Within the last few years the term “liquid biopsy” has come into common usage and the concept is receiving significant attention in both the medical and non-medical literature.
Great hope (and perhaps hype) have also been generated, with claims of liquid biopsies becoming a game-changer primarily in the diagnosis and treatment of cancer. Driving this forward is significant large-scale investment5 in this new and rapidly developing technology, both commercially and academically.
This paper will describe the current status of liquid biopsies in the context of cancer, discuss their multiple potential applications, and assess the possible impact on mortality and morbidity. Specific opportunities and challenges they may bring to the insurance industry will also be reviewed, and RGA’s perspectives presented.
Definition of Liquid Biopsy
A liquid biopsy is any type of test which looks for signs (genetic material, biomarkers, or cells) of cancer in a person’s bodily fluids – most often in blood (the primary focus of this paper), but also in urine, saliva, semen or other fluids.14
Standard tissue biopsy – that is, of tumor tissue – is currently the gold standard for cancer diagnosis and for clinical and molecular profiling of tumor DNA. Tissue biopsies, however, have a number of disadvantages, including tissue inaccessibility, cost, invasiveness, chance of inadequate sampling, and some pain and risk to the patient.
Liquid biopsies have several advantages: they are easily obtained, minimally invasive, quick, and incur minimal patient pain and risk.2 However, a significant current limitation of liquid biopsies is the ability to clearly differentiate genetic variations which may be present in healthy individuals compared to those with cancer.6 Furthermore, genetic variants or mutations need to be identified as “drivers” (i.e., actively driving the cancer pathogenesis) vs. “passenger” (i.e., present, but of no known pathological significance) in order to understand the clinical significance.
Additionally, discussion has also centered on variations in the capability of liquid biopsies to determine cancer tissue of origin or topographic location. While confidence remains high regarding the success of liquid biopsies, there have been some setbacks in the developmental and research process. While these are not unexpected with any new or emerging technology, the general expectation is that over time there will be great technical success.
Types of Liquid Biopsy Tests
Circulating cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA)
Circulating cell-free DNA (cfDNA) are cell-free fragments of DNA that are routinely shed into the circulatory system by all cells in the body. Circulating tumor DNA (ctDNA) is cfDNA that is shed specifically by tumor cells and contains the same genetic variants as those in a primary or metastatic tumor.
This type of liquid biopsy is a non-invasive method of extracting ctDNA from blood samples for the detection and analysis of tumor DNA. Liquid biopsies of ctDNA also allow for the detection of somatic genetic mutations that are present only in the DNA of pre-cancerous or cancerous cells and not in normal cells. As such, ctDNA serves as a very specific biomarker.
Advances in digital genomic technologies have helped overcome the fact that ctDNA often makes up <1% of the total cfDNA in individuals with solid malignancies. These advances mean liquid biopsy is now highly sensitive and allow for mutation(s) in the tumor tissue to match the mutation(s) found in the ctDNA.1
One of the most significant limitations of a standard tissue biopsy is that most advanced cancers are heterogeneous. This means that aside from interpatient tumor heterogeneity (e.g., the same type of tumor can vary between two different people), there can also be intratumoral heterogeneity, where different genetic profiles are found within the same person’s tumor. In addition, there can be intrametastatic heterogeneity, where varying genetic profiles can be found among metastases in the same person. A standard tissue biopsy from just one portion of the tumor or one metastasis may miss this molecular complexity.
Since liquid biopsy of ctDNA contains the same variants as those in all the tumor cells throughout the body, it is assumed that ctDNA is released from diverse tumor sites and heterogeneous tumor cell types. Thus a liquid biopsy should allow for the capturing of tumor and metastatic heterogeneity and the assessment of cancer in real time.1
Additionally, fragments of cell-free nucleic acids (cfNA) such as cfDNA and ctDNA, and circulating non-coding RNAs (ncRNAs) such as messenger RNA (mRNA), micro RNA (miRNA) or long ncRNA (IncRNA),3 can be detected not only in plasma or serum but also in urine, cerebrospinal fluid, or even ascites of patients with cancer.4 Given that this area of research is expanding beyond the measurement of only ctDNA in blood, some experts are of the opinion that the term “liquid biopsy” may not be adequate and that this type of testing might be more appropriately referred to as, for example, “ctDNA in plasma” or “miRNA in urine,” thus providing a more specific and comprehensive description of the test.
Circulating tumor cells (CTCs)
This type of liquid biopsy detects the presence of whole tumor cells in the bloodstream, which are known as circulating tumor cells (CTCs). These cells, first described in 1869, were thought (correctly, as it turns out) to be related to the development of metastases.
Preliminary data suggest that CTCs may also have a role in early cancer detection in a high-risk group as they may be present in the blood even before someone has cancer symptoms or clinically detectable cancer. According to a study which looked at whether CTCs could signal the presence of lung cancer in people with chronic obstructive pulmonary disease (COPD), CTCs may have value for early cancer detection in this high-risk group. Researchers found CTCs in 3% of the participants with COPD but no detectable cancer. However, each of these patients, who were monitored closely, developed lung cancer between one and four years later. Another important aspect of this research is that none of the participants without detectable CTCs developed lung cancer up to five years after the study started.14
Additionally, one of the strengths of CTC analysis is that it not only allows pure (and complete) tumor DNA to be assessed but pure tumor RNA as well,6 thus, allowing for tumor transcriptome analysis. Read More +