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Review JOURNAL

OF HEPATOLOGY

Risk factors and prevention of hepatocellular carcinoma in the era


of precision medicine
Naoto Fujiwara1,2, Scott L. Friedman1, Nicolas Goossens3, Yujin Hoshida1,⇑

Keywords: Cancer screening; Summary


Risk prediction; Chemopreven-
Patients who develop chronic fibrotic liver disease, caused by viral or metabolic aetiologies, are at a high
tion; Cirrhosis; Hepatocellular
carcinoma; Precision medicine. risk of developing hepatocellular carcinoma (HCC). Even after complete HCC tumour resection or abla-
tion, the carcinogenic tissue microenvironment in the remnant liver can give rise to recurrent de novo
Received 21 August 2017; HCC tumours, which progress into incurable, advanced-stage disease in most patients. Thus, early detec-
received in revised form 24 Sep- tion and prevention of HCC development is, in principle, the most impactful strategy to improve patient
tember 2017; accepted 25 Sep-
prognosis. However, a ‘‘one-size-fits-all” approach to HCC screening for early tumour detection, as rec-
tember 2017
ommended by clinical practice guidelines, is utilised in less than 20% of the target population, and the
performance of screening modalities, including ultrasound and alpha-fetoprotein, is suboptimal. Fur-
thermore, optimal screening strategies for emerging at-risk patient populations, such as those with
chronic hepatitis C after viral cure, or those with non-cirrhotic, non-alcoholic fatty liver disease remain
controversial. New HCC biomarkers and imaging modalities may improve the sensitivity and specificity
of HCC detection. Clinical and molecular HCC risk scores will enable precise HCC risk prediction followed
by tailoured HCC screening of individual patients, maximising cost-effectiveness and optimising alloca-
tion of limited medical resources. Several aetiology-specific and generic HCC chemoprevention strate-
gies are evolving. Epidemiological and experimental studies have identified candidate
chemoprevention targets and therapies, including statins, anti-diabetic drugs, and selective molecular
targeted agents, although their clinical testing has been limited by the lengthy process of cancer devel-
opment that requires long-term, costly studies. Individual HCC risk prediction is expected to overcome
the challenge by enabling personalised chemoprevention, targeting high-risk patients for precision HCC
prevention and substantially improving the dismal prognosis of HCC.
Ó 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Introduction advanced stage, currently available medical thera-


Liver cancer, predominantly hepatocellular carci- pies yield only marginal survival benefit and are
noma (HCC) arising in the context of cirrhosis, is not cost-effective.11 Furthermore, the highly com-
the second most lethal cancer worldwide with plex and heterogeneous genetic aberrations in
persistently increasing mortality in Europe, HCC tumours hamper identification of therapeutic
North/South America, and Africa in contrast to strategies, despite the emerging breadth of molec-
the decreasing trend in East Asia.1–3 Cirrhosis ular targeted anticancer agents.12 Thus, it seems
Key point
was estimated to cause over 1.2 million deaths sensible to consider preventing HCC development
(2% of global deaths) in 2013, an increase of 47% and progression in patients at risk, rather than
HCC mortality keeps since 1990.4 Cirrhosis and HCC are the major treating advanced-stage disease with limited
increasing in several
life-limiting consequences of progressive fibrotic health benefit. However, despite the clinically
regions in Europe, Africa,
and the US in contrast to a liver diseases, mainly caused by hepatitis B virus unequivocal factors predisposing patients to cir-
decreasing trend in tradi- (HBV), hepatitis C virus (HCV), alcohol abuse, and rhosis and HCC, cancer prevention in this setting
tionally endemic areas non-alcoholic fatty liver disease (NAFLD).5 In the remains a daunting task, as demonstrated by the
such as East Asia. US, HCC is the fastest growing cause of cancer- dismal HCC prognosis (five-year survival rate
related deaths; HCC mortality rates have been <15%13). Herein, we provide an overview of the
increasing across almost all counties over the past current measures of HCC prevention and the
three decades, particularly in white men aged 55 opportunities to develop tailoured preventive
1
to 64 years old with HCV infection, and Hispanics strategies based on cancer risk in the era of preci-
Division of Liver Diseases,
Department of Medicine, Tisch affected by NAFLD in the Texas region.6–8 A sion medicine.
Cancer Institute, Graduate School model-based simulation is forecasting continued
of Biomedical Sciences, Icahn increases in HCC incidence until 2030, in the
School of Medicine at Mount
1950–1959 birth cohorts, Hispanic men, and black HCC prevention strategies
Sinai, USA;
2
Department of Gastroenterology, women.9 Cancer prevention encompasses a wide variety of
Graduate School of Medicine, HCC is highly refractory to therapeutic inter- medical interventions. Primary prevention
University of Tokyo, Japan ventions. Even after surgical resection or ablation,
3
Division of Gastroenterology and
focusses on preventing exposure to cancer-
Hepatology, Geneva University
70% of patients experience tumour recurrence predisposing factors or eliminating them at an
Hospital, Geneva, Switzerland within five years.10 Once tumours progress to an early stage by vaccination, lifestyle modification,

Journal of Hepatology 2018 vol. 68 j 526–549


JOURNAL
OF HEPATOLOGY
or environmental interventions in an aetiology- rospective and prospective assessments of inter-
specific manner. Secondary or tertiary prevention feron and other agents in patients infected with
covers early detection and chemoprevention of HCV, an HCC-preventive effect started to emerge
HCC occurrence or recurrence, respectively, in approximately two years after enrollment.20–23
patients already exposed to aetiological agents.14 This observation indicates that the duration of
Tertiary prevention after radical HCC treatment the latent period for subclinical neoplastic clones
aims to reduce either recurrence following dis- to become clinically recognisable needs to be
semination of residual tumour cells (disseminative accounted for when designing HCC chemopreven-
recurrence), or de novo carcinogenesis in remnant tion trials.24
fibrotic/cirrhotic livers (de novo recurrence). Regular biannual HCC screening is recom-
The discovery and development of cancer mended based on current HCC guidelines,25 but
chemoprevention strategies have been challeng- its implementation in clinical practice is far from
ing. There has been scarce progress over the past satisfactory, as detailed in the next section. Fur-
decades owing to elusive mechanisms of human thermore, there is currently no established HCC
carcinogenesis.15 It is not feasible to verify mech- chemoprevention therapy. Various precipitants of
anisms of cancer initiation in patients that are chronic liver diseases, for example hepatitis virus
inferred from preclinical studies, because it is eth- infection, hepatic inflammation and fibrosis, and
Key point
ically and logistically difficult to monitor cancer- metabolic syndrome, may serve as chemopreven-
free individuals with molecular assessment for tion targets. However, the obstacles reviewed Regular HCC screening is
long durations until a cancer develops. To over- above hamper the discovery of such chemopre- significantly underutilised
because of multiple
come this challenge, a ‘‘reverse-engineering” vention targets and biomarkers. In addition, these
patient- and provider-
approach has been proposed, in which clinically challenges obscure the optimal timing and dura- related barriers. This chal-
relevant targets are first identified in clinical tion of chemopreventive interventions during the lenge may be overcome by
cohorts with completed long-term follow-up, and lengthy natural history of fibrotic liver disease multi-level clinical and
subsequently validated in experimental systems.10 progression towards HCC, which typically lasts community-based inter-
ventions as well as indi-
Another factor limiting chemoprevention develop- for decades (Fig. 1). In addition, clinical validation vidual risk-based
ment is suboptimal animal models that may not of the findings could easily extend beyond the personalised HCC
resemble human disease, leading to false discov- scope and timeframe of typical research studies screening.
ery of chemoprevention targets and biomarkers; and clinical trials, and may be less appealing for
these approaches may be improved by more the pharmaceutical industry, who may favour a
sophisticated modelling strategies.16,17 Relatively faster return on investment.26
difficult access to liver biospecimens is another
limiting factor, contrasting with easier access to
specimens from other tissues (for example skin, HCC screening
cervix, and gastrointestinal tract cancers) that Screening is a vital component of cancer preven-
have enabled more advanced chemoprevention tion. Current practice guidelines recommend regu-
development.18 Utilisation of liquid biopsy may lar HCC screening by biannual ultrasound with or
resolve the issue of sampling, although it is still without a-fetoprotein (AFP) in clinically identifi-
uncertain whether any informative biomolecules able populations with HCC risk exceeding a certain
are present in the circulation.19 threshold.25 A series of cohort studies and model-
A major difficulty is the design and conduct of based simulation indicate that HCC screening is
clinical trials for chemoprevention, which are gen- cost-effective and associated with improved early
erally very resource-intensive. Chemoprevention tumour detection, curative treatment rates, and
trials typically require large sample sizes and long survival, when it is available to more than 34% of ⇑ Corresponding author.
observation periods for several reasons: subopti- patients at risk.27–31 However, the real-world util- Address: Division of Liver
mal potency of chemoprevention agents that meet isation rate is below 20% for multiple patient- and Diseases, Department of
high safety requirements, insufficient enrichment Medicine, Tisch Cancer Institute,
provider-related reasons.32 Population-based Graduate School of Biomedical
of high-risk patient populations, and lack of reli- interventions such as mailed outreach could Sciences, Icahn School of
able surrogate endpoints of definitive long-term improve the utilisation rate to up to 50%.33 With Medicine at Mount Sinai, 1470
clinical outcomes.18 For instance, two large HCC the currently available resources, the vast size of Madison Ave, Box 1123, New
York, NY 10029, USA.
chemoprevention trials, enrolling patients with the target population is another obstacle, given E-mail address: yujin.hoshi-
advanced fibrosis in Europe and the US, failed to that cirrhosis is estimated to affect 1–2% of the da@mssm.edu (Y. Hoshida).
demonstrate an effect of maintenance low-dose global population and cause over 1.2 million (2%
interferon on HCC incidence in the whole study of total) deaths in 2013, an increase of 47% since Key point
cohort.20,21 However, in subgroup analyses of 1990.4 The magnitude of HCC risk for emerging
patents with more advanced disease (i.e. cirrhosis populations, i.e. patients with non-cirrhotic NAFLD Patients with active or
or portal hypertension), HCC incidence was cured HCV infection and
and those after HCV cure, is yet to be determined,
reduced. This supports the concept of enrichment, individuals with NAFLD or
and screening strategies for these populations metabolic disorders are
whereby high-risk patients are identified and have not been established.32 These issues high- emerging populations for
included in chemoprevention trials, with smaller light the limitation of the current one-size-fits-all HCC development, await-
sample sizes, to better capture the effects of approach, which assumes uniform HCC risk across ing customised HCC
chemoprevention strategies. Interestingly, in ret- screening strategies.
all patients with the same clinical condition (e.g.

