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Liquid Biopsies – Personalizing Cancer Diagnosis and Treatment

December 11 2018

Liquid biopsies have been heralded as a game changer in oncology, with major investments in the sector showing the expectations for numerous potential applications. As a non-invasive alternative to traditional tissue biopsies, liquid biopsies use blood or other easily accessible bodily fluids to detect molecular disease-related biomarkers, thereby opening up the path towards the holy grail of cancer: early detection. Liquid biopsies also play an important role as a tool to guide cancer treatment decisions, and thereby represent a significant step in the field of precision medicine. We have looked into the current trends in liquid biopsies as well as the challenges the field is facing.

The promise of liquid biopsies

Targeted therapy has revolutionised cancer treatment in recent years, showing exceptional effectiveness, durability of response and tolerability. With the ability to specifically block the molecular pathways essential to tumour development and survival, the ever-increasing arsenal of targeted therapies provides a wealth of treatment options in addition to more conventional approaches such as chemotherapy and radiotherapy. However, no one will deny that these treatments come at a cost given the low response rates in the general cancer population. To select the most effective treatment regimen for an individual patient we increasingly rely on biomarkers for early, accurate and objective tumour classification. Adequate detection of tumour-specific mutations as well as therapy resistance gene expression signatures can accelerate personalised approaches, improving treatment and patient’s quality of life while diminishing over-treatment side-effects.

Although tumour tissue biopsy represents an essential tool in cancer management, the information acquired from a single biopsy provides a spatially and temporally limited snapshot of a tumour and often fails to reflect the heterogeneity of the disease. Moreover, tumour biopsies are by definition invasive, which poses a limitation for repeated sampling, which is needed for monitoring treatment response and resistance to targeted therapies. Liquid biopsies could provide a potential revolution in cancer diagnostics as a minimally invasive method for detecting and monitoring diseases and are reported to provide an accurate and comprehensive spatiotemporal snapshot of the tumour and its microenvironment on multiple levels. The potential applications of liquid biopsies are therefore numerous:

  • Early detection (screening);
  • Prognosis for the individual patient: stage and spread;
  • Identification of new targets for personalised treatment;;
  • Pre-treatment classification for personalised therapy/prediction of response to therapy;
  • Early therapy response monitoring, ‘real-time’ assessment of treatment effectiveness;
  • Follow-up and early detection of recurrence of the disease.

 
What is happening in this field?

The field is currently mostly focused on obtaining genetic information from blood, which allows the isolation of tumour RNA/DNA to identify specific biomarker mutations and even advanced genomic measurements, such as mutational load and microsatellite instability. While initial developments covered mainly circulating tumour DNA (ctDNA) and Circulating Tumour Cells (CTCs), other biosources such as Extracellular Vesicles (EVs; such as exosomes) and Tumour Educated Platelets (TEPs) are receiving increasing amounts of attention. For each biosource specific limitations are currently being addressed in both research and commercial settings, such as the relatively low number of CTCs that are typically isolated from blood.

In the past years, many of these emergent technologies have evolved into functional assays making use of enzymatic reactions. Now, CTCs, EVs, and TEPs can all be functionally characterised, and such assays can be turned into diagnostics readouts. Indeed, many of these technologies are highly promising diagnostic tools that more often exceed performance of current state-of-the-art technologies such as imaging and radiomic approaches. However, also here, developments are steering the field towards more accurate and predictive technologies. For example, while imaging technologies are becoming more advanced and are now combined to obtain new insights in pathophysiology, new technologies are being developed to complement the classical imaging approaches. One example, is the use of smart pattern recognition algorithms to analyse imaging data to enable detection of tumors that would otherwise remain undetected.

Using AI to unlock the full potential of liquid biopsies

The continuous development of novel liquid biopsy techniques and the innovations in diagnostic technologies translate to an ever-increasing availability of diagnostic data, both personalised as well as for entire patient populations. To leverage the full potential of the available data, machine learning is an emerging technology frequently utilised to analyse the data. Through the use of self-learning algorithms, data sets from multiple sources can be combined to discover new patterns, disease specific signatures and novel pathways. The use of diagnostic data in this manner allows for more accurate, sensitive and personalised diagnostics whilst decreasing the burden to the patient. Indeed, as machine learning is more frequently employed on the continuous increasing types of data, predictive diagnostics enabling personalised treatment with the highest possible response rate could soon become a reality.

Current challenges

In addition to specific research challenges, one of the main hurdles to overcome is that there is still a significant gap between basic research and clinical application. So far, only a handful of tests based on liquid biopsy approaches have reached the market. One of the problems is that liquid biopsies still lack clinically proven results in terms of beneficial treatment for patients. In addition, implementation of liquid biopsies will require the development of standardized and uniform policies and guidelines for the isolation, processing, analysis, and annotation of biospecimens.

Furthermore, as more diagnostic technologies and tools are developed and validated, it will become increasingly difficult to utilize each approach without knowing how each technology compares to others. The data obtained by one approach is extremely likely to be complementary to that of another technology, either current or future. The main challenge resulting from the emergence of non-invasive diagnostic tools will thus be to determine the individual as well as the complementary value of each technology. How does a new technology compare to other technologies? How could it be combined with other approaches to achieve a more accurate diagnosis than any single approach would?  Given the current available technologies, what is the ideal application of a new technology – in diagnosis, treatment monitoring or follow-up, or all three?

To answer these questions, new methods must be developed to determine the specific positioning of each new technology in the patient journey in order to unlock its maximum diagnostic potential and convey the most benefits to both the patients as well as the clinicians. Indeed, while the clinical value of novel diagnostic technologies is evident, we have yet to determine the true value of liquid biopsies to society.  It is certain, however, that we are only beginning to understand how liquid biopsies will change every aspect of oncological care.

Our contribution

At ttopstart, we have been following the remarkable story of liquid biopsies closely, and are excited about what is to come. Working with several of the most promising researchers and companies in the field, we take pride in our contribution to make these technologies reach the patient faster. For example, we were involved in setting up the European Liquid Biopsies Academy (ELBA). This Marie Curie Innovative Training Network (ITN) is an extensive research and education programme currently training 15 Early Stage Researchers (ESRs) to circumvent the obstacles hampering effective development and commercialisation of liquid biopsy approaches.  

“By using liquid biopsies you only need a minimally invasive blood test to determine a targeted therapy that matches the tumour type or mutation type of the cancer, which makes the outcome of the therapy much better than when you just shoot bullets blindly. ELBA is an ITN funded project, which is training PhD students in this technique. This is something that can really create a breakthrough and I am happy to be on the advisory board on behalf of ECPC. This is clear innovation, which can really change the story of cancer patients.”

-  Jana Pelouchova, Board Member of the European Cancer Patient Coalition (ECPC)

 
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Jost de Bruin, MSc
+31 (0)30 73 70 779