Liquid biopsy technology will usher in a new era

Release date: 2018-02-11

During the 14th National Conference on Colorectal Cancer, Gu Jin, Dean of Shougang Hospital of Peking University, said: “At present, the detection technology of ctDNA (circulating tumor gene) has been applied in clinical practice, and it is often used to detect tumor drug response and monitoring. Cancer resistance mutations, assessment of surgical outcomes, etc."

Coincidentally, Wang Jie, director of the Department of Internal Medicine of the Cancer Hospital of the Chinese Academy of Medical Sciences, also showed at the First International Symposium on Strait Lung Cancer and the Sixth Symposium on Accurate Diagnosis and Treatment of Lung Cancer: "The study of liquid biopsy ctDNA has entered clinical practice and has been written into the United States. National Comprehensive Cancer Network and Guidelines for Lung Cancer in China. If the organization does not get it, liquid biopsy can be used as a supplement. Many studies have demonstrated the role of ctDNA-based liquid biopsy in personalized therapy."

In addition, Xu Ruihua, director of the Cancer Center of Sun Yat-sen University, and Zhang Kang, a professor at the University of California, San Diego, have led a team of Chinese and American scientists who have undergone years of research, occupying a new peak in liquid biopsy technology, by detecting a small amount of circulating ctDNA specific sites in the blood. The level of methylation has reduced the rate of missed diagnosis of liver cancer patients to less than half. The kit for methylation of liver cancer has been put into industrial production. The article of this application was also published in the international academic magazine "Nature-Materials".

The implementation of clinical practice has brought you the dawn of hope. Is the liquid biopsy technology that is expected to come to the fore, and usher in a new era?

Demand determines the liquid biopsy market

Liquid biopsy is an emerging technology for tumor analysis of the whole body by collecting non-solid biological tissues such as blood samples and comparing the biological characteristics of genetic material during blood circulation. What kind of technology can obtain the unanimous attention of the business community and the scientific research community, so that each enterprise can independently research and develop, or introduce technology from overseas, and is selected as the “Top Ten Breakthrough Technology in 2015” by MIT Science and Technology Review. "After that, it was also listed in the "World's Top Ten Emerging Technologies List 2017" by the World Economic Forum.

Demand determines the market, the reason why people are closely concerned, the reason is also the more traditional tissue puncture test method, liquid biopsy is non-invasive, accurate and convenient, largely eliminating the detection inconsistency caused by tumor cell heterogeneity, and Can reduce medical costs. At present, liquid biopsy mainly focuses on circulating tumor cells (CTCs), ctDNA, circulating tumor microRNAs, and exosomes. Among them, clinical application is widely focused on the study of ctDNA, and its quantitative measurement and traceability are correct for us. Understanding the development of oncology and developing related medical programs can be of great help.

ctDNA is mainly derived from circulating free DNA (cfDNA) and carries genes that are mutated or recombined in tumor cells. Although less than 1% of the entire DNA, it is more likely to reflect accurate information in the circulating cells of the tumor because of its half-life of less than 2 hours. The British Chamber of Commerce (BCC) predicts that by 2020, the ctDNA-based liquid biopsy market is expected to reach $22 billion.

Five analytical techniques worthy of attention

In recent years, there are five main aspects of ctDNA related analysis techniques.

Quantitative polymerase chain reaction (qPCR) is considered to be the standard method for DNA quantification. Researchers at the Italian Bioscience Research Institute found that ctDNA levels in patients with 100 healthy individuals and 100 non-small cell lung cancer patients were much higher than those in healthy people. However, qPCR also amplifies the human error of observation and measurement at the same time as the magnification, and cannot accurately grasp the value of ctDNA from the result.

Digital Polymerase Chain Reaction (dPCR) is currently the most mature but not yet patented by the US Food and Drug Administration (FDA) for the detection of ctDNA.

BEAMing technology is based on the dPCR method, mixing inflow magnetic beads, distributing different types of magnetic beads in the corresponding DNA cells, and then detecting the markers by flow cytometry to achieve the purpose of calculating ctDNA. Although BEAMing is an effective method for assessing the characteristics of a patient's blood tumors, there is a measurement error when the tumor polarity is too small.

Surface-enhanced Raman spectroscopy (SERS) is a method of generating surface enhancement by laser irradiation of metal nanoparticles, resulting in a significant enhancement of the Raman signal of the object to be detected, and finally calculating the magnitude of the ctDNA value. Signal changes are derived from the strength of light waves and are highly sensitive.

Next-generation sequencing (NGS), or high-throughput sequencing (HTS), has made a breakthrough in the discovery and understanding of tumors. Many methods for detecting ctDNA have been developed on the basis of NGS. For example, the cancer individualized deep sequencing analysis method (CAPP-Seq), Capp-Seq, which studies ctDNA characteristics by deep sequencing, is the first ctDNA detection technology based on NGS technology. Although the detection price is high, its sensitivity and accuracy are high. Sexuality has caused widespread concern and clinical application.

In addition to ctDNA, circulating tumor cells (CTCs) have also been recognized for their use in the field of oncology. The latest NCCN Breast Cancer Guidelines (2017.v3) have included circulating tumor cells (CTCs) in the TNM staging system.

