Biophysical Properties of Blood and Cancer Overview
AnPac Bio-Medical Science Co., Ltd. (NASDAQ:ANPC) adopts a novel approach to screening and detecting cancer that we see as establishing a new paradigm in routine checkup screening, as well as being complementary to both traditional and new cancer testing, including ctDNA and genetics. The use of biophysical properties to screen for cancer is not mainstream, yet there has been considerable research conducted in the field. Cancer cells are inherently different both metabolically and structurally compared with healthy cells and these differences are manifest in a cell’s characteristics. While there are many types of cancer originating from different sites, the various cancer cells share similar properties that allow them to be distinguished from normal cells. Thus, biophysical screening enables not only the rapid and cost-effective screening for cancer, but the simultaneous screening for a variety of cancers. Studies range from evaluating the transition time of normal and cancer cells through microfluidic channels, to using sound waves to identify the types of cells that pass through a narrow groove. Other investigations found that the electrical capacitance of normal and cancerous blood differs and that the properties of normal and cancerous cells are distinct when scanned with light in the near-infrared spectral range.
Source: AnPac Bio Website
The push for new methods to detect cancer with a high degree of accuracy is justifiable. While there has been some progress with cancer diagnostics and early detection, it has been slow going over the last decades. According to the National Cancer Institute (NCI), due to false positives, screening can not only be ineffective but also harmful when there is low selectivity and specificity. For women age 50 to 59, the NCI finds that more than 1,300 mammography screens are required to save one life. For some cancers, including pancreatic and ovarian, early detection is almost non-existent. Pancreatic cancer is difficult to detect early as the organ is deep in the body and disease is frequently asymptomatic until it has metastasized. There are no general screening tests for pancreatic cancer, but for high risk individuals, an endoscopic ultrasound or MRI may be run. Initial symptoms of ovarian cancer such as bloating, indigestion, pelvic pain and nausea can be attributed to a number of other causes besides cancer. Due to the lack of early detection tools, ovarian cancer frequently progresses to an advanced stage where it is no longer possible to surgically remove the entire tumor. According to the American Cancer Society, despite the existence of two tests (1) for ovarian cancer screening, neither of them provides a high degree of accuracy. These examples highlight the need for alternate approaches that are corroborated by extensive research. As we conducted our literature review to identify alternative approaches, we found a trove of research supporting the use of biophysical properties in identifying cancerous markers in blood.
In “A Brief Review of the Biophysical Hallmarks of Metastatic Cancer Cells,” (2) Zhang et al. found that there are abnormalities in the elastic properties of cells that are associated with disease and its progression. Cellular deformability is greater in metastatic cancer cells, which gives them the ability to invade the basal membrane and endothelial layer. In order to metastasize, tumor cells require a highly contorted cytoskeleton, a characteristic that serves as a biophysical marker for spreading cancer. In one instance, metastatic cancer cells isolated from pleural fluids of breast cancer patients were measured and found to be mechanically stiffer than benign cells. These studies used microfluidics to screen the cells, a process that records transition time and velocity of a cell passing through a microfluidic channel.
Another article titled “Biomechanics and Biophysics of Cancer Cells” (3) also focused on the structural abnormalities of cancer cells. Author Suresh noted that defects in the structure of the cytoskeleton influence disease, including cancer. The increased deformability of cancer cells allows them to leave the tumor and invade surrounding tissue. To achieve this, cancer cells must traverse fibers of the extracellular matrix and pass through micrometer-scale gaps or pores. The cell’s reduced structural rigidity compared to non-metastatic cells allows them to more easily spread. This has prompted the development of biophysical probes to identify the mechanical properties of cancer cells including atomic force microscopy (AFM), magnetic twisting cytometry (MTC) and instrumented depth-sensing indentation methods.
Circulating tumor cells (CTCs) are frequently a target of cancer screening assays. These cells are the embodiment of metastasis, traveling through the blood to distant locations within the body, and have specific physical characteristics that are distinct from accompanying blood cells such as larger size and lower deformability. These characteristics allow for CTCs to be identified through processes that can measure these attributes such as microfiltration (4). In a review article published in BioMed Research International, CTCs show several distinctive characteristics relative to normal cells such as greater nuclear to cytoplasmic ratio, larger size, and distinct nuclear morphology (5). Several approaches have been used to identify the biophysical state of CTCs including measure of hydrodynamic stretching, the use of an optofluidic laser for cell stretching, magnetic twisting cytometry, micropipette aspiration and atomic force microscopy (6).
