Who Will Be the Most Popular Markers in the Liquid Biopsy Market?

Liquid biopsy-based technology for early screening and diagnosis of cancer is currently a hot topic in international cancer research. It is reported that during the decade 2020 to 2030, the liquid biopsy market will grow at a compound annual rate of 16%. Recently, the article "Liquid biopsies: the future of cancer early detection" published in the Journal of Translational Medicine provides an overview of the application of liquid biopsy technology in early cancer screening.

Specific applications of different biomarkers in the field of liquid biopsy

Cancer is the second leading cause of death in the world, and early screening and detection are essential to prevent and treat cancer and improve people's quality of life. Compared with traditional surgical biopsy, which is the gold standard for cancer diagnosis, liquid biopsy has the advantages of low cost, reproducibility and reliable results, and can provide genomic, proteomic and metabolomic information of the test specimens, which is mainly used in the field of early cancer screening and diagnosis, and can be used as a complementary test to tissue biopsy.

Circulating Tumor Cell (CTC)

Circulating tumor cells (CTC) are cells shed from primary tumors into the bloodstream and can metastasize to other parts of the body through the blood system and lymphatic system, potentially leading to distant metastasis of the tumor. There are different molecular markers for CTC, depending on the type of cancer. Most cancers are of epithelial origin and have the universal epithelial molecular marker EpCAM, which can be applied to CTC detection. This marker is mainly used as an aid in the diagnosis of breast cancer, prostate cancer and other cancer types with high EpCAM expression.

The low concentration of CTC in blood makes detection and isolation of these cells more difficult and requires a high level of detection technology. CellSearch platform, a system for identifying, isolating and counting epithelial-derived CTC in blood samples, has been approved by FDA for use as an aid in the clinical assessment of prognosis in metastatic breast, colorectal and prostate cancers. The test takes one week from sampling to reporting, and the cost is about 900 dollars. Data from other observational studies have shown that CTC can also be used to detect the progression of systemic therapy for prostate cancer and help assess the effectiveness of treatment.

Circulating Free DNA (cfDNA)

Under physiological or pathological conditions, DNA in the nucleus or mitochondria is released into body fluids such as blood, pleural fluid, cerebrospinal fluid, urine and sputum during cell necrosis or apoptosis, and circulating free DNA (cfDNA) is an extracellular DNA degradation product. The level of cfDNA is low in the blood of healthy humans and high in the blood of tumor patients. cfDNA has a short half-life in the blood and can be used for dynamic detection of cancer.

Since its discovery, this biomarker has been used in early cancer screening, cancer recurrence prediction and prenatal detection.

DNA Methylation

DNA methylation is an epigenetic mechanism that refers to the process by which DNA molecules selectively add methyl groups to specific bases by the effect of DNA methyltransferases. Bisulfite genome sequencing is considered the gold standard for detecting DNA methylation because this method identifies 5-methylcytosine (5mC) at single base pair resolution and is a qualitative, quantitative and effective assay.

Nowadays, it is very common to use multiple methylation markers simultaneously in the field of early cancer screening. Such techniques can enable researchers to obtain more diagnostic information about the tumor origin tissues, which is superior to the detection of a single biomarker.

Extracellular Vesicles (EVs)

Extracellular vesicles (EVs) are small membrane vesicles secreted by cells that have multiple biological functions, which are basic medium of intercellular communication and play an important role in a variety of diseases and physiological processes.

There are three main types of EVs: exosomes, microvesicles (MVs), and apoptotic vesicles, which differ in size, the amount of blood, and function.

EVs carry and transport a variety of different biomolecular components, such as lipids, carbohydrates, proteins, metabolites, ribonucleic acids and DNA fragments. They inherit molecular information from the parent cells and are highly regarded cancer markers in liquid biopsies, which have been widely used for cancer diagnosis and prognosis.

As a liquid biopsy marker, extracellular vesicles have an advantage than ctDNA and CTCs because extracellular vesicles have a bilayer membrane structure and are not as easily broken down as nucleic acids. Currently, blood biomarker classifiers based on EVs protein profiles have been used to detect stage I and II pancreatic, ovarian and bladder cancers.