Journal of Hepatology 2018 vol. 68 j 526–549 527


Review

HCC Normal Subclinical molecular/ Diagnosed 2nd primary


progression hepatocyte histological IEN 1st primary HCC HCC

Liver disease Chronic Advanced Cirrhosis


progression hepatitis fibrosis

Exposure/presence of risk factors


Type of
Primary Secondary Tertiary (adjuvant)
prevention
HCC screening Post-treatment monitoring

Antiviral therapies

Anti-inflammation therapies
Potential
chemoprevention Anti-fibrotic therapies
strategies
Metabolic disease treatment

Molecular targeted therapies

Fig. 1. HCC-preventive interventions in the natural history of HCC development in progressive fibrotic liver diseases.
HCC-preventive strategy targeting each specific clinical context (i.e., aetiology-specific or independent primary, secondary, and
tertiary prevention) should be developed to ensure its clinically meaningful impact on the course of fibrotic liver disease
progression towards HCC. IEN, intraepithelial neoplasia; HCC, hepatocellular carcinoma.

HCV-related cirrhosis) and results in often harmful at work 2.44).47 Association of metabolic HCC risk
over- or under-estimation of HCC risk for each factors is affected by smoking (interaction p =
patient.34,35 Thus, prediction of individual HCC 0.004).48 Alcohol exposure may also enhance risk,
risk is critical for implementing effective and fea- as suggested by characteristic somatic DNA
sible HCC screening. aberrations.12

Clinical HCC risk scores Molecular HCC risk scores


A combination of readily available clinical symp- Molecular biomarkers of HCC risk have been
toms and laboratory variables have been evalu- actively explored as summarised later. Some of
ated to develop HCC risk-predictive scores, them were combined with clinical prognostic fac-
although their performance is somewhat limited tors to develop integrative HCC risk scores that
and they are yet to be adopted in clinical practice complement clinical scoring systems and refine
(Table 1).32 Semi-quantitative histological fibrosis HCC risk prediction (Table 2). Several germline
stage has been associated with future HCC risk, single nucleotide polymorphisms (SNPs) have
although sampling variability in liver biopsy ham- been identified as indicators of elevated HCC risk
pers its robust determination.36 Quantification of with ORs of around 1.5 in prospective and retro-
collagen proportionate area may enable more reli- spective cohorts: EGF (in HBV- or HCV-infected
able estimation of HCC risk.37–39 The degree of patients), MPO, DEPDC5, and MICA (in HCV-
portal hypertension, measured by hepatic venous infected patients), region in 1p36.22, STAT4, and
pressure gradient, has been associated with HCC HLA-DQ (in HBV-infected patients), and PNPLA3
risk.40 A high liver stiffness measurement (LSM), and TM6SF2 (in patients with alcoholic liver dis-
measured by ultrasound- or magnetic resonance ease and NAFLD).49–57 Shorter telomeres and
imaging (MRI)-based elastography, has been asso- germline mutations in the TERT gene were
ciated with increased risk of HCC, particularly in observed in patients with NAFLD related to
patients with viral hepatitis, including those cured HCC.58 An SNP in MBOAT7 gene was linked to
of HCV infection.41–44 This is presumably because HCC in patients with NAFLD, without cirrhosis.59
LSM captures fibrotic and inflammatory tissue A recent genome-wide association study identified
contents.41–44 Smoking has also been associated an SNP in the TLL1 gene associated with HCC risk
with increased HCC risk (relative risk [RR] 1.51) after HCV cure.60 A seven-gene SNP panel (Cirrho-
in a meta-analysis of 38 cohort and 58 case- sis Risk Score) was associated with fibrosis pro-
control studies,45 and incorporated in several gression in individuals infected with HCV.61 Liver
HCC risk scores. The population attributable frac- tissue-derived transcriptome signatures have been
tion of smoking for HCC was 9% in the US.46 Pas- associated with HCC risk. For example, a 32-gene
sive smoking was also associated with HCC signature in fibrotic liver has been validated as a
development (odds ratio [OR] at home 4.86; OR pan-aetiology HCC risk indicator in patients with

528 Journal of Hepatology 2018 vol. 68 j 526–549


Table 1. Clinical HCC/fibrosis risk indicators.
Risk indicator Study design Endpoint Major aetiology No. subjects Major race/ Cirrhosis Variables Validation Refs.
ethnicity
LSM-HCC score Prospective, cohort HCC (3/5yr) HBV 1,035 + 520* Asian 32% + 31%* LSM, age, albumin, HBV DNA Internal 262

REACH-B Prospective-retrospective, HCC (3/5/10 yr) HBV 3,584 + 1,505* Asian 0% + 18%* Sex, age, ALT, HBeAg, HBV DNA External 263

cohort
CU-HCC Prospective-retrospective, HCC (5yr) HBV 1,005 + 424* Asian 38% + 16%* Age, albumin, bilirubin, HBV DNA, External 264

cohort cirrhosis
Yang, et al. Prospective-retrospective, HCC (5/10 yr) HBV 2,435 + 1,218* Asian n.a. Sex, age, HCC family history, alcohol, Internal 265

cohort ALT, HBeAg, HBV-DNA, HBV genotype C


Hung, et al. Retrospective, cohort HCC (10 yr) HBV 8,252 + 4,125* Asian n.a. Age, sex, ALT, previous liver disease, External 266

HCC family history, smoking, HBV, HCV


PAGE-B Retrospective, cohort HCC (5yr) HBV 1,325 + 490* White 20% + 48%* Age, sex, platelet External 267
Journal of Hepatology 2018 vol. 68 j 526–549

Sohn, et al. Retrospective, cohort HCC (5yr) HBV 990 + 1,071* Asian 39% + 35%* Age, sex, cirrhosis Internal 268

269
FIB-4 Retrospective, cohort HCC HBV 986 Asian 9.9% AST, ALT, platelet, age No
270
GAG-HCC Retrospective, cohort HCC (5/10 yr) HBV 820 Asian 15% Age, sex, HBV DNA, core promoter No
mutations, cirrhosis
43
Shin, et al. Retrospective, cohort HCC (5yr) HBV 227 Asian 50.3% LSM, spleen diameter, platelet No
271
Kim, et al. Retrospective, cohort HCC HBV 2,878 Asian 10% LSM No
Singal, et al. Prospective-retrospective, HCC (3/5yr) HCV 442 + 1,050* White, black, 100% + 41%* 23 clinical variables External 272

cohort Hispanic
REVEAL-HCV Prospective-retrospective, HCC (5yr) HCV 1,095 + 572* Asian 1.4% + 7.0%* Age, ALT, AST/ALT, HCV RNA, cirrhosis, External 273

cohort HCV genotype


Ganne-Carrié, Prospective-retrospective, HCC (3yr) HCV 720 + 360* n.a. 100% Age, past alcohol abuse, platelet, Internal 274

et al. cohort GGT, SVR


275
Lok, et al. Prospective-retrospective, HCC (5yr) HCV 1,005 White, black, 40% (Ishak 5/6) Age, race, platelet, ALP, esophageal No
cohort Hispanic varices, smoking
El-Serag, et al. Retrospective, cohort HCC HCV 5,586 + 5,760* White, black 100% AFP, ALT, platelet, age Internal 276

38
Huang, et al. Retrospective, cohort HCC HCC 533 n.a. 7% CPA No
Motosugi, et al. Retrospective, case-control HCC HCV 66:66§ Asian n.a. LSM by MRE No 41

Chang, et al. Retrospective, cohort HCC (5yr) HCV after IFN 1,252 + 627* Asian 45% (F3/4) Age, sex, platelet, AFP, advanced fibrosis, Internal 277

HCV genotype 1b, SVR


278
Ikeda, et al. Retrospective, cohort HCC HCV after SVR 1,056 Asian 10% Age, AST, platelet before interferon No
treatment
279
scoreHCC Retrospective, cohort HCC HCV after SVR 871 Asian 30% Age, AFP, platelet, advanced fibrosis No
Wang, et al. Retrospective, case-control HCC HCV after SVR 21:355§ Asian 33.8% (F3/4) LSM, advanced fibrosis, diabetes No 44

280
ADRESS-HCC Retrospective, cohort HCC (1yr) HCV, alcohol, 17,124 + White, Hispanic 100% Age, diabetes, race, etiology, sex, Child- External
NASH/cryptogenic 17,808* Pugh score

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Velázquez, et al. Prospective, cohort HCC (4yr) Alcohol, HCV 295 + 168* n.a. 100% Age, HCV, prothrombin time, platelet Internal 281

