Molecular profiling of the tumor is a step towards personalized cancer treatment. Molecular test of the CYP2D6 gene. Medullary thyroid cancer

We are completing a series of articles on oncological diseases.
Today I will tell you in detail what molecular testing is and how it affects the diagnosis.

In the photo: Vladislav Mileiko, head of the department,
biomedical holding "Atlas".

To understand how it works molecular diagnostics and what place it occupies in oncology, you must first understand the mechanisms that occur in the tumor.

Molecular processes in a tumor

Mutations in proto-oncogenes and suppressor genes responsible for cell division and death cause the cell to stop following instructions and synthesize proteins and enzymes incorrectly. Molecular processes are out of control: the cell is constantly dividing, refusing to die, and accumulating genetic and epigenetic mutations. Therefore, malignant neoplasms are often called a disease of the genome.

Hundreds of thousands of mutations can occur in tumor cells, but only a few contribute to tumor growth, genetic diversity, and development. They are called drivers. The remaining mutations, "passenger" (passenger), in themselves do not make the cell malignant.

Driver mutations create different populations of cells, which provides tumor diversity. These populations or clones respond differently to treatment: some are resistant and relapse. In addition, the different sensitivity of clones to therapy can lead to a radical change in the molecular profile during treatment: even cells that are insignificant at the beginning of the population can gain an advantage and become dominant at the end of treatment, which will lead to resistance and tumor development.

Molecular Diagnostics

Driver mutations, changes in the number or structure of proteins are used as biomarkers - targets for which treatment is selected. The more targets are known, the more accurate the selection of potentially effective treatment regimens can be.

It is not easy to separate driver mutations from the rest and determine the molecular profile of the tumor. For this, the technology of sequencing, fluorescence in situ hybridization (FISH), microsatellite analysis and immunohistochemistry is used.

Next-generation sequencing methods can identify driver mutations, including those that make a tumor sensitive to targeted therapy.

With the help of FISH technology, sections of chromosomes on which a certain gene is located are tinted. Two connected multi-colored dots are a chimeric or fused gene: when, as a result of rearrangement of chromosomes, sections of different genes are joined together. This can lead to the fact that the oncogene will fall under the influence of the regulation of another more active gene. For example, the fusion of the EML4 and ALK genes is of key importance in the case of lung cancer. The proto-oncogene ALK is activated under the influence of its rearrangement partner, which leads to uncontrolled cell division. The oncologist, given the rearrangement, may administer a drug that targets the activated ALK gene product (crizotinib).

Fluorescent in situ hybridization (FISH).

Microsatellite analysis shows the degree of damage to the DNA repair system, and immunohistochemistry - protein biomarkers located on the surface, in the cytoplasm and nuclei of tumor cells.

All of these studies are included in New Product biomedical holding "Atlas" - Solo test. With the help of such a test, the oncologist obtains information about the molecular profile of the tumor and how it affects the potential efficiency. a wide range anticancer drugs.

Solo examines up to 450 genes and biomarkers to evaluate how a tumor might respond to more targeted treatments oncological diseases. For some of them, biomarker analysis is dictated by the manufacturer. For others use data clinical research and recommendations of international communities of oncologists.

In addition to selecting targets for targeted therapy, molecular profiling helps to detect mutations that, on the contrary, make a tumor resistant to a particular treatment, or genetic features that are associated with increased toxicity and require an individual selection of a drug dose.

For research, biopsy material or paraffinized blocks of postoperative material are used.

Molecular profiling gives Additional information about the disease, but it is not always applicable to the choice of treatment. For example, in situations where standard therapy is sufficiently effective or surgical treatment is indicated. It is possible to identify clinical situations where such a study may be most useful:

• A rare type of tumor;
• Tumors with unidentified primary focus(it is not known where the tumor that metastasized originally appeared);
• Those cases where a choice of several options for the use of targeted therapy is required;
• The possibilities of standard therapy have been exhausted and it is required experimental treatment or inclusion of the patient in clinical trials.

Solo project specialists consult oncologists or patients and suggest whether a test is needed in this case.

Precision Medicine and Clinical Research

Usually in medical practice, general strategies are used to treat patients with a specific diagnosis. For small cell cancer lung one strategy is used, for non-small cell - another. For oncological diseases, this method is not always suitable. Due to differences at the molecular level, even with the same type of tumor, patients may receive ineffective or unnecessary treatment.

