*6.3.1 CTC*

A significant limitation of utilising CTC as a biomarker in CRC, particularly in early disease, is that they are difficult to detect in the blood due to a large proportion being captured in the liver prior to entering the general systemic circulation [101–103]. Furthermore, there have been a number of heterogenous studies, systematic reviews and meta-analyses which demonstrate conflicting results for the role of CTC as a prognostic biomarker [104–106]. This makes interpretation very challenging. Nonetheless, it is worth noting that detectable ctDNA and CTC as biomarkers are distinct entities and, in isolation, neither can be regarded as optimal surrogates of the multiclonal malignant state in an individual CRC patient. As discussed earlier, ctDNA is likely to be released by apoptotic or necrotic tumour cells, rather than highly proliferative cells, within a multiclonal tumour [103]. However, we do not know whether all clones have the same apoptotic potential, and therefore

detectable ctDNA levels in CRC patients do not always correspond to the ability to detect CTC [102, 107]. As such, it would be worth exploring the concomitant use of both of these biomarkers in a liquid biopsy.