282
VFMAP Retrospective, cohort HCC (5yr) Non-viral, HCV 1,808 Asian 13% LSM, fast plasma glucose, sex, age, AFP No
155
Wen, et al. Retrospective, cohort HCC (10 yr) General population 428,584 Asian n.a. Smoking, alcohol, physical activity, Internal
diabetes, AST, ALT, AFP, HBV, HCV
42
Singh, et al. Meta-analysis of 9, HCC, fibrosis HCV, HBV, alcohol, 4,038, 2,410 n.a. n.a. LSM by TE, MRE n.a.
6 studies (decompensation) NASH
283
Konerman, et al. Prospective-retrospective, Fibrosis (>2 Ishak HCV 184 White 0% 25 clinical variables Internal
cohort score, 1.5/3.5 yr)
(continued on next page)
529
Review

chronic hepatitis B/C, alcohol abuse, and NASH.10

ADRESS-HCC, age, diabetes, race, aetiology of cirrhosis, sex and severity of liver dysfunction-HCC; AFP, a-fetoprotein; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPA, collagen
proportionate area; ELF, enhanced liver fibrosis; FILI, fibrosis improvement after lifestyle interventions; GGT, c-glutamyltransferase; HbA1c, glycated haemoglobin, type A1c; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; HCC,
hepatocellular carcinoma; HCV, hepatitis C virus; IFN, interferon; LSM, liver stiffness measurement; MRE, magnetic resonance elastography; NASH, non-alocoholic steatohepatitis; PIIINP, propeptide of type III procollagen; REACH-B,
Risk estimation for hepatocellular carcinoma in chronic hepatitis B; REVEAL-HCV, Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer in HCV; SVR, sustained virologic response; TIMP1, tissue inhibitor of
Validation Refs.

284

285

286

37
Abundance of serum/plasma proteins such as
insulin-like growth factor 1 (IGF1) and osteopon-
Internal

tin (OPN/SPP1) has also been associated with


HCC risk in cirrhosis.62,63 The N-glycosylation pat-
No

No

No
tern of total serum protein (GlycoHCCRiskScore)
has identified a subset of patients with compen-
sated cirrhosis at risk of HCC.64 Body fluid (e.g.
blood, urine)-based biomarkers will enable less
Advanced fibrosis, age, AST, GGT,

Hyaluronic acid, TIMP1, PIIINP

invasive and more flexible prognostic prediction


given the decrease of liver biopsies in clinical prac-
tice, although tissue acquisition will help ensure
HbA1c change, platelet,

their relevance to liver disease, at least during


ALT normalisation

the process of establishing such assays. Scientifi-


cally rigorous biomarker validation following the
Forns score

predefined phases of biomarker development will


Variables

help ensure clinical validity of the biomarkers.65


CPA

These biomarkers are promising candidates for


clinical translation, although assay development
and implementation, regulatory approval, and
8.9% + 12.7%

25% (F3/4)

reimbursement are challenging obstacles.66


Cirrhosis

Case:control. n.a., not available/applicable. ‘‘Prospective-retrospective” indicates retrospective analysis of prospectively collected cohort in the past.287
100%
(F3)*
0%

HCC screening modalities


Abdominal ultrasound and serum AFP have been
Validation: ‘‘Internal”, validation in patients from the same institution(s); ‘‘External”, validation in patients from independent institution(s).

widely used as the main HCC screening modalities.


The suggested minimal sensitivity for an HCC
Major race/

screening test to be cost-effective is 42%, assuming


ethnicity

a screening access rate of 34%.31 The sensitivity of


White

n.a.

n.a.

n.a.

ultrasound and AFP for detection of early-stage


metalloproteinase-1; VFMAP, virtual touch quantification, fast plasma glucose, sex, age, and AFP; TE, transient elastography.

HCC tumour exceeds the threshold (approxi-


No. subjects

mately 60%), although it is still considered subop-


832 + 457*

timal.67 Operator dependency and patient-related


factors such as obesity are the major sources of
261

300

69

variation in ultrasound sensitivity, which can be


as low as 32%.68–70 Serum AFP levels can non-
specifically rise because of chronic hepatitis-
Major aetiology

related liver regeneration, which raises concern


Alcohol, HCV

about its clinical utility as a screening modality.71


HCV, HBV

New serum/plasma biomarkers have been


NASH
HCV

explored as possible replacements for AFP, and


some of them are awaiting larger clinical valida-
tion for further development and deployment
(Table 3). Integrative scores combining serum
biomarkers with clinical variables have been pro-
(decompensation)
intervention (1yr)

posed to improve diagnostic performance.72,73 In


Fibrosis (F3-4)
(F4, 5/7/10 yr)
Fibrosis after

addition, identification of specific clinical contexts


Endpoint

(e.g. HCV cirrhosis with normal serum alanine


lifestyle
Fibrosis

Fibrosis

aminotransferase [ALT] level) has been suggested


as a strategy to achieve improved performance of
AFP.74
Prospective-retrospective,

Prospective-retrospective,

Prospective-retrospective,

Computed tomography (CT) and MRI may


Tsochatzis, et al. Retrospective, cohort

serve as alternatives to ultrasound with better


performance, and without inter-operator variabil-
ity. Indeed, CT and MRI can double the lesion-
Study design

based sensitivity for small HCC tumours (up to


86%), although the high costs and irradiation (for
cohort

cohort

cohort

Training + validation.

CT) preclude their use as practical widespread


Table 1 (continued)

options for HCC screening.75–77 An abbreviated


Risk indicator

contrast-enhanced MRI (AMRI) has been devel-


oped as an option that is specifically designed for
Lens, et al.

FILI score

ELF score

regular HCC screening at half the cost of a full


*
§

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OF HEPATOLOGY
MRI, while maintaining a high sensitivity (81%) feature that may lead to direct cis/trans activation
Key point
and specificity (96%).78 of oncogenic signals and carcinogenesis, without
requiring a fibrotic tissue microenvironment.91 New HCC screening
Individual risk-based tailoured HCC screening Serum HBV DNA levels, certain HBV strains (e.g. modalities, including
serum biomarkers, inte-
The heterogeneous individual HCC risk among the genotype C in Asia and genotype F in Alaska),
grative scores, and imaging
patients captured by clinical and/or molecular and mutations in the HBV genome (e.g. pre-Core techniques, are under
scores will enable rational allocation of the limited and basal core promoter regions) are associated development or clinical
HCC screening resources to the high-risk patients with increased HCC risk.91–94 evaluation for improved
Universal HBV vaccination is effective as a pri- early HCC tumour
who most need the intervention, and avoid inef-
detection.
fective and wasteful distribution of the demanding mary HCC prevention measure by reducing neona-
screening efforts to low-risk individuals. The cur- tal HBV vertical transmission.95 In a 20-year
rently recommended HCC screening interval of follow-up of a national vaccination programme,
six months was determined based on estimated the annual HCC incidence was significantly lower
tumour volume doubling time.79,80 Uniformly among vaccinated children, aged 6–19 years, com-
longer or shorter intervals did not improve HCC pared with unvaccinated cohorts (RR 0.31).96
detection.81,82 However, given that high-risk Antiviral therapies have been evaluated as a sec-
patients likely develop HCC at a high frequency ondary prevention. In a meta-analysis of 12 clini-
and in a multicentric manner, altering HCC screen- cal trials, involving 2,082 patients, interferon-
ing intensity according to estimated individual based regimens decreased cirrhosis and HCC
HCC risk may enable more efficient early tumour development (RRs 0.65 and 0.59, respectively).97
detection (Fig. 2).34 Such a personalised risk- Suppression of HBV replication by nucleot(s)ide
based cancer screening strategy has been success- analogues (NAs) reduced HCC incidence from
fully implemented in other tumour types, such as 7.4% to 3.9% (hazard ratio [HR] 0.49) in a prospec-
colorectal and breast cancers.83,84 In addition, edu- tive trial enrolling 651 Taiwanese patients, and
cation programmes targeting high-risk communi- from 13.3% to 1.1% in a retrospective survey of
ties with specific HCC risks based on aetiology, 2,795 Japanese patients.98–100 Retrospective stud-
for example African-born immigrants in New York ies conducted predominantly in Asia reported
City with a high prevalence of HBV infection, may HCC risk reductions with newer generation first-
efficiently improve uptake of high-risk individuals line NAs, entecavir and tenofovir, of approximately
to HCC screening.85 30% in patients with cirrhosis and 80% in those
The net benefit of HCC screening is determined without cirrhosis, although evidence in Western
as a function of multiple factors, including screen- patients is still limited.101–103 A cohort study of
ing interval, performance of screening modalities, 330 Taiwanese patients suggested that interferon
HCC incidence in the target population, and may better prevent HCC development than
screening access rate, which has been evaluated NAs.104 In the setting of tertiary prevention (i.e.
by model-based cost-effectiveness analysis. A adjuvant therapy after curative resection or abla-
recent comprehensive assessment of tailoured tion of primary HCC tumours), a meta-analysis of
HCC screening strategies based on risk revealed 13 trials with 6,350 patients reported that use of
superior cost-effectiveness of personalised screen- NAs was associated with lower recurrence-free
ing compared to the currently recommended uni- survival (HR 0.66),105 which was confirmed in a
form biannual screening of all patients.86 For more recent clinical trial (HR 0.65).106 Of note,
instance, exclusive screening of high-risk subjects the HCC incidence was significantly higher in
using AMRI is a robustly cost-effective strategy. patients who had achieved virologic response to
More frequent screening, i.e. four times per year, NAs, HBV DNA level consistently <2,000 IU/ml,
is cost-effective when annual HCC incidence is than in those with inactive chronic hepatitis B,
greater than 3%. Although these results need to indicating residual cancer risk is not eliminated
be clinically verified, testing of such strategies is by current antiviral therapies.107 Even a low-
now technically feasible with the HCC risk tests level viraemia (<2,000 IU/ml) during entecavir
and new screening modalities already available treatment increases HCC risk (HR 1.98) compared
in the clinical setting. to patients with undetectable HBV DNA, especially
in patients with cirrhosis (HR 2.20).108

