Hepatocellular Carcinoma: Examining Its Prevalence and Prognostic Biomarkers

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, and its incidence continues to rise globally. In 2024, SEER data estimates an increase of 2.1 percent of new cancer cases, 4.9 percent of all cancer deaths, and a five-year survival rate of 21.7 percent. New cases of HCC are more common in men than women and highest among Non-Hispanic American Indian/Alaska natives. As the sixth leading cause of cancer deaths in the US, death rates follow similar trends with a median age of 70 years of age, which hasn’t changed in the past two decades.

However, the rate of incidence appears to be on the decline in some populations and increasing in others. So what’s different?

Reports attribute increased incidence to HBV, HCV, metabolic dysfunction, and alcohol consumption to name a few. But decreases have been attributed to the implementation of vaccinations and effective treatments against hepatitis and other liver diseases while others cite early diagnosis as a contributor.

Despite these advancements including treatment options, however, HCC prognosis remains poor due to its asymptomatic nature, leading to late diagnosis and aggressive tumor biology.

But the good news is that prognostic biomarkers offer a promising avenue for improving patient stratification, treatment selection, and overall HCC management. And so with that in mind, let’s explore the current landscape of prognostic biomarkers in HCC, focusing on their clinical utility and future directions.

Characteristics of Prognostic Biomarkers in HCC

There are gaps in the methods currently used to determine prognosis as these methods are primarily used to guide treatment decisions based on tumor burden and liver function. Prognostic biomarkers can address this gap by identifying patients at high risk for recurrence, metastasis, and mortality. There are three broad categories of prognostic biomarkers: serum, genetic, and imaging.

Current Landscape of Promising Prognostic Biomarkers

Several prognostic biomarkers in HCC are under active investigation, with some demonstrating utility. Here are the different categories and specific biomarkers:

• Serum markers are proteins or metabolites detected in blood samples. Examples include:
  • While alpha-fetoprotein (AFP) is the most common biomarker, it has limited sensitivity and specificity. AFP-L3 is the LCA-lectin binding fraction that’s been associated with rapid growth and metastasis. The ratio of AFP-L3 to total AFP (AFP-L3%) is used to screen for HCC but has demonstrated more utility in predicting HCC recurrence in terms of accuracy. AFP-L3% has highly variable sensitivity ranging from 37 percent to 96.9 percent and specificity ranging from 75.7 percent to 92 percent.
  • Des-gamma-carboxy prothrombin (DCP) is an abnormal clotting factor produced by the liver. Increased levels have been associated with some HCCs, with tests demonstrating 85 percent specificity and 87 percent sensitivity. However, DCP is not produced by all HCCs.
  • Glypican-3 (GPC3) is a cell-surface glycoprotein that’s overexpressed in HCCs with roles in growth and metastasis. Studies suggest that elevated GPC3 levels are associated with poorer overall survival. In combination with AFP, it has a sensitivity and specificity of 98.5 percent and 97.8 percent, respectively.  
• Genetic markers assess alterations in genes associated with HCC development and progression. Examples include mutations in TP53, CTNNB1, and CDKN2A/B. Identifying specific mutations can help predict response to targeted therapies. Additionally, small non-coding RNAs that regulate gene expression or microRNAs in blood or tumor tissue may be used for HCC prognosis, although further validation is needed.
• Imaging biomarkers have great utility in advanced imaging techniques such as MRI and diffusion-weighted imaging to assess tumor characteristics like size, vascularity, and diffusion restriction, which can correlate with prognosis.
• Immune-based markers have been useful in evaluating tumor immune microenvironments that play a role in HCC progression. Biomarkers reflecting immune cell infiltration or immune checkpoint expression are being explored for their prognostic potential.

Despite the promising landscape, challenges remain in implementing prognostic biomarkers in routine clinical practice. Challenges like validation and standardization are necessary to evaluate the utility of each biomarker. Further exploration with biomarker panels and other clinical parameters are also being explored to improve the accuracy and robustness of the data. And finally, the potential role of artificial intelligence in analyzing complex and extremely large biomarker and clinical databases to develop predictive models also warrants additional attention.

And so while challenges remain, prognostic biomarkers have the potential to revolutionize HCC management by enabling better patient stratification and treatment tailoring, and ongoing research holds promise for developing a robust panel of biomarkers that can potentially guide clinical decision-making and improve patient outcomes.

References

Abboud Y, Ismail M, Khan H, et al. Hepatocellular Carcinoma Incidence and Mortality in the USA by Sex, Age, and Race: A Nationwide Analysis of Two Decades. J Clin Transl Hepatol. 2024;12(2):172-181. doi:10.14218/JCTH.2023.00356

Cancer Stat Facts: Liver and Intrahepatic Bile Duct Cancer. National Cancer Institute Surveillance, Epidemiology, and End Results Program. Updated April 17, 2024. Accessed May 8, 2024. https://seer.cancer.gov/statfacts/html/livibd.html  

Cai X, Xu F, Wang Z, Chen H, Lin S. Prognostic Biomarkers for Hepatocellular Carcinoma Based on Serine and Glycine Metabolism-related Genes. J Clin Transl Hepatol. 2024;12(3):266-277. doi: 10.14218/JCTH.2023.00457.

Fares S, Wehrle CJ, Hong H, et al. Emerging and Clinically Accepted Biomarkers for Hepatocellular Carcinoma. Cancers (Basel). 2024;16(8):1453. Published 2024 Apr 10. doi:10.3390/cancers16081453

O'Brien TR, Devesa SS, Koshiol J, Marrero JA, Shiels MS. Decreasing incidence of hepatocellular carcinoma among most racial groups: SEER-22, 2000-2019. Cancer Med. 2023;12(19):19960-19967. doi:10.1002/cam4.6537