Metavectum Tumor Test
Founded in July 2008, Metavectum is located as an independent company on the premises of the DESY (Deutsches Elektronen-Synchrotron), a major research institute of the Federal Republic of Germany. Metavectum's main activities are human medical molecular analysis and the synthesis of ultra pure substances for use in complementary medicine. The business relationship and all services of Metavectum will be continued as usual by iQMedix GmbH, Notkestr. 85 Geb. 3, 22607 Hamburg, Germany, from August 1, 2023.
In the team at iQMedix, molecular biologists and biochemists work together with laboratory physicians.
Analysis and validation of assays and reagents are in accordance with the guidelines of the Federal Medical Association (Bundesärztekammer, Rili-BÄK) and international MIQE standards. Equipment used in bio molecular analysis is CE certified.
iQMedix is part of a network of oncologists, surgeons, radiologists, pathologists, specialist physicians and specialist clinics to ensure that immediate implementation of results is possible.
The business model includes the following areas:
- Metavectum Prevention Test
- Metavectum Tumor Test
Metavectum Prevention Test
With the Metavectum Prevention Test, an attenuation, malfunction or disease is diagnosed at an early stage through a new array analysis of overall metabolism. A therapy suggestion is derived from the results and presented to the physician. Abnormalities in metabolism that may lead to disease are detected at a very early stage so that appropriate action can be taken.
The test is also used during and after tumor therapy to obtain information on the onset of metabolic changes indicative of relapse or an early indication of a metabolic shift to cachexia, for example.
For analytical purposes, equipment normally found only in larger pharmaceutical companies is available (600 MHz NMR coupled to mass spectrometer and HPLC). These data at the low molecular level (metabolome) are combined with data from the levels of gene expressions (transcriptome) and proteins (proteome) to provide a detailed picture of overall metabolism.
Metavectum Tumor Test
Tumors and metastases develop a highly individual profile that varies from person to person. Therefore, tumor treatment must also be individualized and the variety of therapeutic methods (radiotherapy, surgery, chemotherapy, complementary therapies, immunotherapy, etc.) must be used in concert.
The Metavectum Tumor Test is used to determine the individual metabolic activity of tumor-specific receptors and proteins ("Achilles heel" of the tumor) at the level of gene expressions in the transcriptome and gene mutations in the genome. The analyses are performed at the written request of the treating physician, and a therapy suggestion is derived from the results and presented to the physician. The testing system determines the optimal drugs for each patient from the total number of approved tumor drugs
Both gene expression and gene mutation data are correlated in the assay. This is because currently, depending on the tumor, only about 2-35% of all tumors exhibit clinically relevant mutations that allow drug inhibition of corresponding receptors.
It should be noted that culture of tumor cells and incubation of the cells with different drugs as evidence of effect is not performed, the procedure does not provide reproducible results. The method used here is based solely on mRNA-based evaluation of relevant gene expression and determination of clinically relevant mutations. DNA or mRNA is extracted from the isolated tumor cells.
On the one hand, excised tissue is used as test material, which is sent by the surgeon/oncologist to iQMedix on dry ice (-80 ºC) or in kerosene after the patient's written consent. Since tumor biopsies contain on average only 10-20% pure tumor tissue, in addition to connective and precancerous tissue, the samples are first sent to the pathologist (in this case Pathology Grandweg, Hamburg). The pathologist describes the type and status of the tumor and indicates the exact location in the tissue. Based on the pathology report, tumor cells are isolated from the biopsy at iQMedix and examined. In parallel or as a mono analysis, circulating tumor cells (CTCs) are isolated from the patient's whole blood ("liquid biopsy"). CTCs form the link between the primary tumor and metastases and provide information about which therapeutic agents can be used to treat the metastases.
Analysis of at least 10 tumor markers ensures that the isolated cells are indeed circulating tumor cells and not endothelial or epithelial cells that are continuously released into the bloodstream by organs or the vascular system and feign false positives of circulating tumor cells in large numbers.
Normally, between 5 and 120 CTCs are found in one milliliter of blood. DNA and mRNA are now extracted from the tumor biopsy and the CTCs. Using real-time PCR (qPCR), the expressions of tumor-relevant genes in the transcriptome are quantified in the tumor RNA (biopsy) and compared with the corresponding expressions of circulating tumor cells (liquid biopsy) and with reference material. Therapy-relevant mutations (BRAF, EGFR, MET, KRAS, NRAS, PTEN, MEK, etc.) are determined in the DNA of the tumor tissue and, for comparison, in the free circulating DNA (cfDNA, cell-free DNA) and correlated with the results of the gene expression analysis.
The final iQMedix report provides a complete picture of individual tumor metabolism and thus clues to drug targets for optimal therapy. The expression levels of the CTCs also allow estimation of tumor aggressiveness. CTC mutation analysis also reveals whether many different clones have formed, complicating therapy.