Aetiology-specific HCC prevention Hepatitis C


Hepatitis B Globally, 71 million individuals are affected with
Chronic HBV infection has been the dominant viraemic HCV infection (prevalence, 1%).109 The
aetiology of HCC in Southeast Asia and sub-Saharan incidence and mortality of HCV-related HCC keep
Africa, although the incidence of HBV-induced rising in specific subpopulations, such as the
HCC is declining.87 Coinfection with hepatitis delta 1945–65 birth cohort (baby boomers) and veter-
virus, food contamination with aflatoxin B1, micro- ans in the U.S.110 HCC incidence is significantly
cystins, and metabolic risk factors facilitate reduced in patients achieving HCV clearance with
fibrosis and/or HCC development.48,88–90 HBV DNA a sustained virologic response (SVR) to antiviral
integration into the host genome is a unique therapies.111 However, interferon-based regimens

Journal of Hepatology 2018 vol. 68 j 526–549 531


532

Review
Table 2. Molecular feature-based HCC/fibrosis risk indicators.
Risk indicator Study design Endpoint Major No. Major race/ Cirrhosis Combined clinical Validation Refs.
aetiology subjects ethnicity variables
288
Circulating microRNA Prospective-retrospective, HCC HBV 373 Asian 34.6% n.a. No
signature cohort
63
IGF 1 (serum protein) Prospective, cohort HCC HCV 104 White 100% n.a. External
289
EGF 61*G (SNP, rs4444903) Prospective-retrospective, HCC HCV 816 White, black 15.4% Age, sex, smoking history, External
cohort ALP, platelet
50
MPO -463*G (SNP, rs2333227) Prospective-retrospective, HCC HCV 205 White 100% n.a. No
cohort
64
Journal of Hepatology 2018 vol. 68 j 526–549

GlycoHCCRiskScore (serum Prospective-retrospective, HCC HCV 125 n.a. 100% n.a. No


glycome) case-control
60
TLL1 (SNP, rs17047200) Retrospective, case- HCC HCV after SVR 123:333 + Asian 24.6% + Age, albumin, AFP after External
control 130:356*,§ 20.1%* (F3/4) SVR
290
PNPLA3 444*G (SNP, Prospective, cohort HCC Alcohol, HCV 532 White 100% Age, sex, BMI External
rs738409)
291
HFE C282Y (SNP, rs1800562) Prospective, cohort HCC Alcohol, HCV 301 White 100% n.a. External
Osteopontin (serum protein) Prospective-retrospective, HCC (2y) Non-viral 100:194§ White n.a. AFP, AST, ALT, GGT No 62

nested case-control
10,292–294
186/32-gene signature (liver Prospective-retrospective, HCC, HCC HCV, HBV, 82 + 25/ Asian + n.a./ 52.4% + n.a./ AFP, vascular invasion, External
tissue transcriptome) cohort recurrence Alcohol, NASH 216/145/ white/white/ 100%/100%/43%* bilirubin, platelet, Child-
263* Asian* Pugh class, AJCC stage
295
HSC signature (liver tissue Experiment + HCC, HCC HCV, HBV Mouse + White/Asian 100%/100% Bilirubin, platelet No
transcriptome) retrospective, cohort recurrence 216/82
296
Activated HSC signature (liver Retrospective, cohort HCC HBV 247+ 226/ Asian 90.7% n.a. External
tissue transcriptome) recurrence 72*
297
HIR signature (liver tissue Retrospective, cohort Late HCC HBV 72 + 96/ Asian 50% + 62.5%/ n.a. External
transcriptome) recurrence 228* 92.5%*
297
65-gene signature (HCC tissue Retrospective, cohort Early HCC HBV 72 + 96/ Asian 50% + 62.5%/ n.a. External
transcriptome) recurrence 228* 92.5%*
Cirrhosis risk score (serum Retrospective, case- Fibrosis HCV 205:66§ n.a. 21.8% (F2) n.a. No 298

glycome) control (5yr)


Validation: ‘‘Internal”, validation in patients from the same institution(s); ‘‘External”, validation in patients from independent institution(s).
Biomarkers evaluated in prospective patient series and/or externally validated in >100 patients are included. AFP, a-fetoprotein; AJCC, American Joint Committee on Cancer; ALP, alkaline phosphatase; ALT, alanine aminotransferase;
AST, aspartate aminotransferase; BMI, body mass index; GGT, c-glutamyltransferase; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HIR, hepatic injury and regeneration; HSC, hepatic stellate cell; IGF
1, insulin-like growth factor 1; NASH, non-alcoholic steatohepatitis; SVR, sustained virologic response.
*
Training + validation.
§
Case:control. ‘‘Prospective-retrospective” indicates retrospective analysis of prospectively collected cohort in the past.287
Table 3. HCC diagnostic biomarkers and scores.
Biomarker Study design Major aetiology HCC stage Major race/ Sensitivity Specificity AUROC Validation Refs.
ethnicity
Biomarker in clinical use
299
AFP Meta-analysis (20 studies) HCV n.a. Asian 4–71% 29–100% 0.65 n.a.
299
Journal of Hepatology 2018 vol. 68 j 526–549

AFP-L3 Meta-analysis (8 studies) HCV n.a. Asian 21–49% 93–100% 0.69 n.a.
299
DCP Meta-analysis (16 studies) HCV n.a. Asian 7–56% 72–100% 0.70 n.a.
Integrative score
GALAD model Prospective, case-control Alcohol, HCV, HBV 25% + 22%* n.a. 94% 83% 0.95 External 73

Doylestown Prospective-retrospective, nested HBV/HCV + HCV/HBV/HCV* 54%/79% + 48%/100%/33%* n.a. 53/58/63% Fixed to 95% 0.84/0.89/0.88 External 72

algorithm case-control
Experimental biomarker
300
GPC3 Meta-analysis (19 studies) HBV, HCV n.a. n.a. 55% 84% 0.76 n.a.
microRNA panel Retrospective, case-control HBV 78% + 75% (BCLC 0/A)* Asian 81% 84% 0.89 External 301

DKK1 Retrospective, case-control HBV 67.2% + 31.1% (BCLC 0/A)* Asian 71% 87% 0.86 External 302

MDK Retrospective, case-control HBV 49.2% + 100% (BCLC 0/A)* Asian 86% 90% n.a. External 303

304
Annexin A2 Retrospective, case-control HBV 81.7% (AJCC I/II) Asian 83% 68% 0.79 No
305
GlycoHCCTest Retrospective, case-control HBV 34.7% (AJCC I/II) Asian 57% 88% 0.81 No
Osteopontin Prospective-retrospective, case-control HCV + HBV* 60% (BCLC 0/A) + n.a.* n.a. + Asian* 93% 61% 0.93 External 306

307
GP73 Prospective-retrospective, case-control HCV 48% (UNOS TNM 1/2) White 69% 86% 0.79 No
64
GlycoHCCRiskTest Prospective-retrospective, case-control HCV n.a. n.a. n.a. n.a. 0.73 No
308
Fucosylated Prospective-retrospective, case-control HCV 60% (UNOS TNM 1/2) n.a. n.a. n.a. 0.88 No
kininogen
Diagnostic performance measures (sensitivity, specificity, AUROC) were derived from meta-analysis or validation studies.
AFP, a-fetoprotein;AFP-L3, lens culinaris agglutinin-reactive fraction of AFP ; AJCC, American Joint Committee on Cancer; AUROC, area under the receiver operating characteristic curve; BCLC, Barcelona Clinic Liver Cancer ; DCP, des-
gamma-carboxy prothrombin ; DKK1, Dickkopf-1 ; GALAD, gender, age, AFP-L3, AFP, des-carboxy prothrombin ; GP73, Golgi protein-73; GPC3, glypican 3 ; HBV, hepatitis B virus ; HCC, hepatocellular carcinoma ; HCV, hepatitis C
virus ; MDK, midkine ; UNOS, United Network of Organ Sharing.
*
Training + validation. ‘‘Prospective-retrospective” indicates retrospective analysis of prospectively collected cohort in the past.287

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Secondary/tertiary chemoprevention could be


