Risk stratification and early detection biomarkers for precision HCC screening

Abstract

Hepatocellular carcinoma (HCC) mortality remains high primarily due to late diagnosis as a consequence of failed early detection. Professional societies recommend semi-annual HCC screening in at-risk patients with chronic liver disease to increase the likelihood of curative treatment receipt and improve survival. However, recent dynamic shift of HCC etiologies from viral to metabolic liver diseases has significantly increased the potential target population for the screening, whereas annual incidence rate has become substantially lower. Thus, with the contemporary HCC etiologies, the traditional screening approach might not be practical and cost-effective. HCC screening consists of (i) definition of rational at-risk population, and subsequent (ii) repeated application of early detection tests to the population at regular intervals. The suboptimal performance of the currently available HCC screening tests highlights an urgent need for new modalities and strategies to improve early HCC detection. In this review, we overview recent developments of clinical, molecular, and imaging-based tools to address the current challenge, and discuss conceptual framework and approaches of their clinical translation and implementation. These encouraging progresses are expected to transform the current "one-size-fits-all" HCC screening into individualized precision approaches to early HCC detection and ultimately improve the poor HCC prognosis in the foreseeable future.

Figure 1

Conceptual framework and clinical implementation strategies of biomarker-guided precision HCC screening. (A) HCC risk stratification and early detection along the natural history of HCC development and progression. Risk stratification is the first step to identify specific patient population with elevated HCC risk (left). Subsequently, to the high-risk population, repeated HCC detection tests are applied at regular interval for diagnosis of early-stage HCC (middle). Intermediate- to advanced-stage HCC is theoretically outside the concept of HCC screening for early detection (right). New early detection biomarkers should achieve higher sensitivity compared to the current modalities, while maintaining a high specificity, ideally in less-invasively accessible biospecimens. Anticipated high sensitivity of the early detection biomarkers may lead to detection of subclinical neoplasia which is not recognizable with the current diagnostic tools such as contrast-enhanced dynamic MRI (i.e., false negative biomarker test based on MRI as goldstandard). Specific recall policies need to be developed according to confirmed association of the detection with subsequent HCC diagnosis. (B) Global shift of HCC etiology from viral to metabolic liver diseases over the past decade and accompanying drastic increase of the number needed to screen (NNS) for the current “one-size-fits-all” HCC screening. (C) Risk stratification by stepwise application of integrative HCC risk biomarkers to identify high-risk patients to focus the effort and resource of HCC screening. Tailored HCC detection tests are regularly applied according to predicted HCC risk by altering intensity of screening. Both HCC risk stratification biomarkers and early detection biomarkers can be integration of multimodal information, e.g., clinical, molecular and/or imaging features.

Figure 2

(A) Phases of cancer screening biomarker development.^[54] (B) Levels of evidence (LOE) for cancer screening biomarkers, defined based on the element category and status of validation studies are determined according to the study design elements.^{[55, 238]} Correspondence to the LOE defined in the International Liver Cancer Association (ILCA) white paper^[239] is shown. (C) Categories of recommendation for clinical implementation by the National Comprehensive Cancer Network (NCCN) according to the levels of scientific evidence and consensus among the NCCN expert panel. (D) Grades of recommendation for clinical implementation by the U.S. Preventive Services Task Force (USPSTF) according to certainty of net benefit for preventive intervention.

Figure 3

Potential use of HCC risk biomarkers in chemoprevention clinical trials. (A) Risk enrichment to select participants to be enrolled in chemoprevention clinical trials. Stepwise approach can be employed to identify super high-risk subgroup to increase HCC incidence rate for detection of chemopreventive effect in shorter time period with smaller sample size compared to conventional all-comer enrollment.^[92] (B) Use of therapeutically modifiable HCC risk biomarker to monitor effect of experimental intervention on quantitative molecular HCC risk level. (C) Use of therapeutic modulation of HCC risk biomarker as a surrogate endpoint to estimate reduction of future HCC incidence.

Figure 4

Performance of the GALAD score according to clinical subgroups and the phase of cancer screening biomarker study (meta-analysis). (A) Sensitivity, specificity, AUROC, and log diagnostic odds ratio (DOR) by clinical subgroups defined by HCC etiology, geographic region, and HCC stage. (B) Summary ROC curves for early-stage HCC in phase 2 (upper panel) and 3 (lower panel) studies are separately presented. DerSimonian and Laird random-effect method was used for the meta-analysis, and heterogeneity was assessed by Cochrane’s Q statistic. See Table 2 and Supplementary table 3 for details of the individual studies used for the meta-analysis.