The most recent advancements in liquid biopsies for cancer management are reviewed in this article.
by Dr Maarja-Liisa Nairismagi and Dr Allen Lai
Liquid biopsies are rapidly changing the landscape of cancer management by enabling analysis of tumour components from bodily fluids such as blood, urine, saliva, ascites, and pleural effusion, among others. Due to their non-invasive nature, liquid biopsies hold great potential to dramatically change a cancer patient’s journey.
However, because of current technical constraints and little clinical validation data, the clinical use of liquid biopsies is still limited to a few specific indications. In this article, we will review the most recent advancements in the field of liquid biopsies, discuss the issues that Asian oncologists face in using liquid biopsies in their daily practice, and speculate how cancer patients in Asia could benefit from this novel technology in the near future.
Overview of Liquid Biopsies
Among all sources of bodily fluids taken for liquid biopsies, the use of peripheral blood is by far the most extensively studied form. Multiple analytes in the blood have been explored in the field of oncology – circulating tumour cells (CTC), circulating tumour DNA (ctDNA), circulating cell-free RNA, extracellular vesicles (EVs) such as exosomes, tumour-educated platelets (TEPs), proteins, and metabolites (Figure 1).
Studying blood-derived analytes enables scientists to understand nearly all layers of the complex tumour biology – from the genome, transcriptome, and epigenome of cancer cells to tumour proteome and metabolome.
Moreover, blood-based liquid biopsies have been applied to all stages of cancer care continuum, although mostly in clinical trial settings, including: (1) Early detection and diagnostics, (2) prognostication, (3) treatment selection, (4) tracking of clonal evolution, (5) monitoring treatment response, (6) detection of recurrence and minimal residual disease, and (7) identification of resistance mechanisms (Figure 2).
The thrust of analysing blood in liquid biopsies is underpinned by its nature of being minimally invasive. This allows multiple sampling at ease and holds the potential of overcoming limitations associated with tissue biopsies, such as tumour heterogeneity, subclonal mutations, and tissue availability.
As a result, using patients’ blood samples to manage their cancerous disease has enhanced the clinical use of liquid biopsies (Figure 3).
Clinical Use of Liquid Biopsies
Among all, CTCs and ctDNA are currently the most commonly explored peripheral blood analytes, and some commercially available liquid biopsy tests have gained US Food and Drug Administration (FDA) approval. For example, both the EGFR mutation test (for lung cancer treatment selection) and SEPT9 methylation analysis (for colorectal cancer detection) utilise ctDNA, while a CTC enumeration test is used to detect metastatic breast, prostate, and colorectal cancer.1
Compared to CTCs, ctDNA is more abundant in the blood stream and thus more capable of informing about tumour volume status in a timely fashion. There is proof of a linear relationship between tumour volume and ctDNA plasma variant allele frequency (VAF) in non-small cell lung cancer2 and high-grade serous ovarian cancer.3 As such, the attention in clinical care focuses mainly on the development of ctDNA as a biomarker test.
The amount of ctDNA is higher in metastatic disease than in localised disease and tallies with cancer stage,4 and monitoring of ctDNA VAF directly correlates to tumour burden in multiple cancers.5
Therefore, most clinical evidence for ctDNA is in monitoring tumour progression, early detection of drug resistance, and disease recurrence. For example, in lung, ovarian, and colon cancer patients, the presence of ctDNA after radical surgery and/or chemotherapy predicts recurrence and poor outcome. In addition, dynamic monitoring of ctDNA changes has been able to better predict disease recurrence, several months earlier compared to standard imaging techniques.6,7
Certain genetic alterations that are associated with drug sensitivity and resistance can also be detected in ctDNA, and this information can provide therapeutic guidance for some patients.
However, if the tumour DNA proportion is low in the blood, such information could be lost in a liquid biopsy. Therefore, it is not surprising that most professional societies recommend tissue genotyping when the liquid biopsy test is negative.8
In light of therapeutic implications enabled by molecular diagnostics, cancer tissues currently still provide more clinical insight compared to genomic findings obtained through liquid biopsies.