Chronic fibrotic liver diseases
(clinical high-risk condition, e.g. cirrhosis) achieved by antiviral therapies, as suggested by
retrospective studies consistently reporting reduc-
tions in annual HCC incidence from 1–8% to 0.07–
HCC risk assessment
1.2% with interferon-based SVR.111 Recent trials
have shown that DAAs are better-tolerated than
interferon, even in patients with compensated
Predicted
HCC risk
High Intermediate Low and decompensated cirrhosis.123,124 HCC inci-
dence and recurrence rates after DAA-induced
SVR are yet to be fully determined.111 Recent large
Intensity of cohort studies reported a comparable magnitude
screening High Low
of reduction in HCC incidence between
interferon- and DAA-induced SVR (HR 0.28–
0.29).124,125 Our understanding of post-SVR HCC
risk drivers is still limited to several host factors,
Priority for High Low
chemoprevention including advanced liver fibrosis, older age,
accompanying metabolic diseases such as dia-
betes, persisting hepatic inflammation, and ele-
Fig. 2. Individual risk-based tailoured HCC screening and
chemoprevention. Individual HCC risk assessment with
vated AFP, as well as viral factors, including core
clinical and/or molecular risk indicators (see Tables 1 and protein variants and genotype 3.111 A liver tran-
2) will enable personalised HCC screening and chemopre- scriptome signature may enable more precise
vention strategies to optimise allocation of limited medical post-SVR HCC risk prediction.10,126 Clinical and
resources and maximise cost-effectiveness of the interven-
experimental observations suggest there are
tions by tailouring intensity of screening (i.e. frequency and
choice of modalities) and prioritising a subset of patients DAA-specific modulations of host immunity and
with higher HCC risk for chemopreventive therapies. HCC, oncogenesis, for example reactivation of co-
hepatocellular carcinoma. infected viruses, remission of follicular lymphoma,
and rapidly restored function/differentiation of
HCV-specific CD8+ T cells, memory T cells, and
had no impact on the incidence at a population normalised natural killer (NK) cells.111 A cell
level because of low treatment uptake (1–3% culture-based study reported restoration of p53
annually) and a modest SVR rate (50%) in a regio- function and ER stress response by interferon,
nal study in Australia.112 Despite the improved but not by DAA.127 Further studies are needed to
SVR rate with direct-acting antivirals (DAAs), determine clinical utility and underlying mecha-
HCC incidence is predicted to further increase nisms of action of DAAs as an HCC chemopreven-
until 2035 unless the treatment uptake rate is tion strategy.
Key point increased more than fivefold by 2018.113,114 HCV
Antiviral therapies can be elimination is hampered by the high DAA costs Alcohol
effective aetiology-specific and lack of comprehensive HCV screening linked Alcohol abuse remains a major and rising HCC
HCC chemopreventive to treatment programmes.115 Undiagnosed HCV aetiology in several regions including northern
interventions, although
infection is estimated to represent 50% or more and central Europe, whereas alcohol consump-
viral cure does not elimi-
nate HCC risk, and there- of the whole infected pool. In addition, high-risk tion and HCC mortality are decreasing in some
fore requires continued populations such as inmates and injection drug countries such as France.128 A meta-analysis of
risk assessment, screening, users contribute to the three to four million new 19 cohort studies showed a dose-dependent
and/or additional chemo- infections each year, and serve as a reservoir that
preventive interventions. increase in HCC risk (HR 1.16).129 Excessive
maintains the pool of patients both newly and alcohol intake drives hepatocarcinogenesis by
re-infected with HCV. This will lead to a sustained increasing a mutagenic ethanol metabolite,
high disease burden in the next decade, even in acetaldehyde, oxidative stress, and DNA dam-
developed countries.114,116,117 age, and by generating a carcinogenic tissue
Development of a prophylactic HCV vaccine as microenvironment, which can synergise with
primary prevention has been challenging because viral hepatitis and metabolic syndrome.130–132
of the high viral genetic variability, although there HCC genome DNA sequencing has identified
is promising progress.118 New experimental mod- recurrent mutations in genes encoding alcohol
els such as HCV-related hepacivirus-infected rats metabolising enzymes, e.g. ADH1B.133 The mag-
may facilitate vaccine development.119 Targeting nitude of risk reduction by abstinence has not
host genes/proteins such as viral entry factors yet been established because of limited evi-
may be an alternative or complementary strat- dence. A meta-analysis of four cohort studies
egy.120 In patients with cirrhosis, DAA treatment showed that abstinence reduced HCC risk by
to prevent re-infection after transplantation is 6–7% annually, despite a large uncertainty in
cost-effective according to disease severity.121 the estimate and evidence that more than
HCV screening that targets high-risk populations two decades are required to normalise the risk
is expected to boost uptake of antiviral treatment to the level of never drinkers, when cirrhosis is
and subsequent HCC screening as needed.122 present.134–136

534 Journal of Hepatology 2018 vol. 68 j 526–549


JOURNAL
OF HEPATOLOGY
NAFLD, obesity, and metabolic syndrome Rho-dependent kinase,159 nuclear factor-jB (NF-
One-fourth of the global population is affected by jB) and tumour necrosis factor (TNF)-mediated
NAFLD, and among biopsied NAFLD patients, IL6 production,160 as well as Hippo pathway effec-
approximately 60% have non-alcoholic steatohep- tor TAZ, and extracellular signal–regulated kinase
atitis (NASH), developing HCC annually at a rate 1/2 (ERK1/2).161 Whereas statins activate the ade-
of 5.29 per 1,000 person-years.137 Obesity, dia- nosine monophosphate-activated protein kinase
betes, and the metabolic syndrome are present in (AMPK) and p38/mitogen-activated protein kinase
51%, 23%, and 43% of patients with NAFLD, respec- (MAPK) pathways,162,163 and induce p53-
tively, suggesting highly heterogeneous pathogen- dependent apoptosis164 (Fig. 3). Statins also limit
esis across patients.137 Obesity and type 2 diabetes fibrogenic hepatic stellate cell activation via nitric
with insulin resistance are independent risk fac- oxide synthase,165 paracrine signals from hepato-
tors of HCC. In 5.24 million individuals registered cytes166 and endothelial cells,167 induction of
in the Clinical Practice Research Datalink, high sterol regulatory element-binding protein 1
body mass index (BMI) was significantly associ- (SREBP-1) and peroxisome proliferator-activated
ated with liver cancer risk (HR 1.19 per BMI 5 kg/ receptor (PPAR)-c,168 and reduction of portal
m2).138 In a meta-analysis of 13 case-control and hypertension via non-canonical hedgehog
13 cohort studies, diabetes was associated with signalling.169
increased HCC risk (OR 2.5 and HR 2.5, respec- A dose-dependent reduction of HCC incidence
tively).139 A more recent meta-analysis of 23 was observed in Korean patients with diabetes
cohort studies reported a pooled RR of 2.0.140 (ORs 0.32 to 0.53),170 as well as Taiwanese
Metabolic risk factors also increase HCC risk in patients infected with HBV (HR 0.34 to 0.66) and
patients with viral hepatitis.48 The absence of HCV (HR 0.33 to 0.66).171,172 In 7,248 HCV-
established cirrhosis is more frequently associated infected persons in the US ERCHIVES database, sta-
with HCC in NAFLD compared to other aetiologies tin use was associated with less frequent progres-
such as HCV and alcohol abuse, which suggests sion to cirrhosis (HR 0.6) and HCC (HR 0.51).173
NAFLD-specific mechanisms of carcinogenesis that Fibrosis progression was reduced in the HALT-C
are less dependent on hepatic fibrosis.141 Dysregu- cohort,174 and decompensation, mortality, and
lated hepatic and circulating pro-inflammatory HCC were reduced in Taiwanese patients with
cytokines and adipokines, oxidative and endoplas- HBV-, HCV-, and alcohol-related cirrhosis (HRs
mic reticulum stress, and changes in intestinal 0.39, 0.46 and 0.52, respectively).175 In 18,080
microbiota (dysbiosis) are likely associated with patients with NAFLD, without cirrhosis, even
obesity-related hepatocarcinogenesis.142–145 higher HCC suppressive effects were suggested
Potential mechanisms of NAFLD carcinogenesis (HR 0.29).176 However, the protective effect was
include: bacterial metabolite (deoxycholic acid)- not observed in meta-analyses of 27 prospective
induced senescence-associated secretory pheno- studies involving 175,000 individuals with multi-
type (SASP), which mediates hepatic stellate cell ple cancer types, including HCC.177,178 Differential
activation;146 disruption of circadian rhythm;147 effects between statins have also been suggested.
depletion of antitumour CD4+ T cells by linoleic In a systematic pair-wise comparison, fluvastatin
acid from hepatocytes;148 induction of metabolic was shown to be more effective in reducing HCC
inflammation-associated interleukin 17A risk (RR 0.55) than other statins.179 Atorvastatin
(IL17A);149 and prostaglandin E2 (PGE2)- and fluvastatin were associated with more signifi-
mediated suppression of antitumour immunity cant anti-fibrotic effects than lovastatin, pravas-
by gut microbiota.150 Clinically relevant animal tatin, rosuvastatin, and simvastatin.173
models of NAFLD fibrosis and/or HCC will enable Randomised clinical trials are currently ongoing
more reliable preclinical assessment of experi- to determine the role of statins in HCC chemopre-
mental therapies.10,151–153 vention (Table 4). The secondary preventive effect
Lifestyle intervention may serve as secondary of simvastatin in patients with cirrhosis is being
prevention as suggested by observational studies. tested in a phase II trial, looking for a change in
A meta-analysis of 19 studies, involving AFP-L3% (NCT02968810). Atorvastatin is being
1,290,045 individuals, reported that increased evaluated for tertiary prevention after complete
intake of vegetables, but not fruits, may reduce HCC resection or ablation (Statin for preventing
HCC risk (RR 0.72).154 In a prospective cohort of HCC recurrence after curative treatment [SHOT]
428,584 subjects (HBV and HCV were positive in trial, NCT03024684).
15.7% and 2.6%, respectively), higher physical
activity (metabolic equivalent tasks ≥7.5/h) was Metformin
associated with lower HCC risk (HR 0.69).155 Given the elevated HCC risk in patients with type
2 diabetes, anti-diabetic therapies may be rational
Statins HCC chemopreventive strategies. Metformin, a
In experimental systems, statins elicit a variety of biguanide derivate, inhibits gluconeogenesis and
pleiotropic anti-neoplastic and cholesterol- improves peripheral tissue insulin sensitivity,
lowering effects. Statins inhibit oncogenic path- whilst eliciting various anti-neoplastic effects.
ways, including Myc,156 Akt,157,158 integrin and Metformin inhibits the mammalian target of

Journal of Hepatology 2018 vol. 68 j 526–549 535


Review

AM063 Perindopril

Lysophospholipids Ang I

ATX ACE
Gut microbial Viral infection
Metformin Erlotinib components,
LPA metabolites DAMPs Ang II

