Biomarkers: The precursor to successful liquid biopsy implementation
Liquid biopsy in cancer diagnosis and monitoring
The current state of liquid biopsy development
References 
Further reading 

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Liquid biopsy refers to the analysis of tumors using biomarkers circulating in several bodily fluids such as the blood. In recent years it has received a large amount of attention in the diagnostic sphere as it presents a minimally invasive and repeatable means to test for the presence of several diseases with large clinical implications.

Considerable progress has been made in developing devices capable of performing such an analysis; however, the liquid biopsy technique is not currently a standardized tool in the clinical setting owing to several limitations. Liquid biopsies play a central role in cancer diagnosis.

Biomarkers: The precursor to successful liquid biopsy implementation

Two of the most well-developed biomarkers used in liquid biopsy or circulating tumor cells (CTCs) and circulating cell-free tumor DNA (ctDNA); are subject to technical variability in both the pre-analytical and analytical steps. CTCs are a highly effective means of effectively monitoring patient response to treatment and can aid in the personalization of treatment choice, facilitating a more defined classification and stratification of patients. In the context of lung cancer, for example, they are instrumental in early diagnosis. This is because they can be categorized into epithelial, mesenchymal, and epithelial-mesenchymal CTCs using epithelial mesenchyme and transformation biomarkers.

This presents an issue for the widespread uptake of liquid biopsy. To mobilize liquid biopsy in the clinical setting, further research is needed to develop the utility of biomarkers themselves.

Several efforts are currently underway to address the technical variability in the pre-analytical and analytical steps to enable the mobilization of liquid biopsies in the clinical setting, including the European Liquid Biopsy Society and the US-based BloodPAC project. Both of these consortia combine industry and academic expertise and aim to develop reproducible and robust liquid biopsy assays.

Liquid biopsy in cancer diagnosis and monitoring

In cancer, the spatially and temporally limited tissue biopsies do not represent the overall tumor profile and cannot capture any changes that occur at different sites; therefore, traditional tissue biopsies are limited in their ability to monitor disease progression. At present, tissue biopsies are the gold standard for profiling tumors – yet they are still plagued with several limitations including their invasiveness and riskiness of procedure, and are difficult to perform for some sites.

Tissue biopsies are also unable to provide the full tumor profile. This limitation is particularly problematic as tumors are heterogeneous entities and contain subpopulations of cells that harbor different alterations. Tumors also undergo several epigenetic and genetic alterations throughout the disease course due to external and internal factors, such as therapeutic stress, which further exacerbate tumoral heterogeneity and produce differences between the primary and metastatic lesions.

Given these limitations, liquid biopsies, which rely on the detection of CTCs and ctDNA, RNA, tumor-educated platelets, and extracellular vesicles in the fluids of patients, have become an increasing focus in oncology. The use of liquid biopsies as a clinical tool is intended to improve screening, diagnosis, and prognosis as well as facilitate the classification of heterogeneous tumor masses, enable specified patient monitorization, assess treatment response, and detect the presence of treatment-resistant clones.

Liquid biopsies offer minimally invasive means that are highly reproducible and may be repeated several times throughout disease progression without any undue stress or harm being placed on the patient. In addition, liquid biopsies enable genetic characterization of the tumor to reflect its heterogeneity and aid in the early detection of any potential aggressive clones which may disseminate.

The growing role of liquid biopsies in oncology is a model which reflects the growing trend toward precision medicine across the medical and clinical settings. Precision medicine is particularly instrumental in oncology as the development of screening and early detection tests, paired with the development and implementation of efficient monitoring methods, promise improvements in the efficacy of therapies and reduce cancer mortality.

Precision medicine is primarily achieved through molecular profiling; this can be applied to gain insight into the alterations that underlie the tumor formation process. This subsequently contributes to the development of a range of accurate diagnostic and prognostic biomarkers as well as the selection of treatments that consider the individual's variables.

The current state of liquid biopsy development

The extent to which liquid biopsy may present the new gold standard over tissue biopsy remains to be seen. In diagnosing primary tumors or determining metastatic lesion staging in which tissue extraction is difficult, liquid biopsies provide a practical and reliable alternative. A liquid biopsy also circumvents complications that may occur after tissue biopsies, such as infections, pain, and bleeding.

Although the clinical potential of liquid biopsies has been clear for over a decade, widespread use is limited by their lack of study; interventional clinical trials are needed alongside the development of an algorithm that can reliably and accurately combine them with the detection of the appropriate circulating biomarkers.

At present, of the few interventional clinical trials ongoing, the STIC CTC METABREAST study has demonstrated the clinical applications of CTCs in assigning people with metastatic breast cancer to one of two treatment modalities, namely chemotherapy or hormonal therapy. In most patients, a CTC count was an appropriate confirmation of the clinical choice. The success or failure of systemic therapies such as hormonal, chemo, and over-targeted therapies can be achieved by the sequential measurements of CTCs or ctDNA.

As such, most sufficient evidence is necessary to support the transformation of liquid biopsy from its current research stage to clinical use. However, its potential in the diagnostic and treatment phases of several types of cancer is promising; further advanced molecular biological detection means to enhance the translatability and reliability of liquid biopsy are required before its wide use in clinical practice.

References

• Alix-Panabières C. The future of liquid biopsy. Nature. 2020;579(7800):S9. doi: 10.1038/d41586-020-00844-5. 
• Alix-Panabières C, Pantel K. Clinical Applications of Circulating Tumor Cells and Circulating Tumor DNA as Liquid Biopsy. Cancer Discov. 2016;6(5):479-91. doi: 10.1158/2159-8290.CD-15-1483. 
• Martins I, Ribeiro IP, Jorge J, et al. Liquid Biopsies: Applications for Cancer Diagnosis and Monitoring. Genes (Basel). 2021;12(3):349. doi: 10.3390/genes12030349. 
• Osei-Bordom DC, Sachdeva G, Christou N. Liquid Biopsy as a Prognostic and Theranostic Tool for the Management of Pancreatic Ductal Adenocarcinoma. Front Med (Lausanne). 2022;8:788869. doi: 10.3389/fmed.2021.788869.

Further Reading

• All Biopsy Content
• Biopsy – What is Biopsy?
• Types of Skin Biopsy
• What is a Breast Biopsy?
• What is a Skin Biopsy?

  

Written by

Hidaya Aliouche

Hidaya is a science communications enthusiast who has recently graduated and is embarking on a career in the science and medical copywriting. She has a B.Sc. in Biochemistry from The University of Manchester. She is passionate about writing and is particularly interested in microbiology, immunology, and biochemistry.