, a multistep validation is required in order to understand test performance characteristics. These steps include case-control validation, followed by validation in prospective cohorts of at-risk patients. Until recently, we lacked adequate longitudinal validation cohorts for early HCC detection; however, several validation cohorts are maturing, including the Hepatocellular Carcinoma Early Detection Study and the Texas Hepatocellular Carcinoma Consortium, which will allow for rigorous validation of candidate biomarkers. While there are several promising biomarkers awaiting validation, in order to supplant abdominal ultrasound, a candidate biomarker must show adequate test performance and overcome practical hurdles to ensure adoption in clinical practice. The promise of blood-based biomarkers is significant, especially given the limitations of ultrasound-based screening; however, they require adequate validation and several logistical obstacles must be overcome prior to clinical implementation.

Keywords: HCC; biospecimen; liver cancer; surveillance.

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Conflict of interest statement

Dr. Parikh has served as a consultant for Bristol Myers-Squibb, Exact Sciences, Eli Lilly, and Freenome; has served on advisory boards of Genentech, Eisai, Bayer, Exelixis, Wako/Fujifilm; and has received research funding from Bayer-supportTarget RWE, Exact Sciences, Genentech and Glycotest. Dr. Tayob has no conflicts to declare. Dr. Singal has served on advisory boards or as a consultant for Bayer, FujiFilm Medical Sciences, Exact Sciences, Glycotest, and GRAIL.

Please refer to the accompanying ICMJE disclosure forms for further details.

Figures

Fig. 1.
Fig. 1.. Phases of biomarker validation.
(A) Phase I - preclinical exploratory to identify candidate biomarkers; (B) Phase II – clinical assay validation using a case-control design; (C) Phase III – longitudinal prospective-specimen collection in at-risk patients, with retrospective blinded-evaluation of biomarker performance; (D) Phase IV - prospective cohort studies or clinical utility trial where the biomarker is tested against a gold standard; (E) Phase V – cancer control studies to determine the impact of biomarker screening on cancer mortality. HCC, hepatocellular carcinoma.
Fig. 2.
Fig. 2.. Schematic of the interplay between test sensitivity and adherence that determines overall effectiveness.
HCC, hepatocellular carcinoma.
Fig. 3.
Fig. 3.. Proposed schema for a phase IV clinical utility trial for HCC biomarker validation.
AFP, alpha-fetoprotein; HCC, hepatocellular carcinoma; US, ultrasound.
See this image and copyright information in PMC

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