Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine

Abstract

Patients who develop chronic fibrotic liver disease, caused by viral or metabolic aetiologies, are at a high risk of developing hepatocellular carcinoma (HCC). Even after complete HCC tumour resection or ablation, the carcinogenic tissue microenvironment in the remnant liver can give rise to recurrent de novo HCC tumours, which progress into incurable, advanced-stage disease in most patients. Thus, early detection and prevention of HCC development is, in principle, the most impactful strategy to improve patient prognosis. However, a "one-size-fits-all" approach to HCC screening for early tumour detection, as recommended 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. Furthermore, 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 allocation of limited medical resources. Several aetiology-specific and generic HCC chemoprevention strategies 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 development 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.

Keywords: Cancer screening; Chemoprevention; Cirrhosis; Hepatocellular carcinoma; Precision medicine; Risk prediction.

Figure 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., etiology-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 toward HCC. IEN, intraepithelial neoplasia; HCC, hepatocellular carcinoma.

Figure 2. Individual risk-based tailored HCC screening and chemoprevention

Individual HCC risk assessment with clinical and/or molecular risk indicators (see Tables 1 and 2) will enable personalized HCC screening and chemoprevention strategies to optimize allocation of limited medical resources and maximize cost-effectiveness of the interventions by tailoring intensity of screening (i.e., frequency and choice of modalities) and prioritizing a subset of patients with higher HCC risk for chemopreventive therapies.

Figure 3. Molecular targets of potential HCC chemoprevention therapies

Intra- and extracellular targets of potential HCC chemopreventive therapies are summarized. 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; ASK1, apoptosis signal-regulating kinase 1; AT1, angiotensin type 1 receptor; CCR, C-C chemokine receptor; 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; NFκB, 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, tumor necrosis factor receptor; TSC, tuberous sclerosis complex; VEGFR, vascular endothelial growth factor receptor; YAP, Yes-associated protein.