Gene expression analysis maps the expression or formation of certain receptors used by the tumor for its purposes to the corresponding approved drugs. For example, if topoisomerase II (TOPOIIA1) is highly expressed compared to non-tumor tissue, it is concluded that the use of the appropriate inhibitor (> anthracyclines) is advisable. If the tumor instead uses topoisomerase I (TOPOI) for its growth, topotecan should now be used as the corresponding TOPOI inhibitor. In this case, the use of anthracyclines would be ineffective, associated with serious side effects and the development of resistance.
This can then be fought only at very high cost. Resistance and certain transport routes that the tumor can use to remove drugs from the cell play an important role. Medical-molecular biological laboratory tests by means of qPCR and mutation analysis for the optimization of a treatment decision are basically routine both in Germany and worldwide.
In tumor therapy, the four best known biomarkers ERBB2/Her2neu (e.g. drug Herzeptin: yes or no), PGR, ER1 and KI67 are routinely analyzed for gene expression by immunohistochemistry in almost every oncology practice and clinic. Determination of EGFR and KRAS mutations, etc., are mandatory for the use of certain drugs.
iQMedix has expanded its panel of biomarkers or determination of gene expressions to more than 90 expressions. This allows iQMedix to identify drug targets for all currently approved drugs for the treatment of solid tumors and make individual therapy suggestions based on this information. This allows the physician to target therapy, which also saves costs. The procedure and selection of gene expressions are based on clinical studies, which will be gladly shared upon request.
Apart from the four aforementioned markers, most tumor drugs are currently used without appropriate testing, which explains the relatively low cure rate and increased incidence of metastases and resistant cells. The physician is forced to try different therapies on a trial-and-error basis. This brings significant side effects (toxicity) to the patients and significant additional costs, which can be avoided.
iQMedix's analytical system can then be used to monitor the success of the therapy.
The data also provide important information for long-term prognosis regarding the occurrence of recurrences and metastases. If molecular biological analyses after surgical or radiotherapeutic removal of the primary tumor show that tumor aggressiveness and likelihood of recurrence are low, low-dose therapy can be initiated or, in individual cases, medication can be omitted altogether. However, this requires twice-yearly monitoring.
The method is also suitable for interim monitoring and therapy adjustment, e.g., when tumors or metastases are rendered operable by individual chemotherapy but residues are likely based on molecular biological data.
The cost of the Metavectum Tumor Test is usually reimbursed by private health insurance if requested by the oncologist.
Circulating tumor cells (CTC)
There are a number of companies worldwide focusing on circulating tumor cells and trying to obtain medically useful results from their analysis. Most of these companies simply quantify CTCs before and after chemotherapy, from the standpoint that a reduction should be detectable if therapy is successful.
However, recent studies have shown that the number of CTCs fluctuates over time: CTCs are not evenly distributed throughout the body's blood vessels, CTCs are replenished from epithelial tissue and bone marrow, CTCs disintegrate by intravasation and extravasation, EMT transitions alter the CTC barcode used for identification, the immune system destroys CTCs in the bloodstream according to activity, CTCs aggregate into clusters.
This makes it clear that dealing with circulating tumor cells is a complex field and requires an extensive periphery of equipment and methods to arrive at a medically useful finding for the therapist.
The difficulties in dealing with CTCs can be well illustrated by a graph from a review published in 2013 [Lit: Bin Hong et al.; Theranostics 2013, Vol. 3, p 377-394]. The graphic shows the occurrence and development of CTCs in blood vessels and in the body up to metastases.
The primary tumor releases single cells and clusters that enter the bloodstream under EMT (epithelial-mesenchymal transition) junctions. There, most of the CTCs are driven into apoptosis and necrosis, either by pre-damage to the cell structure during detachment from the primary tumor or during invasion into blood vessels or by the immune system. During apoptosis, cellular contents are released (CTMat = circulating tumor material, CTDNA = circulating tumor DNA), including low molecular weight substances, proteins and DNA.
Surviving CTCs can now leave the bloodstream again and establish metastases at a suitable location or they associate in the bloodstream to form clusters (CTM). These clusters act as conglomerates that integrate other blood components, such as erythrocytes and leukocytes, and also contain the aforementioned CTDNA and CTMat. These cell clusters (CTMs) are further transported through the bloodstream, settle in capillaries because of their size and form micrometastases and later metastases there.
This shows that certain techniques and methods are essential for the investigation of CTCs and their derivatives to reach a medically relevant conclusion. These include:
- Mutation analysis in the genome
- Gene expression analysis in the transcriptome
- Protein qualification and quantification in the proteome
- Analysis of low molecular substances (amino acids, etc.) in the metabolome Immunohistochemistry on individual CTCs
To analyze the chain of primary tumor, CTC, secondary products and metastases from the point of view of a therapeutically relevant statement, iQMedix links information from the genome, transcriptome, proteome and metabolome, as these four levels interact.
This also means that individual levels (genome, proteome, metabolome) are able to ignore, block or even reverse work orders or information from another level. For example, the work order that arrives in the transcriptome to trigger apoptosis of a cell is sometimes reversed at the proteome level to the opposite.
For these reasons, it is necessary to look at all levels if valid conclusions are to be drawn.
This examination is covered by health insurance in Germany. In the Netherlands it is not.
