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Curated Papers > Recent research on high-impact "liquid biopsies" (IF≥30, past 5 years)

Liquid biopsy in hepatocellular carcinoma: circulating tumor cells and circulating tumor DNA. ​

Literature Information ​

DOI10.1186/s12943-019-1043-x
PMID31269959
JournalMolecular cancer
Impact Factor33.9
JCR QuartileQ1
Publication Year2019
Times Cited202
KeywordsCirculating tumor DNA, Circulating tumor cells (CTCs), Clinical application, Hepatocellular carcinoma, Liquid biopsy
Literature TypeJournal Article, Research Support, Non-U.S. Gov't, Review
ISSN1476-4598
Pages114
Issue18(1)
AuthorsQianwei Ye, Sunbin Ling, Shusen Zheng, Xiao Xu

TL;DR ​

Hepatocellular carcinoma (HCC) is a prevalent cancer with significant mortality, and traditional invasive biopsies often fail to capture tumor heterogeneity and progression, highlighting the need for less invasive diagnostic methods. This review discusses the promising applications of liquid biopsy techniques, specifically circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), which offer a noninvasive approach for early detection and monitoring of HCC, thus enhancing clinical decision-making and patient management.

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Circulating tumor DNA · Circulating tumor cells (CTCs) · Clinical application · Hepatocellular carcinoma · Liquid biopsy

Abstract ​

Hepatocellular carcinoma (HCC) is one of the most common cancers and a leading cause of death worldwide. Due to latent liver disease, late diagnosis, and nonresponse to systemic treatments, surgical resection and/or biopsy specimens are still generally considered as the gold standard by clinicians for clinical decision-making until now. Since the conventional tissue biopsy is invasive and contains small tissue samples, it is unable to represent tumor heterogeneity or monitor dynamic tumor progression. Therefore, it is imperative to find a new less invasive or noninvasive diagnostic strategy to detect HCC at an early stage and to monitor HCC recurrence. Over the past years, a new diagnostic concept known as "liquid biopsy" has emerged with substantial attention. Liquid biopsy is noninvasive and allows repeated analyses to monitor tumor recurrence, metastasis or treatment responses in real time. With the advanced development of new molecular techniques, HCC circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) detection have achieved interesting and encouraging results. In this review, we focus on the clinical applications of CTCs and ctDNA as key components of liquid biopsy in HCC patients.

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Primary Questions Addressed ​

  1. What are the specific advantages of using liquid biopsy over traditional tissue biopsy in the early detection of hepatocellular carcinoma?
  2. How do circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) differ in their ability to reflect tumor heterogeneity in HCC?
  3. What recent advancements in molecular techniques have improved the detection rates of CTCs and ctDNA in patients with hepatocellular carcinoma?
  4. How can liquid biopsy contribute to personalized treatment strategies for patients diagnosed with HCC?
  5. What are the challenges and limitations currently faced in the clinical implementation of liquid biopsy for monitoring HCC recurrence?

Key Findings ​

Background and Purpose ​

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers and a leading cause of cancer-related mortality globally. The late diagnosis and limited treatment options contribute to poor prognosis, with high recurrence rates following surgical interventions. This review focuses on the emerging diagnostic strategy of "liquid biopsy," which involves the analysis of circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) as non-invasive biomarkers for early detection, monitoring, and management of HCC.

Main Methods/Materials/Experimental Design ​

The review summarizes the methodologies for detecting CTCs and ctDNA, emphasizing their clinical applications in HCC.

Methodology Overview ​

Mermaid diagram

  1. CTC Detection: Utilizes both physical (e.g., size-based filtration) and biological (e.g., antibody-based methods) techniques to isolate CTCs from blood samples. The CellSearch system is highlighted as a clinically validated method.

  2. ctDNA Detection: Involves techniques such as digital PCR and next-generation sequencing (NGS) to identify genetic mutations and methylation changes in ctDNA, which is a small fraction of total circulating cell-free DNA.

Key Results and Findings ​

  • CTCs: The review indicates that CTCs can serve as prognostic biomarkers, correlating with poor outcomes in HCC patients. However, their low prevalence in early-stage cancers limits their utility as a standalone diagnostic tool.

  • ctDNA: ctDNA has shown higher sensitivity and specificity for diagnosing HCC compared to traditional biomarkers like alpha-fetoprotein (AFP). Methylation patterns in ctDNA have emerged as significant indicators for early detection and prognosis.

BiomarkerDiagnostic ValuePrognostic Value
CTCsLimited due to low prevalence in early stagesAssociated with poor overall survival
ctDNAHigher sensitivity and specificityCorrelates with disease-free survival and treatment response

Main Conclusions/Significance/Innovation ​

The review underscores the potential of liquid biopsy as a transformative approach in HCC management. By providing a non-invasive means to assess tumor dynamics, liquid biopsy can facilitate early detection, monitor treatment responses, and improve personalized therapy strategies. The integration of CTC and ctDNA analysis represents a significant advancement in the precision medicine paradigm for cancer care.

