Liquid Biopsy ­– The key to cancer diagnostics, monitoring and treatment

Accelerating the commercialization of non-invasive tests for liquid biopsy of solid tumor cancers. (LIQ-BIOPSY)

Cancer is not one disease, but several – which partly explains the complexity and variability in treatment, management and prognosis of patients. In 2018, there were over 18 million people diagnosed with cancer, and more than 9 million deaths because of it¹. By 2030, due to population growth and increased life expectancy, the number of new cases is expected to increase to 21 million, with the number of deaths rising to 13 million². Cancer is defined as the uncontrollable growth of mutated (altered) cells, and an important factor contributing to cancer management and survival are the tools used today to diagnose, treat and monitor a person with cancer.

Indisputably, the key to effective cancer control and one of the global challenges to reducing the impact of cancer is diagnostic delays. If cancer is detected early, when the tumor is still small and hasn’t metastasized to other organs yet, chances of successful treatment are higher. Currently, cancer detection is achieved via screening and diagnostic tests. Screening tests are used as a first line of cancer detection to identify a small group of people that are high-risk of having cancer and to refer them for diagnostic tests. Screening tests are usually simpler and less invasive than diagnostic tests, which give a definite answer on whether the patient has cancer.

Screening procedures include colonoscopy for colorectal cancer; analysis of prognostic biomarkers like evaluating the CA-125 levels through a blood test for ovarian cancer; and medical imaging, such as a screening mammography for breast cancer. Screening tests can be useful as a first line of detection because of their simplicity, but some limitations exist as they could still be invasive, painful, or subject patients to harmful radiation. Additionally, not all cancers have a reliable screening test. Lastly, some screening tests have low specificity, and thus may unnecessarily refer many patients for intrusive diagnostic tissue biopsies. The biggest shortcoming of screening tests though, is that they detect cancer when it has become prominent – not during the early stages, where immediate response is critical and most beneficial.

Currently, traditional cancer diagnostics also face challenges related to feasibility (a tissue biopsy for a lung cancer may not always be achievable), and the delay in recovering from these invasive procedures which could further stress the immune system and compromise the efficiency of cancer therapy. Further limitations include the inability to obtain a fully accurate genomic picture of the tumor as this depends on the biopsy site and the cells collected. Advanced and metastatic cancers especially tend to be heterogeneous (composed of different genetic mutations), and therefore, a single biopsy from one tumor site may not represent the whole tumor.

Hence, an area of particular interest in the cancer field is the liquid biopsy test. Performed via a simple blood draw, a liquid biopsy test can detect circulating tumor DNA (ctDNA) released into the bloodstream from cancerous cells and tumors³. This ctDNA varies from ‘normal’ DNA as it has acquired genetic mutations related to the tumor. Therefore, detection of ctDNA can be key for early cancer detection and diagnosis.

Liquid biopsy tests offer advanced sensitivity than conventional detection methods because ctDNA has tumor characteristics from all cancerous sites in the body and can assess tumor heterogeneity that could otherwise go unnoticed in a traditional tumor biopsy. By providing an accurate picture of the disease, liquid biopsy testing could help in providing tumor-specific treatment via targeted therapies. Looking at the particular mutations in a patient’s sample will allow their physician to determine the most appropriate treatment option and prescribe therapies that are the most effective for the specific mutations present. This has the potential to cause less side effects for the patients, and will undoubtedly provide them with the best chances of successful treatment. Additionally, liquid biopsy can work as a prognostic tool, tracking and assessing the risk of relapse and prognosis of patients, and of acquired treatment resistance over the course of therapy via serial blood-draws which would examine the changing ctDNA. Liquid biopsy is the ideal test for serial testing, due to its fast, painless and safe application – this would not be possible with conventional cancer diagnostics due to the tests’ invasiveness. For example, a study on colorectal cancer has demonstrated that ctDNA levels indicating recurrence were detected on average 10 months before cancer relapse was picked up by other methods⁴. This indicates that liquid biopsy can monitor tumor dynamics and detect disease much earlier than other means, which would be extremely beneficial for quick medical action and effective treatment that could prove life-saving.

Lastly, the key advantage of liquid biopsy testing is how early the test can detect cancer. Compared to current screening and detection methods that confirm the presence of cancer typically after the onset of symptoms, a liquid biopsy can identify ctDNA presence in the bloodstream much earlier. This is integral in preventing metastasis and encouraging improved chances of treatment.

The presence of ctDNA in the bloodstream is well-known for over 20 years³. The extremely low volume of ctDNA compared to non-pathogenic DNA makes the design of a ctDNA test intricate and challenging. The story of ctDNA is similar with that of cell-free fetal DNA (cffDNA). More than two decades have passed since the discovery of cff-DNA in 1997, to the routine implementation of non-invasive prenatal tests (NIPT) to pregnant women of all ages. Implementation of next generation sequencing for cell-free fetal DNA detection revolutionized prenatal testing by allowing for the detection of multiple aneuploidies, microdeletions and even single gene disorders prenatally; informing prospective parents and healthcare providers of the health of the unborn baby and allowing them to take informed decisions regarding management and possible treatment. With the leaps of technological advances we have witnessed in recent years, the wealth of information obtained and the ability of the scientific community to transform these into clinical actions, the application of liquid biopsy into clinical practice will soon be a reality that will benefit millions.

NIPD Genetics is currently developing a liquid biopsy assay for the detection of cancer using ctDNA. In line with NIPD Genetics’ vision of providing safe, sensitive and reliable tests, our liquid biopsy assay will provide valuable clinical utility for the detection of solid cancers, and would have applications in many clinical decision-making points such as early cancer detection, diagnosis, monitoring of tumor dynamics, identification of mutations for targeted therapy and assessment of treatment resistance. Leveraging our powerful technology, we aim to bring to the market an affordable and accurate liquid biopsy assay that will benefit and revolutionize cancer care worldwide. 70% of this research is funded by the Research and Innovation Foundation, Cyprus, under the program RESTART 2016-2020 after receiving the Seal of Excellence from the European Commission⁵ under the H2020 program.

References:

1. World Health Organization Press Release (2018). ‘Latest global cancer data: Cancer burden rises to 18.1 million new cases and 9.6 million cancer deaths in 2008’. International Agency for Research on Cancer.
2. World Health Organization (2019) ‘Key Statistics’,
3. https://www.who.int/cancer/resources/keyfacts/en/
   Sorenson GD., et al. (1994) ‘Soluble normal and mutated DNA sequences from single-copy genes in human blood. Cancer Epidemiology, Biomarkers & Prevention; 3(1): 67-71
4. Reinert T., et al. (2016) ‘Analysis of circulating tumor DNA to monitor disease burden following colorectal cancer surgery’. Gut; 65:625-634
5. https://www.nipd.com/company/science/