Liquid biopsy has seen a lot of development and many applications in the field of cancer diagnostics. Key applications include the early detection of cancer, monitoring of disease progression and therapeutic response, and the detection of minimal residual disease.
Early cancer detection
It is well established that when cancer is detected at an earlier stage, it is not only easier to treat, but also reduces patient suffering and increases survival. However, there are several issues with the current gold-standard methods for the early detection of cancer, that limit this in clinical practice.
These include difficulties in accessing certain tumours, changes in tumour genetic composition arising from malignant neoplasms and intra-tumour heterogeneity. Liquid biopsy has shown that it is a technique that has the potential to address these problems, revolutionising the early detection and diagnosis of cancer.
Although detecting cancer early with liquid biopsy is starting to deliver on its potential, many challenges still remain. Circulating biomarkers are at extremely low levels in early-stage cancer and they can also show a high level of variability. This means that liquid biopsy tests must be highly sensitive, which may in turn impact the specificity.
The variability of biomarkers may also result in different blood samples from the same individual yielding different results. A deeper understanding of the biological processes underpinning the release of circulating tumour DNA (ctDNA), and other circulating biomarkers, is also required. This can come in the form of more discovery and translational research, supplementing the many ongoing liquid biopsy clinical trials.
Monitoring disease progression and therapeutic response
One of the unique aspects of liquid biopsy is the minimally invasive process involved when taking a blood sample. This considerably reduces patient discomfort when sampling and means that multiple samples can be taken from the same patient over a prolonged period of time. Liquid biopsy is therefore a particularly powerful tool for monitoring the progression of cancer and patient response to therapy.
Specifically, the prognostic significance of ctDNA in cancer progression and therapeutic response has been shown. In several cancer types, including lung cancer, ovarian cancer and colorectal cancer, the presence of ctDNA correlates with poor clinical outcomes and tumour relapse. Similar results have been shown by extracting and profiling tumour-related genes using circulating tumour cells (CTCs).
The molecular and genetic profiling of circulating biomarkers using liquid biopsy delivers real-time monitoring of constantly changing tumours and their genotypes. These changes would otherwise not be detectable with conventional tissue biopsy. The molecular characterisation of tumours using liquid biopsy can therefore track disease progression, predict therapeutic outcomes and prevent disease relapses.
The metastasis of a primary tumour to a secondary site is responsible for approximately 90% of all deaths caused by cancer. The process of metastasis and liquid biopsy are intrinsically linked. Tumour cells from the primary site are able to enter the bloodstream and travel as CTCs, before deposition at a distant site and the formation of secondary tumours. This process also means that the analysis of CTCs using liquid biopsy can reveal unique insights about metastasis and the types of primary tumours that are able to metastasise.
A growing area of research is the exploration of circadian rhythm and cancer cell metastasis. Very recent findings are establishing a connection between circadian rhythm, sleep and the release of CTCs. While this increases the understanding of cancer cells in circulation, it also presents an opportunity for the liquid biopsy community to target the timing of CTC sampling and testing.
Measuring minimal residual disease
Minimal residual disease, also known as molecular residual disease, (MRD) is when cancer persists in a patient after treatment but is no longer detectable through current medical imaging procedures. The high sensitivity of liquid biopsy technologies has enabled the detection of MRD in patients, in whom the disease is not otherwise detectable through radiological imaging.
Relapse is thought to be caused by micro-metastases, where a small number of cancer cells have spread from the primary tumour to other parts of the body, but where there are too few to be picked up in imaging or using diagnostic tests.
Liquid biopsies detecting small numbers of CTCs or low levels of ctDNA can enable the detection of MRD in various malignancies. By monitoring CTCs and ctDNA during post-surgical follow-up assessments, disease relapse can be detected many months earlier than with current radiological imaging procedures.