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Genomic Medicine Part 2
A world where genes and data are used in preventing & treating diseases

Discovery Before Visibility:
Ultra-early cancer detection

Mai Orii, Healthcare and Wellness Division 27 April 2020

High Expectations for Ultra-Early Cancer Detection

The Ministry of Health, Labour and Welfare’s (MHLW) demographic statistics show that the leading cause of death in Japan since 1981 has been malignant tumors (i.e. cancer). This accounted for 27.4%, about one third, of the all deaths in the country in 2018.*1

Researchers around the world are working on numerous forms of medication and treatments to overcome cancer. Cancer immunotherapy and national insurance coverage for gene panel testing of cancer have attracted particular attention in recent years.

Cancer immunotherapy first received wide attention in 2014 when Ono Pharmaceutical Co., Ltd. launched the sale of an immune checkpoint inhibitor, Nivolumab, in Japan. Sold under the Opdivo brand outside of Japan, the medication received large press coverage in part due to its high price. The American pharmaceutical company Merck followed with the release of its own checkpoint inhibitor, Keytruda (Pembrolizumab), sparking a wave of several other types of checkpoint inhibitors. Such developments resulted in the ability to treat a wider range of cancers with immunotherapy and has inspired numerous clinical trials testing the combination of immunotherapy and chemotherapy.

Recently added to the coverage of the national insurance system, genomic-panel testing of cancer is a form of examination that classifies patients according to their cancer-related genetic mutations to determine the best treatment for each patient in what is known as precision medicine. In April 2018, MHLW established a designation system for cancer genomic medicine hospitals—medical institutions throughout the nation providing gene panel testing of cancer. Another key element of MHLW’s measures is the approval of insurance coverage for genetic profile testing, which enables multiple cancer mutations to be detected simultaneously and the genetic characteristics of individual patients to be catalogued for use in treatment. Specific examples include the development in June 2019 of the OncoGuide™ NCC OncoPanel System, a joint effort by the National Cancer Center Hospital and Sysmex, and the FoundationOne®CDx Cancer Genomic Profile from Chugai Pharmaceutical Co. Although we are not yet at the point where all patients can receive genomic testing to determine the best medication for their condition, cancer treatment in Japan is poised for a large shift as genomic testing is no longer confined to clinical tests but covered by the national health insurance system.

Despite increased efforts to research and develop new medications and therapies for cancer, particularly immunotherapy and precision treatment, overcoming cases of cancer that have already advanced remains difficult. Colon cancer, for instance, has more than a 90% rate of 5-year survival if treated while in the localized stage (i.e. restricted to the organ of origin). However, this figure declines dramatically with the progression of the disease to about 70% for the regional stage (i.e. metastasis of regional lymph nodes or invasion of neighboring organs or tissues) to less than 20% for the distant stage (i.e. metastasis or invasion of organs or tissues distant from the point of origin).*2 In addition to the development of new treatments, early detection too is indispensable in overcoming cancer. However, the fact that current forms of examination can sometimes fail to detect cancer in its early stages is a known issue. Moreover, cancer screening currently has a low uptake rate due to the time required and the physical burden imposed. Consequently, decreasing the burden of early detection methods represents another challenge that must be resolved.

With the goal of overcoming cancer, corporations and research organizations are currently conducting research to develop technologies for ultra-early detection using either urine odor or DNA and RNA from the patient’s blood. A handful of these projects are close to practical application and are detailed below.

miRNA

miRNA (micro-RNA) is attracting attention as a tool for the ultra-early detection of cancer. DNA, the blueprint of organisms, is translated into proteins via RNA. These proteins then function both inside and outside the cell to induce a range of physiological phenomena. On the other hand, miRNA is a short fragment of RNA and is known to function without being translated into proteins, modulating physiological phenomena by regulating the expression of a wide range of proteins. Recent research has found that each form of cancer releases a unique type of miRNA from the cell starting in the early stages of onset, and that this miRNA then circulates throughout the body in the bloodstream. Thus, by checking for the presence of miRNA specific to a particular type of cancer, doctors can determine whether or not a person has the disease. Moreover, because miRNA is released by cancer cells earlier than ctDNA (circulating tumor DNA), further described below, it enables for earlier detection of cancer.

At present, research is underway to develop a testing method to detect tumors that are too small to be seen through conventional imaging studies. The method is characterized by its extraction and measurement of miRNA levels. A research group led by Professor Takahiro Ochiya of Tokyo Medical University analyzed several thousands of samples of breast, colon, and lung cancer from the National Cancer Center Japan along with 20,000 samples from healthy individuals in the biobank at the National Center for Geriatrics and Gerontology. The group identified three to ten unique types of miRNA for 13 different forms of cancer, including the ‘big five’ (stomach, colon, breast, liver, and lung cancers). In other words, it has become possible to determine what type of cancer a patient has based on the respective levels of miRNA in the blood specific to each form of cancer. For example, it was found that ovarian cancer can be detected with a sensitivity of 99% and a specificity of 100% by measuring the levels of 10 types of miRNA.*3 The Tokyo Medical University team is collaborating with Toray Industries to develop this technology into a testing kit. Already, renditions of the kit for pancreatic cancer and biliary tract cancer have been earmarked for fast-track review prior to approval. The discovery that miRNA is contained within urine has prompted efforts to develop an even faster and more convenient testing method than those using blood. The advent of ultra-early cancer detection through only a miniscule amount of blood, a revolutionary form of testing, is just around the corner.

