Exploring Advanced Detection and Treatment Strategies for Hepatocellular Carcinoma (HCC)

A new review has shed light on the latest advancements in detecting and treating hepatocellular carcinoma (HCC), a major global health challenge due to its significant socio-economic impact. This article delves into innovative approaches like liquid biopsy and various biomarkers that offer promise in the early detection and personalized treatment of HCC.

At a Glance:

• Liver cancer, especially HCC, remains a significant global health issue.

• Major risk factors for HCC include HBV/HCV infections, chronic liver diseases, alcohol abuse, and diabetes.

• Standard diagnostic tools include imaging (CT/MRI), tissue biopsy, and serum biomarkers (AFP, PIVKA-II).

• Liquid biopsy offers a non-invasive method to gain real-time insights into tumor heterogeneity.

• Recent advancements in genomic, transcriptomic, and epigenomic studies show promise.

• Emerging biomarkers include circulating tumor DNA (ctDNA), non-coding RNAs (ncRNAs), and extracellular vesicles (EVs).

The Growing Challenge of HCC

Liver cancer ranks as the second most lethal cancer worldwide, with HCC accounting for 90% of cases. Diagnosing HCC is challenging due to its asymptomatic or ambiguous early-stage symptoms. Early detection is crucial for improving survival rates, leading to various screening and surveillance programs targeting high-risk populations.

Diagnostic Tools and Biomarkers

Imaging and Tissue Biopsy

The American Association for the Study of Liver Diseases recommends biannual ultrasound surveillance for high-risk HCC patients. While ultrasound is convenient, its sensitivity is only 50%, making CT and MRI preferable for their higher sensitivity and specificity.

Serum Biomarkers

Alpha-fetoprotein (AFP) has long been the "gold standard" for HCC screening. However, its sensitivity fluctuates, and it's often combined with imaging techniques. "AFP alone has a sensitivity of about 60% when the cut-off value is at 20 ng/mL." Other notable biomarkers include AFP-L3%, PIVKA-II, and glypican-3 (GPC3), each contributing to a more comprehensive diagnostic approach.

Liquid Biopsy: A Promising Alternative

Liquid biopsy offers a minimally invasive method to obtain valuable information about tumor heterogeneity. It involves analyzing circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and extracellular vesicles (EVs) in blood or other body fluids.

Circulating Tumor Cells (CTCs)

CTCs are isolated from tumors and can travel through the bloodstream, providing direct evidence of cancer. Although isolating CTCs is challenging, they offer insights into tumor heterogeneity and mutations, aiding in personalized treatment strategies.

Circulating Tumor DNA (ctDNA)

ctDNA analysis reflects the genetic and epigenetic profiles of tumors. Techniques like quantitative PCR and next-generation sequencing (NGS) are employed to detect ctDNA, which can indicate tumor burden and guide treatment decisions.

Non-coding RNAs (ncRNAs)

MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) regulate gene expression and have shown potential as diagnostic markers. For instance, miR-375 has demonstrated a high area under the receiver operating characteristic (ROC) curve of 0.96, making it a promising biomarker for HCC detection.

Biomarkers for Treatment Options and Therapeutic Response

Biomarkers Related to Surgical Resection

Certain biomarkers are critical for postoperative monitoring and predicting recurrence. A recent study identified that serum AFP levels greater than 400 ng/mL pose a risk for overall survival (OS) and recurrence-free survival (RFS). Combining AFP with sulfite oxidase levels can predict postoperative outcomes and recurrence risk with high sensitivity and specificity.

Other research focuses on DCP (des-gamma-carboxy prothrombin) and GPC3 (glypican-3), which are both linked to a worse prognosis in HCC patients.

Biomarkers Related to Chemoembolization and Chemotherapy

Transarterial Chemoembolization (TACE) and Hepatic arterial infusion chemotherapy (HAIC) benefit from biomarkers like Pyruvate kinase muscle isozyme M2 (PKM2) and serum VEGF levels, which predict therapeutic response and survival.

Biomarkers for Ablation and Transplantation

Local ablation involves using electrical equipment to destroy tumor tissues. Biomarkers like AFP, DCP, and certain miRNAs correlate with overall survival (OS) and disease-free survival (DFS) after ablation. Liver transplantation remains an option for unresectable HCC tumors, with AFP levels being a key consideration for patient eligibility.

Targeted Therapies and Immunotherapies

Sorafenib is a common first-line drug for unresectable HCC, but resistance often develops. Biomarkers such as plasma Tregs, CD56Dim NK cells, and certain ncRNAs have been studied to predict drug response. Similarly, biomarkers like FAT1 and LRP1B genes relate to the efficacy of Lenvatinib as a second-line therapy.

Immunotherapy shows promise in treating HCC, with biomarkers like AFP and CRP levels used to develop the CRAFITY score, predicting survival and therapeutic response. Other biomarkers, including PD-L1+ CTCs and SLAMF7, have potential for predicting immunotherapy response.

Discussions and Perspectives

As the number of non-heritable risk factors for HCC rises, it is very important to find biomarkers that can be easily measured for early detection and therapeutic indicators through liquid biopsy. Personalized medicine, integrating genetic alterations, tumor phenotypes, and immune microenvironment information, is key to successful treatment. AI and machine learning offer significant potential to analyze vast datasets, enhancing diagnostic accuracy and predicting treatment responses.

Conclusion

Identifying reliable biomarkers for HCC through liquid biopsy offers a non-invasive, cost-effective alternative to traditional diagnostic methods. Continued research into novel technologies and methodologies will enhance diagnostic sensitivity and specificity, improving patient outcomes. Collaborative efforts will overcome HCC challenges, significantly benefiting patients affected by this devastating disease.