The AJCC eighth edition cancer staging system, which was launched globally on January 1, 2018, listed CTC in peripheral blood of breast cancer as a prognostic factor.

Circulating tumor cells (CTC) are a general term for various types of tumor cells present in the peripheral blood in trace amounts. It spreads throughout the body through the blood circulation and proliferates in a suitable environment, leading to recurrence and metastasis of the tumor.

The role of CTC in the assessment of distant tumor metastasis and prognosis has been confirmed by the international authoritative guidelines for cancer diagnosis and treatment. Let's take a look at the following, CTC gradually entered the course of clinical practice guide.

2010

US AJCC Guide (Seventh Edition)

The American Cancer Joint Committee AJCC listed CTC in the TNM staging system for the first time in the 2010 Cancer Staging Manuel, as a new M staging (remote transfer) standard, listed as cM0 ( i+) staging, appearing between M0 and M1.

cM0(i+) staging is defined as: no clinical or symptomatic evidence of metastatic clinical signs or signs, no distant metastasis, but tumors found in circulating blood, bone marrow, or other non-regional lymph node tissue by molecular or microscopic examination Cells or micrometastases ≤ 0.2 mm.

2017

NCCN Breast Cancer Clinical Practice Guide

The latest version of the Breast Cancer NCCN Guide 2017.v3 version, officially introduced cM0 (i+) staging.

2018

American AJCC Guide (eighth edition)

In the AJCC eighth edition cancer staging system, which was launched worldwide on January 1, 2018, in addition to retaining the cM0(i+) staging, the clinical value of CTC testing was further clarified. The latest guidelines list CTC as another prognostic tool for breast cancer following four biological indicators, ER/PR, HER2, Ki67, and tumor histology. It is believed that the presence of CTC in peripheral blood of breast cancer suggests a poor prognosis.

In addition, the 8th edition staging system elaborates the rules for the use of M staging: pM0 is not a meaningful staging, pathological negative should not be used as pM0; all patients should be classified as cM0 or cM1; if cM1 is subsequently confirmed by pathology, pM1.

Tips

AJCC Guide:

The American Joint Committee on Cancer (AJCC) developed the first edition of the cancer staging system in 1977 and has been in use for 40 years. It is a consistent basic principle to adhere to the evaluation of tumor staging based on anatomical primary tumor (T), lymph node (N) and metastases (M). 2016-10-06, AJCC version 8 cancer staging system update is published, and it is determined that it will be launched globally at 2018-01-01. Among them, the increase in non-anatomical information in the breast cancer staging system is the biggest highlight of the update. From the continuous refinement of macroscopic anatomical staging to the analysis of tumor biology information by genetic testing, the AJCC cancer staging system promotes the sublimation of clinical oncology comprehensive prognostic evaluation system from quantitative to qualitative.

NCCN Oncology Clinical Practice Guide:

The NCCN Oncology Clinical Practice Guidelines were developed by the National Comprehensive Cancer Network (NCCN?). The NCCN guidelines are not only the standard for clinical decision making in the field of cancer in the United States, but also the most widely used guide for clinical practice in cancer worldwide. They have also been recognized and favored by a wide range of oncologists in China, and are highly recommended to decision makers in the healthcare system. Important information about value.

Industry is still in the exploration stage

Although the development prospect of liquid biopsy is very promising, the whole industry is still in the stage of scientific research exploration and verification, and some problems need to be paid attention to in clinical practice. First of all, there is a lack of a unified technical solution, and different detection techniques lead to different results. Second, the processing of data must be cautious in the case of large orders of magnitude, and human error may be magnified a lot to become statistical errors. Finally, the level of medical ethics is also worthy of our attention and thinking. The application of immature medical technology to the clinic is bound to be contradicted.

At present, there are many kinds of cancers involved in liquid biopsy in the market, and leading enterprises in the segmentation field have also emerged, but the mature market pattern has not yet formed. As an emerging technology, there are only a handful of liquid biopsy products approved at home and abroad, including CellSearch from Cancer Research, EpiproColon from Epigenomics, Robas's cobas EGFR mutation detection kit, and folic acid receptor-positive CTC from Genosbo. The detection kit and the rapid staining solution of circulating tumor cells of Aozhiyou Company.

The biopsy has different maturity in different directions, and the targeted drug guidance is more mature, which is also a hot spot for genetic testing companies. Under the strong promotion of capital, many companies quickly promoted the detection products to seize the market, and the competition is fierce. After the company obtains the clinical supervision license, the competitive advantage will be more obvious.

The vast market imagination space has made everyone come to the fore, and the investment amount has repeatedly hit new highs. Securities company Piper Jaffray estimates that the liquid biopsy market capacity will reach $32.6 billion in 2026, including $28.6 billion in cancer, and the compound growth rate for the next 10 years will remain around 21.7%.

Precision medicine is a never-ending medical investment opportunity. What we need to do is to give liquid biopsy a relatively loose technology research and development environment, and gradually overcome the relevant technology of liquid biopsy to make it better for the benefit of the people.

Source: Gene Valley

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