Acoustic properties of cells can indicate whether or not a cell is normal or cancerous. Researchers at Duke University, Lund University and MIT used an ultrasound technique on blood flow past a sensor. The scientists forced cell solutions through a micro-channel inside a chip. The acoustic field was then applied and able to separate the cells and identify the characteristics of the cells that passed through a channel. The group found that cancer cells cultured in the lab had different acoustic properties compared with healthy cells (7). Other work has found that the electrical capacitance of normal and cancerous blood is different (8, 9). Blood samples that were tested in pediatric hematological cancers had higher values of capacitance when compared to normal samples. The optical properties of cancer cells have also been explored using visible and near-infrared spectrum in a skin cancer model. Light scatters differently when directed at cancerous compared to healthy tissue (10). The small study conducted in Boston, Massachusetts provided many examples of a statistically significant difference in light scattering at specific wavelengths between healthy tissue and cancerous tissue. Researchers have also developed an optical probe that is able to detect precancerous and early cancer changes in cell rich epithelia (11) and optical spectroscopy has been used to diagnose cancer in patients undergoing endoscopy (12).
This is but a brief sample of the research done in cancer biophysics. AnPac and its founding executives have realized the utility of this approach and are continuing to refine the platform to fill an unmet need for accurate, inexpensive and rapid cancer screening that can improve time to treatment and improve outcomes.
AnPac Bio-Medical Science
AnPac Bio was launched at the start of 2010 by founders Chris Yu, Ph.D. and Herbert Yu, Ph.D. who began conducting research and development around the creation of a new machine which could screen for and detect various cancer types based on biophysical properties. The company was founded upon the goal of improving the ability to accurately screen for cancer, which has become one of the most pervasive diseases in the world lacking an effective early detection approach. Despite an early desire to be a physician and coming from a family of doctors, Dr. Chris Yu earned a Ph.D. in physics and had worked for many years in the semiconductor industry for well-known companies such as Micron Technology and Motorola. Even though he advanced the leading edge of chemical mechanical processing in the semiconductor industry, Dr. Yu maintained his interest in using his knowledge to improve health. After a meeting with Dr. Herbert Yu, a professor at Yale’s school of medicine, the two experts discussed the opportunities and shortcomings in early disease detection. Dr. Herbert Yu had been working to find a way to successfully detect cancer at its earliest stages, a problem that no one had been able to solve. Chris felt that he could use his background in physics and weak signal processing and detection to identify a solution. The duo teamed up and developed a new technology employing integrated circuits to fabricate highly sensitive transducers able to detect a biophysical signal in the blood.
Early work by the two Ph.D.’s found that there was a statistically significant difference between cancer patients’ blood and that of normal individuals. Their efforts expanded research into many different cancer types and found continued success at a much lower cost than other diagnostic approaches even in pre-cancer and prior to Stage I conditions. Retrospective studies were run and new employees were hired but instead of adding individuals from the health care space, the group added professionals from the semiconductor industry. Various approaches were tested against blood samples, including acoustical, optical and electrical properties.
Beginning in 2011 a number of R&D, manufacturing and marketing subsidiaries were created. By the end of 2015, AnPac had commercialized tests in China and created a subsidiary in the United States to conduct research and clinical studies in the US market. The research performed in the US and Chinese institutions would later be presented at the American Society of Clinical Oncology (ASCO) annual meetings and other conferences. Since 2015, more than 140,000 blood samples have been tested split between CDA testing and research studies.
CDA Device and Test
AnPac developed its Cancer Differentiation Analysis (CDA) technology in the first years after its foundation and performed the first commercial CDA test in China in 2015. The unit consists of a blood sample unit, a sample transport unit, a sample mixing chamber, a testing unit and a data storage unit. The machine employs a microfluidic device consisting of micro channels, micro sensors and measurement instruments with automated data recording capabilities. It is connected to a fluid delivery line inside the testing unit. When the sample enters the micro-channels of the microfluidic device, it is probed and analyzed to measure the desired parameters. Results are measured over discrete units of time and further analyzed by Anpac’s proprietary algorithm.
CDA Device (13)
After the test has run, the CDA value is generated along with the protein tumor factor (PTF) and the cell tumor factor (CTF). These two outputs measure changes in protein and cell properties in the blood, respectively.
The CDA technology is a blood-based diagnostic that relies on biophysical properties of blood to determine cancer risk. Retrospective studies were conducted that were able to determine a correlation between biophysical properties and cancer occurrence. The change in biophysical properties over time is a potential symptom of the loss of immunity and increased likelihood of cancer. AnPac conducted a number of retrospective studies that examined the ability of the CDA technology to accurately determine the likelihood of cancer. There were 25 studies that were conducted with hospitals and medical institutes in China and ~170,000 blood samples were evaluated. Several of these studies have been presented at American Society of Clinical Oncology conferences including the breast cancer prognosis and lung cancer prognosis study.
