What is a Liquid Biopsy?

Blood contains two types of cancer-derived materials that are susceptible to detailed molecular analysis: intact circulating tumor cells (CTCs) and cell-free circulating tumor DNA (cfDNA; also referred to as circulating tumor DNA, or ctDNA). As tumors increase in volume, the capacity of phagocytes to eliminate and clear apoptotic and necrotic fragments can be exceeded, leading to passive release of cfDNA into the bloodstream. Physicians can use the blood drawn from a patient's arm to analyze DNA that tumors typically shed into the bloodstream. Depending on the tumor size and vascularity, the amount of cfDNA released in the circulation can vary from 0.01% to 90% of all DNA present in plasma. Therefore, liquid biopsies provide a noninvasive approach to tumor molecular profiling without having to obtain tumor tissue.For more information on liquid biopsies as they relate to clinical practice, see the section "Liquid Biopsies."

The evolution of sensitive CTC and cfDNA detection technologies has enabled the development of liquid biopsies with many clinical applications, including:

• screening for presence of disease;
• patient stratification and therapy selection (companion diagnostics);
• monitoring treatment response and drug resistance; and
• detection of minimal residual disease after surgery/recurrence.

The molecular analyses enabled by isolation of CTCs and cfDNA in liquid biopsies may be applied to guide different treatment strategies at different events in the initial diagnosis and treatment of patients with cancer (Figure).

Figure. Use of liquid biopsies for treatment strategy in various stages of cancer

Risk versus benefit

Although liquid biopsies hold the promise of overcoming many of the drawbacks associated with tissue biopsies, it is likely that the latter will remain the gold standard for years to come. Until better technologies are available for testing liquid biopsies, tumor tissue will allow for a more thorough analysis, including the identification of more mutations than what is possible with a blood sample. However, having the option of a blood draw to learn about the genomics of a particular cancer will be valuable for many applications described earlier in this review. Advantages and disadvantages to liquid biopsy analysis are summarized below.

Advantages and benefits

• Non-invasive method for identification of tumor markers, either as an alternative for patients whose tissue is unable to be biopsied or as an adjunct to evaluate drug response.
• Possibly less costly than tumor biopsy and analysis.
• Provides an accurate snapshot of the genomic landscape of the tumor, bypassing issues such as intratumor heterogeneity, as it is speculated that CTCs and cfDNA carry the driver mutations causing metastases.
• Able to obtain serial samples during treatment to assess for drug resistance and tumor progression. This is not picked up with a tumor biopsy given that tumor biopsies are generally only done prior to treatment, therefore mutations indicating resistance would not be picked up as these generally arise after starting therapy.
• Unlike tissue biopsy where the tumor DNA is preserved in formalin-fixed paraffin embedded (FFPE) blocks, DNA cross linking does not occur with liquid biopsy; thereby facilitating tumor DNA sequencing.

Disadvantages and challenges

• Potentially miss biomarkers expressed in the tumor
• Test variability and assay sensitivity and specificity
• CTCs are rare, fragile and heterogenous
• Lack of consensus in technical approaches of choice

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