AM095 Excess dietary


fat, sugars Telmisartan

VEGFR PDGFR LPARs EGFR IGFR TLRs TNFR IFNR AT1

Cytoplasm

Rho HMG-CoA Ras LKB1 PI3K JAK

Metformin COX2 inhibitor, Metformin


Statins Statins Lovastatin Aspirin
AMPK
Caffeine Statins IKK IκB
TAZ COX2
YAP NF-κB
Mevalonate MEK TSC1/2 AKT
Fish oil Statins
FGF21 GSK3β
BCAA PGE2
p38 mTOR MDM STATs
ERK1/2 Peretinoin β-catenin
Nucleus
JNK p53
TDZs Statins
Atorvastatin
p38 β-catenin NF-κB
ERK1/2 Pravastatin
TAZ Myc Cyclin D1 HIF1 STATs
p21
YAP RAR
JNK Vitamin D
RXRα Metformin
AKT
Lovastatin

Aberrant cell Tumor Anti-tumor


Inflammation Anti-apoptosis Invasiveness Inflammation
proliferation initiation immunity

Fig. 3. Molecular targets of potential HCC chemoprevention therapies. Intra- and extracellular targets of potential HCC chemopreventive therapies are
summarised. Solid line with arrowhead or bar indicates activation or inhibition, respectively. Dotted line with arrowhead indicates translocation between
intracellular compartments. ACE, angiotensin-converting enzyme; AMPK, adenosine monophosphate-activated protein kinase; Ang, angiotensin; AT1,
angiotensin type 1 receptor; BCAA, branched-chain amino acid; COX2, cyclooxygenase 2; DAMPs, damage-associated molecular pattern; EGFR, epidermal
growth factor receptor; ER, endoplasmic reticulum; ERK, extracellular signal–regulated kinase; FGF21, fibroblast growth factor 21; GSK3, glycogen synthase
kinase 3; HIF, hypoxia inducible factor; HMG-CoA, 3-hydroxy-3nethyl-glutaryl-coenzyme A; IFNR, interferon receptor; IGFR, insulin-like growth factor 1
receptor; JAK, Janus kinase; JNK, c-Jun N-terminal kinase; LKB1, liver kinase B1; LPAR, lysophosphatidic acid receptor; MDM, mouse double minute; mTOR,
mammalian target of rapamycin;NF-jB, nuclear factor-kappa B; PDGFR, platelet-derived growth factor receptor; PGE2, prostaglandin E2; PI3K,
phosphoinositide 3-kinase; RAR, retinoic acid receptor; ROS, reactive oxygen species; RXR, retinoid X receptor; STAT, signal transducers and activator of
transcription; TLR, Toll-like receptor; TNFR, tumour necrosis factor receptor; TSC, tuberous sclerosis complex; VEGFR, vascular endothelial growth factor
receptor; YAP, Yes-associated protein.

rapamycin (mTOR) pathway via activation of suppresses progenitor/stem cell activation and
AMPK and its upstream regulator, LKB1;180 it reduces HCC burden in a rat model of
inhibits angiogenesis via suppression of hypoxia cirrhosis-driven carcinogenesis, although the
inducible factor 1 a (HIF1A) and vascular HCC-preventive effect is observed only when
endothelial growth factor (VEGF);181 it blocks cell metformin treatment is started before develop-
cycle progression by decreasing cyclin D1 expres- ment of cirrhosis.185
sion;182 it suppresses cell survival by upregulating A meta-analysis of 19 studies involving
IjBa, which inhibits NF-Κb;180 whilst it 550,882 patients with diabetes suggested that
induces apoptosis via a p53-independent mecha- metformin use reduced HCC incidence (OR 0.52)
nism183 and CCAAT/enhancer-binding protein d compared to non-users.186 In exploratory sub-
(CEBPD)-induced autophagy184 (Fig. 3). Metformin group analysis, metformin remained protective in

536 Journal of Hepatology 2018 vol. 68 j 526–549


Table 4. Ongoing clinical trials of HCC chemoprevention.
Trial number Agent/intervention Type of agent/intervention Phase Type of Target population Primary endpoint No. planned Estimated
prevention subjects completion date
NCT02224456 Tenofovir disoproxil Anti-viral IV Secondary CHB with advanced fibrosis HCC development 240 1/2021
fumarate
NCT02968810 Simvastatin Statin II Secondary Cirrhosis Change in AFP-L3 80 1/2020
NCT02306070 Metformin Anti-diabetic II Secondary CHC with diabetes Change in LSM 60 9/2017
NCT02779465 Vitamin D3 Nutritional supplement IV Secondary CHB on anti-viral Change in serum 1,500 12/2026
levels of 25(OH)D
NCT02098785 Caffeine Nutritional supplement I Secondary Healthy VAP-1 serum levels 63 9/2018
Journal of Hepatology 2018 vol. 68 j 526–549

NCT02273362 Erlotinib Kinase inhibitor I Secondary Cirrhosis Safety, pEGFR, 186- 45 1/2018
gene signature
NCT03024684 Atorvastatin Statin IV Tertiary HCC (BCLC 0/A) after curative HCC recurrence 240 1/2022
ablation or hepatectomy
NCT03184493 Metformin, celecoxib Anti-inflammation, Anti-diabetic III Tertiary HCC after hepatectomy HCC recurrence 200 6/2021
NCT02281266 Thymalfasin Immune modulator IV Tertiary HBV-HCC after hepatectomy DFS 360 10/2018
NCT02686372 HBV antigen specific TCR Immune modulator I Tertiary CHB after transplantation Safety 10 11/2020
redirected T cell
NCT01924624 Thalidomide Immune modulator, anti- IV Tertiary HCC after hepatectomy DFS 140 12/2019
angiogenesis
NCT02447679 Thalidomide, tegafur- Immune modulator, anti- II Tertiary HCC after hepatectomy HCC recurrence 40 Completed, not
uracil angiogenesis, cytotoxic agent reported
NCT03178929 SAMe Nutritional supplement n.a. Tertiary HCC (BCLC 0/A) after radical HCC recurrence 207 8/2020
treatment
NCT01770431 Huaier granule Traditional herbal medicine IV Tertiary HCC (BCLC A/B) after hepatectomy HCC recurrence, 1,080 Completed*
metastasis
NCT02399033 Xihuang Capsules Traditional herbal medicine IV Tertiary HCC (BCLC 0-B) after hepatectomy HCC recurrence 1,000 12/2019
NCT01717066 Ginsenoside Rg Chemo-sensitiser, anti- III Tertiary HCC (BCLC A) after hepatectomy HCC recurrence 480 Completed, not
angiogenesis reported
NCT00116454 131 I-lipiodol Cytotoxic agent III Tertiary Viral/alcohol-HCC after hepatectomy HCC recurrence 73 Completed, not
or ablation (≤2 tumors) reported
NCT02767375 Hepatic arterial infusion Cytotoxic agent II  Tertiary HCC after hepatectomy DFS 192 12/2018
chemotherapy III
AFP-L3, lens culinaris agglutinin-reactive fraction of a-fetoprotein; BCLC, Barcelona clinic liver cancer; CHB, chronic hepatitis B; CHC, chronic hepatitis C; DFS, disease-free survival; HBV, hepatitis B virus; HCC, hepatocellular
carcinoma; LSM, liver stiffness measurement; SAMe, S-adenosylmethionine; TCR, T cell receptor; VAP-1, vascular adhesion protein 1; 25(OH)D, 25-hydroxy vitamin D.

OF HEPATOLOGY
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*
Presented in J Hepatol 2017;66:S622.
537
Review