Implications of Liquid Biopsies to Asia
Cancer in Asia puts a tremendous disease burden on the whole world. Globally, Asia contributes to about 44 percent of cancer cases and about 51 percent of cancer-related deaths.9
Next generation sequencing (NGS)-enabled liquid biopsy holds promise for cancer patients who hope to monitor their disease regularly in a non-invasive way. Such technique is particularly useful when either biopsied cancer tissue is too scarce for sequential molecular diagnostics tests or a rebiopsy is unfeasible. This approach has profound implications to Asia.
In a recent survey of Asian cancer specialists’ practice of deploying NGS testing for cancer management,10 one-fifth of interviewees expressed their biggest frustration in adopting NGS stems from both poor quality and insufficient quantity of tissue samples, making it difficult to conduct tissue genotyping.
On the contrary, the sample requirement for liquid biopsy is comparatively more forgiving as it only requires one or two tubes of peripheral blood (less than 16 mL in total). More importantly, drawing blood is much more feasible (and less intimidating) to cancer patients versus taking a small piece of tumour lesion.
The second implication lies in the level of complexity presented in molecular profiling reports.
NGS-based multiplex tissue profiling tests, compared to liquid biopsy results, contain more genetic alterations and complex molecular information that requires deep knowledge to comprehend the vast genomic information and involved signalling pathways. Without proper training and guidance in tumour biology, tissue genotyping reports may pose substantial challenges for medical practitioners to discuss with patients about choosing the most appropriate therapeutic options, not to mention some genomic alterations may suggest off-label use of anti-cancer drugs.
Unsurprisingly, the survey points to a strong overall consensus (90%) that it is critical to familiarise oncology practitioners with scientific education before genomic testing can be widely used.
Current Limitations of Liquid Biopsies
In Asia, three major interdependent hurdles cripple the development and adoption of liquid biopsies: (1) Awareness of cancer molecular diagnostics, (2) availability of approved drugs, and (3) affordability of genomic profiling.11
To (partially) address these limitations, our proposal is three-fold. First, it is paramount for cancer researchers to gain a better understanding of tumour biology and liquid biopsy components to allow for true tumour-specific tests, such as the removal of mutations associated with normal ageing that can often resemble those identified in cancer patients.12
Second, for diagnostics developers to make technical improvements in detection methods that will allow enhanced analytical sensitivity and specificity, and reduction in cost.
Third, and probably the most important, it is crucial for clinicians to conduct more prospective clinical trials incorporating liquid biopsies as biomarkers so as to establish the clinical validity and utility of these assays. Before the above are resolved, it is unlikely that liquid biopsies will replace analysis of tumour tissues.
Potential Developments in the Near Future
The field of liquid biopsies has been moving fast and is likely to continue to keep pace. With more information coming from studies using analytes other than ctDNA and CTCs, we can expect development of assays that incorporate multiple parameters in a single test. This will increase analytical sensitivity and specificity, and will have the greatest implication on assays tackling early cancer detection.
Machine learning is likely to play a major role in the above to enable analysis of massive amounts of data associated with a multitude of liquid biopsy parameters and to distinguish cancer-specific signatures.
Lastly, with a few companies already in talks with the FDA,13,14 more regulatory approvals can be expected in the future for assays that provide treatment selection options for late stage, advanced cancer patients.
Way Forward for Cancer Patients in Asia
Knowledge of tumour biology and treatment advances constantly shape the diagnostics approach in cancer management. In this era of precision cancer care, the demand for detecting various biomarkers in tumour samples is on the rapid rise. Coupled with technological breakthroughs, it is now feasible to detect ctDNA, tumour-derived compounds or CTCs in peripheral blood.
As such, liquid biopsies open up the possibility of a non-invasive, timely, safe, and easily repeatable testing platform. It may serve as an attractive alternative approach in aiding diagnosis, disease monitoring, and detection of recurrence and resistance mechanisms to guide clinical management.
For patients seeking cancer care in Asia, liquid biopsies will also shed light in cases where obtaining tissue sample is not feasible. However, there are still limitations and challenges ahead. Further investigation, technological advancements, and clinical validation are mandatory to explore the full clinical utility of liquid biopsies.15 [APBN]
About the Authors
Dr Maarja-Liisa Nairismagi is the medical science liaison and project manager at ACT Genomics Singapore.
Dr Allen Lai is the senior vice president at ACT Genomics Singapore.