With the increase in research and the invention of targeted drugs, the approach to cancer treatment has begun to change. To increase the relapse-free period and life expectancy of the patient, it is necessary to take into account the molecular profile of the tumor, the body's response to drugs and chemotherapy (pharmacogenomics), and to know the main biomarkers.

Precision medicine can significantly improve the prognosis of a particular patient, avoid serious side effects of oncological drugs and significantly improve the patient's quality of life. But this method also has disadvantages.

Targeted drugs are on the rise and have two main limitations: most molecularly targeted agents provide only partial suppression of signaling pathways, and many are too toxic to be used in combination.

Imagine that you are an architect of Moscow. Standing in front of you not an easy task- Solve the problem of traffic jams during rush hour by building one bridge. Molecular mechanisms can be compared with the movement of machines, and the bridge - main drug which should solve the underlying problem. It seems that several drugs (a series of bridges) targeting the major molecular disturbances may solve this problem. But the toxicity of drugs increases and can be unpredictable.

We have a better understanding of molecular processes malignant tumors, but the current methods of introducing precision oncology into clinical practice are far behind. To speed up the study of targeted therapy, scientists have developed two new approaches - Basket and Umbrella.

The essence of the Basket method is that patients with a certain biomarker are selected for the study, regardless of the location and name of the tumor. In May 2017, the FDA approved such a treatment for a biomarker called high microsatellite instability (MSI-H) or mismatch repair defect (dMMR).

Molecular disorders differ not only in different patients, but also within the same tumor. Heterogeneity - a big problem in oncology, for which the Umbrella study design was developed. For the Umbrella method, patients are first selected according to the type of malignant neoplasms, and then genetic mutations are taken into account.

Such studies help not only to collect information about the effect of targeted drugs - sometimes it the only possibility for patients who do not respond to standard treatment registered drugs.

Clinical example

We decided to give an illustrative example of what the use of advanced molecular profiling might look like.

A patient with skin melanoma and liver metastases consulted an oncologist. The doctor and the patient decided to do molecular profiling in order to obtain more complete information about the disease. The patient was biopsied and tissue samples sent for analysis. As a result of diagnostics in the tumor, several important genetic disorders:

• Mutation in the BRAF gene. Indicates activation of the RAS-RAF-MEK oncogene signaling pathway, which is involved in cell differentiation and survival.
• Mutation in the NRAS gene. Indicates additional activation of the RAS-RAF-MEK signaling cascade.
• An inherited variant of the TPMT gene. Indicates the features of the metabolism of the anticancer drug "Cisplatin".

Based on the results of clinical studies and recommendations, we can come to the following conclusions:

• Drugs of the BRAF inhibitor class (Vemurafenib) can be potentially effective, moreover, the presence of an NRAS mutation can serve as an additional reason for prescribing a double blockade of the signaling cascade - a combination with MEK inhibitors (Trametinib).
• Although there is no approved therapy that directly targets the NRAS oncogene, mutations in it are known to increase the likelihood of successful treatment when prescribing immunotherapy (Ipilimumab and Pembrolizumab).
• The hereditary genetic variant in the TPMT gene indicates an increased individual toxicity of Cisplatin, which requires dose adjustment when prescribing platinum-containing therapy regimens.

Thus, the doctor gets the opportunity to navigate among options treatment based not only on the clinical parameters of the patient, but also taking into account the molecular features of the tumor.

Molecular diagnostics is not a panacea for all cancers. But this is an important tool for the oncologist, which allows you to approach the treatment of malignant tumors from a new perspective.

Thank you for reading and commenting on our materials on oncology. Here is the complete list of articles.

Republican Scientific and Practical Center of Oncology and Medical Radiology named after A.I. N. N. Alexandrova is currently carrying out 56 scientific projects, 23 of which are related to molecular genetic research. They are carried out at the Republican Molecular Genetic Laboratory of Carcinogenesis (oncology department of genetics, cellular and biochip technologies, virology, immunology and proteonics).

Traditional diagnostic tools are exhausting their potential, - says the Deputy Director for Research of the Republican Scientific and Practical Center, Corresponding Member of the National Academy of Sciences of Belarus, Doctor of Medicine. sciences, professor Sergey Krasny. - It's time to use such a reserve as molecular genetic research. They make it possible to test tumors with high accuracy to determine chemosensitivity, to establish the hereditary nature of the disease by the patient's genetic portrait, and to purposefully act proactively by prescribing targeted treatment.