ctDNA

Circulating tumor DNA (ctDNA) refers to DNA fragments of cancer cells which circulate in the bloodstream after they are released from the cancer cell upon its death. This ctDNA provides information about the characteristics of the cancer from which it is derived. Some of the genetic profile tests that are now in the clinical research stage analyze genetic mutations in cancer cells based on ctDNA and are used in determining the proper plan for treatment.

ctDNA is also being used to detect cancer. GRAIL, an American startup, identified anomalies in the methylation pattern in tissue-specific ctDNA resulting from the development of cancer. This means that testing the ctDNA in a patient’s blood can determine the presence of cancer and the tissue from which it originated. At its Breakthrough 2019 conference, the American Society of Clinical Oncology (ASCO) reported that in a test targeting over 20 types of cancer, including the ‘big five,’ GRAIL’s technology had a specificity of 99% (with a total false positive rate of 1% for all types of cancer tested). The sensitivity irrespective of cancer type was 59-86%. Broken down by stage of cancer, the sensitivity was 34% for stage I, 77% for stage II, 84% for stage III, and 92% for stage IV. Furthermore, the test was able to determine the tissue from which the cancer originated in 94% of the cases, with a 90% rate of accuracy.*4

ctDNA is a highly attractive tool for cancer testing because, like miRNA, it reduces the burden on patients by enabling multiple types of cancer to be tested for using only a blood sample. However, while blood contains large quantities of DNA fragments, the proportion of ctDNA is extremely small, thus requiring a highly sensitive method of detection. Expectations are high for the development of a technology capable of detecting miniscule quantities of ctDNA.

Nematodes

Nematodes are about 1 mm in length and often used as an animal model in experiments. In January 2020, HIROTSU BIO SCIENCE INC., a medical startup, began research to develop a cancer test using the nematode’s ability to detect the odor of cancer in urine. Nematodes are attracted to urine when cancer cells are present and repelled when cancer cells are absent. The test is intended to serve as an initial screening tool to determine the risk of 15 types of cancer throughout the body. Merits of the new form of test include a minimal burden on patients and relatively low costs. As of September 2019, HIROTSU BIO SCIENCE reported a sensitivity of 85% for the test as well as the ability to determine the presence of cancer as early as stage 0-I. However, the test’s shortcomings lie in the fact that it is only an initial screening test and thus incapable of determining which of the 15 types of cancer has been contracted. A secondary test is required to determine which tissue has developed cancer following a result indicating a high risk.

The urine test is of little burden from the perspective of a patient, and this accessibility may lead to a greater number of people getting tested. Also, the lower cost of testing may lead to an increase in younger people, who are normally not the target group for cancer testing, to undergo tests. The nematode, albeit a tiny creature, has the potential to adapt cancer testing to patient needs.

The Growing Presence of Cancer Testing in Our Lives

We are nearing an era in which cancer testing is a familiar facet of life thanks to the emergence of testing methods that places less of a burden on patients. If fully materialized, these testing methods will allow for increased detection of cancer among patients while simultaneously decreasing the burden of testing for recurrences, thus contributing greatly to cancer treatment as a whole. To come closer to achieving the goal of overcoming cancer, hopes are high for continued progress in the development of new treatment techniques, tests to determine the optimal treatment for each patient, and methods of detecting cancer that are accurate, simple, and convenient.
Additionally, recent research has reported on a relationship between miRNA and dementia, indicating the possibility for miRNA’s use in the screening and definite diagnosis of dementia. This is just one example of how we can expect a wider application of technologies developed for the ultra-early detection of cancer to different fields in the future.

Figure

Benefits of Ultra-Early Detection

Source: Created by Mitsubishi Research Institute based on the Foundation of Promotion of Cancer Research 2018 Cancer Statistics

  • *1: Ministry of Health, Labour and Welfare (2019) “Summary of Vital Statistics”
    https://www.mhlw.go.jp/toukei/saikin/hw/jinkou/kakutei18/index.html ( Accessed February 26, 2020 )
  • *2: Foundation for Promotion of Cancer Research (2019) “Cancer Statistics in Japan-2018 ”
    https://ganjoho.jp/data/reg_stat/statistics/brochure/2018/cancer_statistics_2018.pdf ( Accessed February 26, 2020 )
  • *3: Yokoi et al. (2018) “Integrated extracellular microRNA profiling for ovarian cancer screening” Nature Communications (vol. 9; article 4319)
  • *4: Oxnard et al. (2019) “Simultaneous multi-cancer detection and tissue of origin (TOO) localization using targeted bisulfite sequencing of plasma cell-free DNA (cfDNA)” ASCO Breakthrough Conference, 11-13 October 2019, Bangkok, Thailand.
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