patients with HBV/HCV infection (OR 0.50), cirrho- neoplastic cells in the liver, which can be inhibited
sis (OR 0.49), and obesity (OR 0.42). However, by gut sterilisation in mice.196 Overexpression of
pooled results of two randomised controlled trials cyclooxygenase 2 (COX2) has been implicated in
enrolling 8,798 patients found no significant dif- hepatocarcinogenesis in experimental models.197
ference in HCC risk according to metformin use COX2 expression in hepatocytes is sufficient to
(OR 0.84; p = 0.87). A phase III trial was initiated induce HCC through induction of promoter hyper-
to evaluate the secondary HCC chemopreventive methylation by reducing tet methylcytosine
effect of metformin in compensated HCV-related dioxygenase 1 (TET1) expression, silencing tumour
cirrhosis and insulin resistance in France, however suppressor genes and activating oncogenic path-
the trial was terminated based on the decision of ways.198 Hepatic translocation of lipoteichoic and
the investigator (NCT02319200). A phase II trial deoxycholic acids from gut microbiota enhances
is planned to evaluate change in liver fibrosis by SASP of hepatic stellate cells to upregulate COX2-
metformin in patients infected with HCV, with or mediated PGE2 production via TLR2, and sup-
without HIV coinfection (NCT02306070). presses antitumour immunity in a mouse model
of obesity/NAFLD-associated HCC.150 HCC upregu-
Fibroblast growth factor 21 (FGF21) lated long non-coding RNA (HULC) stabilises COX2
FGF21 is a pleiotropic hormone with various ben- protein and promotes HCC cell growth.199 Acti-
eficial effects on glucose metabolism and sugar vated hepatic stellate cells enhance immunosup-
intake and preference, which can be regulated by pressive cell populations, including myeloid-
a variety of mechanisms including adipose- derived suppressor cells and regulatory T cells
derived circulating miRNAs and genetic polymor- (Tregs) via COX2-PGE2-EP4 signalling.200 Co-
phism (rs838133).187–189 Lack of FGF21 acceler- administration of a COX2 inhibitor, NS398, and
ates the development of NASH and HCC in simvastatin synergistically reduces proliferation
diabetic mice.190 FGF21 inhibits mTOR and and enhances apoptosis of HCC cell lines.201
improves insulin resistance, making it a candidate In a clinical trial enrolling 232 patients who
treatment for type 2 diabetes.191 A synthetic underwent curative HCC resection or ablation
FGF21 protein, LY2405319, reduces transforming (i.e. tertiary prevention), a COX2 inhibitor, meloxi-
growth factor b1 (TGFb1) and collagen I expres- cam, did not improve overall and disease-free sur-
sion as well as NF-jB, p65, c-Jun N-terminal vival, although subgroup analyses suggested a
kinase 1/2 (JNK1/2), and p38 phosphorylation, possible chemopreventive effect in non-viral
and inhibits NASH progression in leptin-deficient HCC.202 A phase III trial of another COX2 inhibitor,
ob/ob mice fed methionine- and choline-deficient celecoxib, with or without metformin for tertiary
diet, suggesting that FGF21 may have a role in prevention in patients who underwent curative
chemoprevention of NAFLD cirrhosis and/or HCC resection is now recruiting participants
HCC.192 (NCT03184493). In a phase III trial conducted in
Korea, adjuvant immunotherapy with activated
cytokine-induced killer cells (an NK cell subset
Generic chemoprevention strategies incubated with patient-derived peripheral blood
Anti-inflammatory and immunomodulatory mononuclear cells, IL2, and CD3 antibody) reduced
therapies recurrence-free survival (HR 0.63) and overall
Chronic hepatic inflammation is a well- death (HR 0.21) in patients with HCC treated with
established driver of hepatocarcinogenesis.14 The resection or ablation.203 Thymalfasin, an immune
HCC-preventive effect of low-dose maintenance modulator with pleiotropic activities towards T
interferon therapy in patients with HCV cirrho- cells, NK cells, and dendritic cells, prolonged the
sis20,21 is likely due to reduced hepatic inflamma- time to HCC recurrence and increased survival,
tion, so called ‘‘biochemical response”, instead of when used as an adjuvant therapy for patients
viral clearance, although the drug’s intolerability with HBV-related HCC, in several pilot studies.204
hampers its wider use.24 Hepatic expression of A multicentre clinical trial is planned to evaluate
an interferon-stimulated gene, retinoic acid- the effect of thymalfasin on two-year recurrence-
inducible gene-I (RIG-I), and downstream STAT1 free survival rate and the tumour immune
signalling are suppressed in association with microenvironment in patients with curatively
increased HCC risk, which possibly contributes to treated HBV-related HCC (NCT02281266).
the higher HCC incidence in men than women.193
There is somewhat conflicting epidemiological Anti-fibrotic therapies
evidence about the HCC-preventive effect of non- Anti-fibrotic therapies may serve as HCC chemo-
steroidal anti-inflammatory drugs (NSAIDs), prevention by halting progression of fibrotic liver
including aspirin.194 A pooled analysis of 10 US- diseases towards carcinogenesis, as suggested by
based cohorts (679 HCC cases in 1,084,133 indi- experimental studies and recent clinical trials.5
viduals) suggested a protective effect of aspirin Hepatocyte apoptosis caused by chronic injury
use (HR 0.68).195 Intestinal microbiota can induce leads to the release of inflammation-mediating
innate immune signalling via Toll-like receptor 4 damage-associated molecular patterns (DAMPs),
(TLR4) and support promotion of transformed including TNF, IL6, IL1b, reactive oxygen species

538 Journal of Hepatology 2018 vol. 68 j 526–549


JOURNAL
OF HEPATOLOGY
(ROS), and hedgehog ligands, and triggers fibro- (RXR), and inhibits liver fibrosis and HCC.216 A
genic hepatic stellate cell activation.5 Apoptosis clinical trial of vitamin D3 is planned for preven-
signal-regulating kinase 1 (ASK1) activates JNK tion of HCC in chronic hepatitis B patients on
and p38 MAPK in response to various cellular nucleos(t)ide analogue treatment (VDHCC trial,
stresses. A phase II trial of ASK1 inhibitor, selon- NCT02779465).
sertib (GS-4997), reduced liver fibrosis (>1 stage) Excessive dietary iron and/or genetic polymor-
in 43% of NASH patients (NCT02466516). Ceni- phisms such as HFE C282Y and H63D variants can
criviroc, a dual inhibitor of fibrosis-promoting induce oxidative DNA damage and inflammation
CCR2/CCR5 reduced liver fibrosis in a phase II trial that increase HCC risk independently or alongside
(CENTAUR trial),205 and is now being tested in a other aetiologies, including HCV and alcohol.14
follow-up phase III trial (AURORA, Liver-specific b-catenin knockout increases sus-
NCT03028740). PPARs, a group of nuclear recep- ceptibility to dietary iron and steatohepatitis,
tors for various fatty acids and derivatives, tran- fibrosis, and HCC via AKT, ERK, and NF-jB path-
scriptionally regulate metabolic processes to ways in mice, which are protected by N-Acetyl-
maintain energy homeostasis.5 A dual PPARa/d L-(+)-cysteine (NAC).217 Long-term phlebotomy
agonist, elafibranor, reduced fibrosis progression can lower serum ALT level and incidence of HCV-
in non-cirrhotic NASH in a phase II trial,206 and a related HCC.218 An oral iron chelator, deferasirox,
follow-up phase III trial has been initiated suppresses N-nitrosodiethylamine-induced mur-
(RESOLVE-IT, NCT02704403). Despite promising ine liver carcinogenesis, and upregulates expres-
results, the framework for assessing the clinically sion of hepcidin, transferrin receptor 1, and
meaningful effect of anti-fibrotic therapies on hypoxia inducible factor-1a, but its use in humans
HCC chemoprevention is not yet established. Ther- is limited by dose-limiting toxicities.219
apeutically amenable cancer risk biomarkers such Branched-chain amino acid (BCAA), used for
Key point
as HCC risk gene signatures may serve as surrogate hepatic encephalopathy, enhances mTOR
endpoints, enabling the completion of clinical tri- signalling-mediated cellular senescence, and A variety of aetiology-
als with achievable cohort sizes, within a realistic reduces liver fibrosis and HCC in DEN-treated specific and independent
interventions are evolving
time frame. In addition, drug development pipeli- rats.220,221 In HCV-transgenic mice, BCAA reduces
as potential HCC chemo-
nes are largely designed to assess either anti- hepatic iron and ROS with elevated hepcidin-25, preventive measures,
fibrotic or anticancer effects but not both in the which is also observed in HCV fibrosis patients.222 although the framework of
same trial, posing a logistical difficulty in justify- In high-fat diet-fed atherogenic NASH mice, BCAA their clinical testing and
ing evaluation of agents from the anti-fibrotic represses TGFb1-stimulated pro-fibrogenic gene implementation needs to
be developed.
pipeline in the context of cancer. expression in hepatic stellate cells, protects hepa-
tocytes from apoptosis, and reduces transforma-
Dietary and nutritional agents tion of WB-F344 rat liver epithelial stem-like
In large-scale cohort or population-based studies, cells in an mTOR-dependent manner.223 In
intake of unsaturated fat (HR 0.71), n-3 polyunsat- C57BL/KsJ-db/db obese mice, BCAA increases the
urated fatty acids (PUFAs) (HR 0.64), eicosapen- expression of PPARc, p21CIP1, and p27KIP1, whilst
taenoic acid (EPA) (HR 0.56), docosapentaenoic suppressing the expression of IL6, IL1b, IL18, and
acid (DPA) (HR 0.64), and docosahexaenoic acid TNF, reducing inflammation in both the liver and
(DHA) (HR 0.56) are associated with lower HCC white adipose tissues, and inhibiting spontaneous
risk.207,208 Omega-3 PUFAs, DHA, and EPA inhibit hepatic carcinogenesis.224 In an observational
HCC growth through inhibition of COX2 and study of 299 Japanese patients with cirrhosis,
GSK-3b-mediated b-catenin degradation.209 BCAA supplementation was associated with less
PUFA-forming Fat-1 transgenic mice are protected frequent HCC development (RR 0.45).225
from diethylnitrosamine (DEN)-induced hepato- Coffee consumption (>2 cups/day) has been
carcinogenesis, with reduced TNF and COX2 associated with reduced HCC risk in a meta-
expression.210 Intake of white meat (chicken, tur- analysis of 18 cohorts, involving 2,905 HCC cases
key, and fish) was associated with a lower risk of (RR 0.71) and eight case-control studies, involving
HCC (HR 0.52), whereas red meat (beef and pork) 1,825 HCC cases (RR 0.53).226 Caffeinated and
was associated with a higher risk (HR 1.74) in decaffeinated coffee was associated with 27% and
the NIH-AARP cohort.211 14% reduced HCC risk, respectively. The reduced
Higher vitamin D, 25(OH)D, levels have been HCC risk was partly attributed to reduced hepato-
associated with reduced risk of HCC (RR 0.51).212 cellular injury measured by IL6, ALT, aspartate
Low serum levels of 25(OH)D3 are associated with aminotransferase (AST), and c-glutamyltransferase
adverse outcomes, including HBV-related HCC (HR (GGT).227,228 In a European prospective cohort
1.90).213 Vitamin D3 upregulated protein 1 including 201 HCC cases, tea intake was also asso-
(VDUP1) suppresses TNF and NF-jB signalling, ciated with reduced HCC risk to a lesser extent (HR
and protects mice from DEN-induced hepatocar- 0.41) than coffee (HR 0.28).229 A caffeine analogue,
cinogenesis.214 Expression of KLF4 sensitises HCC CGS 15943, inhibits HCC cell growth by targeting
cells to the anti-proliferative effects of 25(OH) phosphoinositide 3-kinase (PI3K)/AKT pathway.230
D3.215 p62/SQSTM1 promotes heterodimerisation A phase I trial of caffeine is planned to assess its
of the vitamin D receptor with retinoid X receptor effect on serum vascular adhesion protein 1