AnPac’s breast cancer study evaluated (14) 426 samples divided into a control and breast cancer group. Blood samples were taken and then measured using the CDA medical device. Output from the study generated a CDA mean result of 34.03 with a standard deviation of 7.65 for control patients while the breast cancer group generated an output of 50.84 with a standard deviation of 9.69. The result indicated that breast cancer could be significantly distinguished from the control with a p-value of less than 0.001.
The non-small cell lung cancer (NSCLC) screening study evaluated 635 samples divided into three groups: a control group, a non-cancerous disease group and a NSCLC group. Whole blood was collected and analyzed by the CDA device generating output broken down by group. Test results were significantly distinguishable among each of the groups at better than the 5% level of significance. Sensitivity and specificity were calculated at 87.7% and 79.9% respectively.
Additional studies for hepatocellular carcinoma, esophageal cancer, breast cancer and others were conducted generating statistically significant results between the control and cancer group. AnPac has conducted a number of studies regarding the accuracy of the CDA technology in partnership with Chinese hospitals and medical institutes. Results have been published at ASCO meetings and other medical conferences in China and the United States. There are an additional ten unpublished studies, the results of which are presented below along with the results for the published studies. Over 42,300 samples were used to generate the results. Below we provide a summary of studies that were conducted and include the calculated sensitivity and specificity for the tests.
Research Studies (15)
There has been extensive work conducted regarding the biophysical properties of cancer cells demonstrating cancer cells are quantifiably different from normal cells. Despite a broad selection of research in this area, there have been few attempts to use biophysical properties in a commercial technology. This reality led AnPac’s founders to launch a company that would use this this information to screen for a variety of cancers and as a result, the cancer differentiation analysis (CDA) device was born. It has shown in a selection of its own work the ability to identify patients who are at risk of cancer and group them into low risk, medium risk and high risk categories, allowing early treatment to be administered, thereby improving outcomes and lowering costs to the healthcare system. Backed up by numerous research studies, we see the CDA technology as a valuable service to cancer prevention and as a necessary complement to other screening approaches now used.
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1. The two screens for ovarian cancer are the transvaginal ultrasound (TVUS) which is unable to determine if a mass is cancer or benign and the CA-125 blood test; however, its association with ovarian cancer is weak.
2. Zhang, W., et al. A Brief Review of the Biophysical Hallmarks of Metastatic Cancer Cells. Cancer Hallm. 2013 Aug-Dec; 1(2-3): 59–66.
3. Suresh, Subra. Biomechanics and biophysics of cancer cells. Acta Biomater. 2007 Jul; 3(4): 413–438.
4. Zinggeler, M., Brandstetter, T. & Rühe, J. Biophysical Insights on the Enrichment of Cancer Cells from Whole Blood by (Affinity) Filtration. Sci Rep 9, 1246 (2019). https://doi.org/10.1038/s41598-018-37541-3
5. Low, W.S., Abas, W., Benchtop Technologies for Circulating Tumor Cells Separation Based on Biophysical Properties. BioMed Research International, Volume 2015.
6. Che, J., et al. Biophysical isolation and identification of circulating tumor cells. Lab Chip. 2017 Apr 11; 17(8): 1452–1461.
7. Pham, Xuan. Acoustic Properties May Reveal Cancer Cell’s Identity. May 18, 2016.
8. Ghanbarzadeh-Daghian, A. et al. Quick, Single-Frequency Dielectric Characterization of Blood Samples of Pediatric Cancer Patients by a Cylindrical Capacitor: Pilot Study. Electronics 2020, 9(1), 95; https://doi.org/10.3390/electronics9010095
9. Gascoyne, P., et al. Dielectrophoretic Separation of Cancer Cells from Blood. IEEE Trans Ind Appl. 1997; 33(3): 670–678. doi: 10.1109/28.585856
10. Salomatina, E. et al. Optical properties of normal and cancerous human skin in the visible and near-infrared spectral range. Journal of Biomedical Optics 1.16, 064026 November/December 2006
11. Vackman, V. et al. Detection of Preinvasive Cancer Cells. Early-Warning Changes in Precancerous Epithelial Cells Can Now be Spotted In Situ. Nature, 406, Pp. 35-36 (2000).
12. Badizadegan, Kamran, et al. Spectroscopic Diagnosis and Imaging of Invisible Pre-Cancer. 2004;126:265-79; discussion 303-11. doi: 10.1039/b305410a.
13. Source: AnPac Corporate Presentation, November 2019
14. Tao, H. et al. Investigations of Breast Cancer Screening Using a Novel in vitro Diagnostics Technology. J Clin Oncol 33, 2015 (suppl 28S; abstr 13)
15. Source: AnPac corporate filings and author’s work.