Proteins

Prostate specific antigen (PSA) is a protein antigen produced by prostate cells and is currently used for prostate cancer screening, but elevated PSA levels are affected by a number of factors, such as prostatitis and benign prostatic hyperplasia, and the high false-positive rate of this indicator leads to over-screening in some patients.

CA-125 is a high molecular weight glycoprotein that exists on the surface of ovarian cancer cells and is one of the indicators for early screening of ovarian cancer, but its elevated level is also affected by various factors. In women's menstrual period, pregnancy, and patients with endometriosis, the value of this indicator is high, and the false positive rate of this indicator limits its application in early screening of cancer.

Currently, to improve diagnostic accuracy and reduce the number of false-positive and false-negative patients, researchers have developed collection panels of multiple proteins in an attempt to facilitate progress in the study of proteomic biomarkers.

Circulating Free RNA (cfRNA)

Circulating free RNA (cfRNA) is an RNA fragment that is degraded and released into the bloodstream by necrotic or apoptotic cells. Compared to DNA, RNA is considered an unstable molecule with a naked half-life of approximately 15s. The lack of stability is a major limitation for this molecule application and the optimal extraction method has not been determined.

However, non-coding RNA (ncRNA) and microRNA (miRNA) have received much attention in recent years because of their stability and abundance. Drokow et al. conducted a meta analysis to comprehensively assess the overall accuracy of miRNA for detecting blood cancers. The results of the study showed that the overall sensitivity of miRNA for detecting blood cancers was 81% and specificity was 85%, and the performance of the detection was not inferior to that of other cancer biomarkers.

Tumor-educated Platelet (TEP)

Although blood platelets do not have a nucleus, they contain megakaryocyte-derived mRNA precursors that can be spliced into mature mRNAs and translated into thousands of different proteins upon stimulation. Some studies have shown that the RNA spectrum derived from tumor-educated platelet (TEP) can be used to distinguish early and late stage cancer patients from healthy individuals.

Compared to other blood based biomarkers, TEP has the advantage of easy separation and sufficient abundance. Best et al. demonstrated the ability of TEP to differentiate cancer patients from healthy individuals using mRNA sequencing of tumor-cultured platelets in a cohort of 283 patients (228 with limited and metastatic cancer and 55 healthy patients) and showed a detection accuracy of 96%. In addition, TEP as a biomarker can also distinguish six different primary tumor types (non-small cell lung cancer, colorectal cancer, glioblastoma, pancreatic cancer, hepatobiliary cancer, and breast cancer), with a detection accuracy of 71%.

Autoantibodies

Tumor autoantibodies are a response state produced by humoral immunity. In recent years, cellular immune technology has been widely used in clinical practice, and both PD-(L)1 and CTLA-4 antibodies play a key role in the anti-tumor process of cellular immunity in vivo.

Autoantibodies can also be used for early cancer screening, and their efficacy has been demonstrated in early screening for lung cancer.

Spectroscopic Detection

Fourier-transform infrared spectroscopy (FTIR) is a simple, rapid, inexpensive and non-invasive analytical method that can be used as one of the auxiliary tools for cancer diagnosis. This technique enables early diagnosis of tumors by reflecting the intracellular content, conformation and conformational changes of biomarkers and comparing the infrared spectral characteristics of tumor cells.

Spectroscopic detection analysis technology is inclusive: it can be embedded in the analysis of metabolites, electrolytes, carbohydrates, lipids, proteins, exosomes, tumor methylation markers, and circulating free tumor cell markers. Ameron et al. conducted a prospective blinded clinical study to demonstrate the use of spectral detection in brain cancer and showed that the use of spectral technology enabled algorithm adjustments with higher sensitivity or specificity, which facilitates the further construction of machine learning models.

Multi-cancer Detection

Multi-cancer detection evaluates multiple signals simultaneously to determine if a person has cancer and can further confirm the location of the tumor.

Public data shows that the positive predictive value PPV of Galleri, a multi-cancer product, is 44.6%, and the accuracy of Galleri in predicting the origin of first or secondary tissues when cancer is diagnosed is 96.3%.

Comparison of Global Single Cancer Products

Comparison of Global Multiple Cancer Products