In 2016, about 10,000 patients passed through the Republican Scientific and Practical Center, approximately 7,000 of them underwent molecular biological studies; large-scale tumor profiling for individualization of therapy was carried out on about a hundred people. On the basis of molecular biological markers, tumors of the central nervous system, soft tissues and bones, lymphoma were diagnosed, studies were conducted to assess the hereditary risks of developing malignant neoplasms, monitoring the concentration of drugs in body fluids for individual dose adjustment of the drug, cell therapy technologies were developed and implemented.

To implement the achievements of molecular biology in the domestic clinic, the first international certificates have already been received, modern equipment has been purchased for performing fluorescent in situ hybridization, molecular sequencing, polymerase chain reaction (PCR), immunohistochemistry, chromato-mass spectrometry, flow cytometry, enzyme immunoassay.

Biologist Victoria Mayorova prepares samples for PCR reaction.

New developments

A method for assessing the prognosis of the clinical course of bladder cancer through a comprehensive analysis of the clinical and morphological parameters of the tumor and the molecular genetic status of the FGFR3 gene.

Based on this analysis, a model of molecular pathways for the pathogenesis of bladder cancer was created. Depending on the presence of a particular mutation, pathology can develop in two ways: the so-called superficial cancer, characterized by low malignancy and a favorable prognosis (mutations in the FGFR3 and HRAS genes); a more aggressive muscle-invasive cancer that metastasizes early and is characterized by a poor prognosis (mutations in the TP53 and RUNX3 genes).

Using this method, a group of patients with very high risk progression of the disease, in which mutations in the TP53 and RUNX3 genes have been identified. This is important for predicting the course of the disease and determining the degree of aggressiveness of treatment. Knowing that the patient's tumor will develop as a superficial one, after treatment, the bladder will be mainly controlled.

If progression of the disease is expected, then in relation to metastasis, the status of other internal organs. In addition, patients may be identified who must immediately undergo a radical removal of the bladder, otherwise metastases will develop.

Non-invasive complex method of molecular genetic and radiodiagnosis prostate cancer.

Such testing should be done when a patient with a high level of prostate-specific antigen (PSA) in the blood has an initial biopsy that is negative. Usually, another biopsy is performed six months later, followed by another (and so on 10-15 times), but this is an aggressive study, so a solution was required that would allow limiting ourselves to only one such intervention. Scientists have found a way. By detecting the expression of the PCA3 oncogene and the chimeric TMPRSS2-ERG gene in urine, it is possible to isolate patients who really need to undergo a biopsy (the rest can be delayed).

Development and implementation of the method of tissue engineering transplantation respiratory tract with their lesions of tumor or cicatricial etiology.

It's about about the category of patients who die within 2–5 months. A method was proposed for decellularization of the cadaveric trachea, in fact, with the preparation of a matrix, then populating it with chondrocytes and after that with epithelial cells. In addition, the technology provides for tracheal revascularization with subsequent transplantation to patients. All this is done in order to replace the defect of the trachea after removal of the tumor or scar. Currently, 3 surgeries have been performed. All patients have been living for more than six months - this is considered an encouraging result.

Doctor laboratory diagnostics Stukalova Irina Vladimirovna and senior laboratory assistant Pishchik Natalia Zakharovna are preparing the analyzer for DNA isolation of the human papillomavirus.

Together with the Institute of Genetics and Cytology of the National Academy of Sciences of Belarus, the topic “Proteomic and molecular genetic studies of tumor stem cells (SSC)” is planned colorectal cancer for the development of new methods of targeted cell therapy” (program Union State « stem cell- 2").

Using a model of a 5-fluorouracil-resistant colorectal cancer cell line, it is planned to study the role of COCs in the mechanisms of tumor progression and to select possible molecular targets for direct action on COCs using vaccine-based cell therapy methods using dendritic cells and/or dendritic cells and lymphokine-activated killers. . This will be a new stage in the immunotherapy of malignant tumors.

Biologist Igor Severin in the cryobank of tumor cell lines.

Another project is “Development of technology for detecting the risk of cancer based on molecular genetic and epigenetic markers” (Union State program “DNA identification”). It is planned to develop an innovative DNA technology to identify molecular genetic and epigenetic markers of the risk of recurrence or progression of the disease in patients with colorectal cancer. According to experts, new technology will allow timely preventive treatment and prevent the appearance of metastases.