Limitations and Future Directions ​

The review notes several limitations in the current methodologies, including:

  • Variability in detection techniques leading to inconsistent results.
  • The need for standardization in the collection and analysis processes.
  • Challenges in isolating ctDNA specifically from other cfDNA.

Future research should focus on:

  • Large-scale, multi-center clinical trials to validate the utility of liquid biopsy.
  • Development of standardized protocols for CTC and ctDNA detection.
  • Exploration of multi-marker panels to enhance diagnostic specificity and sensitivity.

Overall, liquid biopsy is positioned as a crucial component in the evolution of cancer diagnostics and treatment, with the potential to significantly improve outcomes for HCC patients.

References ​

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  2. High frequency of promoter hypermethylation of RASSF1A in tumor and plasma of patients with hepatocellular carcinoma. - Winnie Yeo;Nathalie Wong;Wai-Lap Wong;Paul B S Lai;Sheng Zhong;Philip J Johnson - Liver international : official journal of the International Association for the Study of the Liver (2005)
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Literatures Citing This Work ​

  1. Detection of ctDNA in the plasma of patients with papillary thyroid carcinoma. - Huiqiang Li;Jiangman Zhao;Jianhua Zhang;Congren Wang;Mingzhu Li;Shouxin Wu;Zijian Su;Qunxiong Pan - Experimental and therapeutic medicine (2019)
  2. The Role Of Circulating Tumor DNA In Therapeutic Resistance. - Chenxin Xu;Haixia Cao;Chen Shi;Jifeng Feng - OncoTargets and therapy (2019)
  3. Using circulating tumor DNA as a novel biomarker to screen and diagnose hepatocellular carcinoma: A systematic review and meta-analysis. - Ziying Zhang;Peng Chen;Hui Xie;Peiguo Cao - Cancer medicine (2020)
  4. Circulating tumor cells in cancer patients: developments and clinical applications for immunotherapy. - Xiaoming Zhong;Hangtian Zhang;Ying Zhu;Yuqing Liang;Zhuolin Yuan;Jiachen Li;Jing Li;Xin Li;Yifan Jia;Tian He;Jiangyuan Zhu;Yu Sun;Wengting Jiang;Hui Zhang;Cheng Wang;Zunfu Ke - Molecular cancer (2020)
  5. Detection of Circulating Tumor Cells and Their Implications as a Biomarker for Diagnosis, Prognostication, and Therapeutic Monitoring in Hepatocellular Carcinoma. - Joseph C Ahn;Pai-Chi Teng;Pin-Jung Chen;Edwin Posadas;Hsian-Rong Tseng;Shelly C Lu;Ju Dong Yang - Hepatology (Baltimore, Md.) (2021)
  6. Sequential Circulating Tumor Cell Counts in Patients with Locally Advanced or Metastatic Hepatocellular Carcinoma: Monitoring the Treatment Response. - Kun-Ming Rau;Chien-Ting Liu;Yu-Chiao Hsiao;Kai-Yin Hsiao;Tzu-Min Wang;Wei-Shan Hung;Yu-Li Su;Wei-Ching Liu;Cheng-Hsu Wang;Hsueh-Ling Hsu;Po-Heng Chuang;Ju-Chien Cheng;Ching-Ping Tseng - Journal of clinical medicine (2020)
  7. Novel Liquid Biopsy Test Based on a Sensitive Methylated SEPT9 Assay for Diagnosing Hepatocellular Carcinoma. - Yurika Kotoh;Yutaka Suehiro;Issei Saeki;Tomomi Hoshida;Masaki Maeda;Takuya Iwamoto;Toshihiko Matsumoto;Isao Hidaka;Tsuyoshi Ishikawa;Taro Takami;Shingo Higaki;Ikuei Fujii;Chieko Suzuki;Yoshitaro Shindo;Yukio Tokumitsu;Hiroaki Nagano;Isao Sakaida;Takahiro Yamasaki - Hepatology communications (2020)
  8. LncRNA FLJ33360 accelerates the metastasis in hepatocellular carcinoma by targeting miRNA-140/MMP9 axis. - Zhenhui Lu;Yingzi Yu;Xiangchun Ding;Dong Jin;Genwang Wang;Yu Zhou;Yongzhao Zhu;Li Na;Yaqin He;Qi Wang - American journal of translational research (2020)
  9. Emerging and Innovative Theranostic Approaches for Mesoporous Silica Nanoparticles in Hepatocellular Carcinoma: Current Status and Advances. - Yaoye Tao;Jianguo Wang;Xiao Xu - Frontiers in bioengineering and biotechnology (2020)
  10. Impact of Next-Generation Sequencing on Outcomes in Hepatocellular Carcinoma: How Precise Are We Really? - Dana A Dominguez;Xin Wei Wang - Journal of hepatocellular carcinoma (2020)

... (192 more literatures)

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