CTCs, cfDNA and Tissue Biopsies: A Comparison

CTCs, cfDNA and Tissue Biopsies: A Comparison

The diagnosis and monitoring of cancer has historically been hindered by the need to obtain tissue biopsies, which can require invasive and costly surgery that itself presents risks.  Generally one or two biopsies/ excisions are performed, but tumors may then continue to mutate, spread, or gain resistance to drugs without any direct measurement.  Ideally the doctors would like to have ongoing access to the tumor's genetic data as it changes, well before it would be noticed using medical imaging.  

There is the potential for revolutionary improvements in diagnosis and treatment using "liquid biopsies", the analysis of circulating tumor DNA (ctDNA, a subset of cell-free DNA, cfDNA) and circulating tumor cells (CTCs).  These are shed by tumors into the blood and other body fluids, and have provided the ability to identify specific types of cancer, their progression, mutations, metastasis, drug resistance, etc.  Technological advances primarily related to next-generation sequencing (NGS) and digital PCR (dPCR) have allowed scientists to overcome the extremely low concentrations of these analytes.  For example, ctDNA can be present at under 0.1% relative to the normal DNA floating in blood; and CTCs make up only 1 to 10 cells per mL of whole blood, in a background of millions of white blood cells and around a billion red blood cells per mL.  These technologies and the markets for them are fully explored in Kalorama Information's, Cell-free DNA Markets 

A comparison of the pros and cons of ctDNA, CTCs, and tissue biopsies is presented in this figure.  The ease of sample collection makes both ctDNA and CTCs highly advantageous, but the isolation of CTCs is currently more technically challenging.  Many factors make it difficult to predict whether one, or both, or neither, will become a typical approach for diagnostic oncology applications and the like.  There are still challenges being addressed, and the extent of their medical applicability is mostly unknown.  It would seem that ctDNA and CTC analyses have already firmly established some territory for several applications.

In the absence of alternatives, this should continue to grow for both, application by application.  However, in the longer term it is possible that one of them may have major advantages and become the predominant test.  Cost, low abundance, and technological difficulty appear to be the main barriers for CTCs.  It could be that exosomes, which are a subset of cfDNA but slightly distinct, turn out to provide the most valuable data due to some of their characteristics.  Due to the ability to isolate exosomes and cfDNA together and obtain sequence data using some overlapping procedures, it is conceivable that they would often both be tested at the same time if the data merits.