Liquid Biopsy is a term given to a minimally invasive method of analyzing Tumor cell DNA circulating in the blood. This is a useful and very promising approach and opens new vistas compared to the Biochemical Biomarkers and Tissue Biopsies dependent monitoring of cancer. However, it throws its own challenges too.
Circulating Tumor Cell DNA is present in the blood in a very miniscule amount. Cell free DNA (CfDNA) in itself is very small and tumor cell DNA (CtDNA) is even smaller. In fact, less than 1% of all CfDNA is CtDNA. This makes is very challenging to look for small mutations usually point mutations in such a small sample.
Cell free DNA (CfDNA) has shown lot of success in case of fetal DNA and diagnosis of aneuploidies and related complications. Technology has made it possible to reach up to molecular level and sequence for tell-tale signs like:
- Mutations
- Rearrangements
- Epigenetic markers
- Methylation
- Aneuploidies
Apoptosis, Necrosis and cell free DNA from circulating Tumor cells is responsible for circulating tumor cell DNA in the blood. Higher the tumor burden higher is the CtDNA in the blood. The advent of technologies like BEAMing, PAP, Digital PCR, TAM-Seq allows for the analysis of tiny amounts of DNA.
Applications of Liquid Biopsies in Cancer:
- Early Detection
- Assessment of Molecular Heterogeneity of overall diseases
- Monitoring of tumor dynamics
- identification of generic determinance for targeted therapy
- Evaluation of treatment response.
- Monitoring of minimal residual diseases
- Evaluation of resistance
One big advantage of Liquid biopsies that is emerging now in full scape is the ability to assess and evaluate intertumoral heterogeneity. Tumors within the same patient seldom are homogenous and this implies that a tissue biopsy taken from one portion will never yield comprehensive picture. Compared to this Liquid Biopsies provide a more comprehensive picture as CtDNAis basically a sum total of all. With increase in tumor burden the heterogeneity increases and so does the efficacy of Liquid Biopsies in all such cases of advanced tumors.
Circulating biomarkers have played an increasingly important role in assessing disease burden, especially in circumstances where imaging delivers indeterminate results. PSA, cancerantigen(CA)19-9, carcinoembryonicantigen and CA-125 are examples of protein biomarkers that aid in assessment of therapeutic response. Unfortunately, many malignancies do not have a reliable protein biomarker and even in those diseases with useful biomarkers these markers often lack specificity and may be elevated as a result of clinical situations not related to tumor growth or progression. Furthermore, most protein biomarkers persist in circulation for weeks, thereby only allowing accurate assessment over weeks to months. There are clear advantages to measuring ctDNA as a marker of tumor dynamics over conventional protein biomarkers or even imaging studies. For one, ctDNA has a comparatively short half-life (approximately 2 hours), allowing for evaluation of tumor changes in hours rather than weeks to months. Changes in ctDNA can predate those seen in imaging studies or using protein biomarkers by weeks to months.
Another striking advantage of CtDNA is that each assessment is specific to individual as somatic cancer mutation are identified by their presence in tumor DNA and absence in matched normals.
Liquid Biopsies exploiting the advances in technology to target CtDNA holds lots of promise in revolutionizing cancer treatment with earlier intervention and closer real-time monitoring of disease progression. It is well understood that these can change the outcome of therapy and intervention very positively in times to come.