Journal of Hepatology 2018 vol. 68 j 526–549 539


Review

(VAP-1), which is linked to hepatic inflammation cellular signals via G-protein-coupled receptors,
and fibrosis in NASH5 (NCT02098785). and regulate cell survival, differentiation, prolifer-
Dietary phytochemicals such as curcumin (tur- ation, and migration.239 In the liver, expression of
meric extract), resveratrol (polyphenol in grapes, autotaxin (ATX), which converts lysophos-
red wine, and berries), silymarin (herbal flavo- phatidylcholine into LPA, increases HCV replica-
noid), and carotenoids have been evaluated as tion and is elevated in the serum of patients
potential HCC chemoprevention agents because infected with HCV, in association with hepatic
of their ability to activate cytoprotective mecha- fibrosis and HCC.240 In NAFLD, lipotoxic lipids,
nisms such as the Keap1/Nrf2 pathway in including LPA, are generated from excess dietary
carcinogen-induced rodent models, although sup- fat and sugars, and induce phenotypic manifesta-
porting clinical evidence is lacking.14 This class of tions of NASH, fibrosis, and HCC in the Substrate
compounds may need careful assessment given Overload Lipotoxic Liver Injury model of NAFLD
the recent classification of curcumin as a pan- pathogenesis.142 In a transcriptome-based meta-
assay interference compound that likely shows analysis of 523 human fibrotic livers, LPA receptor
false experimental activity.231 A reduction of 1 (LPAR1) signalling was identified as a pan-
DNA damage biomarkers including urine 8- aetiology HCC risk driver, and Rho kinase and
hydroxydeoxyguanosine (8-OHdG) was observed Ras/MAPK/ERK, but not PI3K/AKT/mTOR sig-
for epigallocatechin gallate (EGCG, green tea nalling, were identified as its downstream effector
polyphenol) and broccoli sprout in human, pathways in cirrhotic livers.10 Genetic knockout of
although their HCC-preventive effect is undeter- ATX, as well as pharmacological inhibition of ATX
mined.14 The liquorice root extract glycyrrhizin or LPAR1, ameliorates liver fibrosis and HCC in
reduced HCC incidence when ALT was normalised multiple rodent models,10,241 reinforcing the LPA
(HR 0.39).232 S-adenosylmethionine (SAMe), a pathway as a promising chemoprevention target.
ubiquitous major methyl donor, is reduced in The renin-angiotensin system is involved in
rodent HCC models, and SAMe treatment sup- liver fibrosis and carcinogenesis.14 Angiotensin II-
presses HCC development.14 In a phase II trial, mediated NF-kB activation promotes fibrogenic
24 weeks of SAMe treatment did not alter AFP myofibroblast survival, which can be inhibited by
levels or biomarkers of liver injury and oxidative an angiotensin-converting enzyme (ACE) inhibitor,
stress, in 87 patients with HCV-related captopril.242 Hepatic stellate cell-targeted delivery
cirrhosis.233 of an angiotensin II type 1 receptor blocker (ARB),
losartan, reduced liver fibrosis by inhibiting
Molecular targeted therapies expression of NADPH oxidase and collagen type
The PI3K/AKT/mTOR pathway is involved in cell I.243 An ARB, telmisartan, prevents hepatic carci-
cycle progression and proliferation, and is an noma in CDAA-induced NASH fibrosis and HCC in
appealing target for HCC chemoprevention.14 rats.244 In a retrospective single centre clinical
AKT was indeed identified as a key HCC risk driver study, the use of ARBs was associated with longer
in a meta-analysis of the human liver transcrip- time to HCC recurrence and increased survival
tome.10 Retrospective studies and their meta- after radiofrequency ablation.245 An ACE inhibitor,
analysis suggest that mTOR inhibitor-based perindopril, combined with vitamin K2 reduced
immunosuppression reduces post-transplant HCC HCC recurrence after curative therapy.246 A
recurrence,234 but adverse effects, including hep- clinical trial of perindopril in combination with
atic artery thrombosis and decreased patient and BCAA reduced serum VEGF level and post-
graft survival, have been noted in patients receiv- ablation HCC recurrence in 54 patients with insu-
ing the mTOR inhibitor sirolimus.235 In animal lin resistance.247
models of chemical- and obesity-driven HCC A synthetic acyclic retinoid (vitamin A ana-
development, sirolimus activates IL6/STAT3 and logue), peretinoin, inhibits multiple cellular sig-
enhances HCC development, despite a transient nalling pathways, including Wnt and platelet-
reduction in steatosis.236 To determine the benefit derived growth factor; it also induces differentia-
or harm of mTOR inhibition, sirolimus and evero- tion and apoptosis of hepatic stem cells, and is
limus have been tested in prospective trials for assumed to suppress neoplastic clones.248–250 Per-
prevention of post-transplantation HCC recur- etinoin also inhibits HCV replication and infec-
rence.237 In a phase III trial of 525 patients (viral tious virus release in cultured cells.251 In
hepatitis, 48%; alcoholic, 31%) sirolimus after atherogenic high-fat diet-fed mice, peretinoin
transplantation did not improve recurrence-free activates autophagy and suppresses NASH and
survival beyond five years (HR 0.84), although HCC development.252 In a phase III trial of pereti-
subgroup analyses suggested that patients with noin in 377 patients with curatively treated
less advanced HCC tumours, within Milan criteria HCV-related HCC, a lower trend of HCC recurrence
or younger age, may benefit from the therapy (SiL- was observed for the entire study period (HR
VER trial).238 0.73), and also after two years of randomisation
Bioactive lipids, e.g. lysophosphatidic acid (LPA) (HR 0.27).23 A follow-up survey reported a longer
and sphingosine-1-phosphate (S1P), transmit overall survival in patients treated with a higher

540 Journal of Hepatology 2018 vol. 68 j 526–549


JOURNAL
OF HEPATOLOGY
dose of peretinoin compared to untreated controls to specific molecular risk mechanism and chemo-
(HR 0.58; p = 0.03).253 Prospective trials in prevention targets. However, the requirement for
patients cured of HBV-related HCC are ongoing.248 large sample sizes and long observation periods
Several kinase inhibitors initially developed are the major logistical challenges in chemopre-
and evaluated for treatment of advanced-stage vention clinical trials, diminishing physicians’
cancers have also been tested as adjuvant thera- motivation to engage asymptomatic individuals
pies in HCC. Activation of epidermal growth factor and adhere to the protocol. Diversity in HCC inci-
receptor (EGFR) signalling in hepatic stellate cells dence according to aetiology, patient race/ethnic-
and macrophages promotes HCC development in ity, and clinical context (e.g. post-SVR cirrhosis)
rodent models.254,255 A small molecule EGFR inhi- needs to be considered when assessing clinical
bitor, erlotinib, reversed a high-risk pattern of the utility and real-world effectiveness of preventive
liver transcriptome and suppressed HCC develop- interventions. Drug safety in patients with cirrho-
ment in rodent models of fibrosis-driven carcino- sis is another critical factor. The precision medi-
genesis.256 Based on these animal studies, a cine approaches rely on molecular information
phase I HCC chemoprevention trial was initiated derived from biospecimens. Although liver tissue
using the transcriptome signature as a companion is deemed the most reliable source to interrogate
biomarker (NCT02273362). A multi-kinase inhibi- pathogenic molecular dysregulation, transition to
tor, sorafenib, did not alter recurrence-free sur- less invasive types of biospecimen during the pro-
vival (HR 0.94) after complete resection or cess of clinical translation will widen applicability.
ablation of primary HCC tumours in a phase III Sampling bias and robustness in molecular read-
trial.257 out should also be determined in preclinical and
The oestrogen pathway is deemed to play a key clinical studies. Once these issues are resolved
role in the sex disparity in HCC risk.258 In a meta- and the preventive strategies are clinically imple-
analysis of 87 studies, variations in oestrogen mented, the tailoured approach will enable more
receptor 1 (ESR1) gene were associated with cost-effective and precise preventive intervention
increased HCC risk.259 In a case-control study of in the clinical care of patients at risk of HCC, which
234 female patients with treated HCC and 282 will substantially improve its dismal prognosis.
healthy controls, oestrogen replacement (meno-
pause hormone therapy) was associated with a
reduced risk of HCC (OR 0.53) and prolonged Financial support
survival (HR 0.55).260 Systemic delivery of This work is supported by Uehara Memorial Foun-
mi-R101, downregulated in HCC tissue, inhibits dation (to N.F.), U.S. NIH/NIDDK R01 DK56621 and
some of the candidate HCC chemoprevention U.S. Department of Defense W81XWH-16-1-0455
targets, e.g. COX2 and Rho-GTPase, and suppresses (to S.L.F), and U.S. NIH/NIDDK R01 DK099558,
tumourigenesis in mice.261 European Union ERC-2014-AdG-671231 HEPCIR,
Irma T. Hirschl Trust, and U.S. Department of
Defense W81XWH-16-1-0363 (to Y.H.).
Conclusions
Clinical evaluation and implementation of
HCC-preventive strategies, encompassing HCC Conflict of interest
screening and chemopreventive intervention, will No conflict of interest to report.
not be successful and/or feasible without individ- Please refer to the accompanying ICMJE disclo-
ual risk-based tailoured approaches. Comprehen- sure forms for further details. Key point
sive, multi-omics, and multi-cell type Anti-inflammatory,
characterisation of diseased liver tissue microen- immunomodulatory, anti-
vironment at risk of cancer development will facil- Supplementary data fibrotic, metabolic, dietary,
itate cataloguing of candidate chemoprevention Supplementary data associated with this article physical, and molecular
targeted interventions may
targets. Such coordinated efforts will lead to tai- can be found, in the online version, at serve as generic HCC
loured intervention for each individual, according https://doi.org/10.1016/j.jhep.2017.09.016. chemoprevention
therapies.

Journal of Hepatology 2018 vol. 68 j 526–549 541


Review

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