A promising area of ​​research is the study of epigenetic mechanisms of regulation, i.e., processes that do not affect the structure of genes, but change their level of activity. One of them is RNA interference - a mechanism for suppressing gene expression at the stage of translation, when RNA is synthesized, but does not manifest itself in a protein. And if found high level expression of some microRNA, it can be assumed that there is a problem in this organ.

The miRNA gene family makes up slightly more than 1% of the entire human genome, but regulates the expression of almost a third of all genes. A number of ongoing scientific projects are devoted to the study of miRNAs in various tumors. The department is developing a non-invasive diagnostic method germ cell tumors testis, based on the determination of the expression of a microRNA panel in the blood. The same family of molecules, in addition to diagnosing diseases, is used to predict the course of oncological diseases and to select an individual drug therapy.

The task of the study is to identify markers poor prognosis(you can select a group of such patients and select additional treatment). It is also important to determine the miRNA spectrum. It will indicate sensitivity to certain chemotherapy regimens (we are talking about breast cancer, for which a panel of markers was found).

By studying the molecular characteristics during treatment, it is possible to adjust the treatment regimen when additional mutations appear. The method is called a “liquid” biopsy: a blood test can monitor genetic changes and suggest the progression of the disease much earlier.

Drugs for therapy are expensive and highly toxic, so it is important to determine drug resistance at an early stage and find a replacement.

Molecular profiling involves the determination of genetic disorders characteristic of each specific tumor, since it is known that the same nosological forms differ in molecular characteristics. Know molecular portrait tumors is also necessary for predicting the course of the oncological process and individualizing treatment. A personalized approach to prescribing cytotoxic drugs and targeted therapy in cancer patients, taking into account molecular biomarkers of sensitivity and toxicity, provides the most accurate selection of drugs.

Within the framework of molecular profiling of tumors, based on a large-scale analysis of data from world publications, multiplatform panels of biomarkers for breast cancer, ovarian cancer, colorectal cancer, non-small cell lung cancer, and melanoma have been developed, designed to select systemic antitumor therapy.

Chemist Olga Konstantin Kolos launches the synthesis of oligonucleotides.

Is it necessary to expand the geography of research?

Anna Portyanko,

head of the Republican

molecular genetic

laboratory of carcinogenesis,

doctor med. Sciences:

At the present stage, from the group of glioblastomas, variants have been identified that are characterized by different forecast. From a morphological point of view, it is easy to confuse glioblastoma and anaplastic oligodendroglioma: when stained with hematoxylin-eosin, they look almost the same. But thanks genetic tests we find differences. Moreover, it is routinely performed in our pathology department.

In a similar way, lymphomas also “multiplied”. For example, several lymphomas have been isolated from Hodgkin's lymphoma through molecular genetic testing. Previously, based on hematoxylin-eosin histology, they were classified as Hodgkin's lymphoma, and when molecular genetic analysis for the T-cell receptor appeared, it turned out that this was follicular T-cell lymphoma.

How does this affect treatment? First of all, it is possible to give a more accurate forecast. If a person has glioblastoma, then the median survival is 1 year, and if we are talking about anaplastic oligodendroglioma, then 10 years.

We develop contacts with foreign experts from the best European scientific centers. Together with colleagues from Germany, we are trying to develop important areas of proteomics - the analysis of not just one protein, but the proteome as a whole. The whole cycle has been created, starting from a cytological preparation, there is a laser microdissection system based on a microscope, which allows you to isolate tumor cells from a large tumor, then do mass spectrometry and determine the spectrum of all proteins in this tumor.

Is it necessary to expand the geography of research? I think that it is enough for the country to have one such center - the Republican Molecular Genetic Laboratory of Carcinogenesis, where you can quickly perform all the necessary molecular biological studies (including histological material obtained from regions).

We have the opportunity to carry out not only histological diagnostics, but also preliminary diagnostics using a flow cytometer. Literally within an hour after a person was removed The lymph nodes, we can preliminarily tell if there is a lymphoma (and if so, which one). This is a great help for clinicians.

Biologist Anastasia Pashkevich loads samples into a genetic analyzer.

What was Angelina Jolie afraid of?

We study genetic damage that occurs during the development of a tumor, - says Elena Suboch, head of the oncological department of genetics of the Republican Molecular Genetic Laboratory of Carcinogenesis. - The current direction is the assessment of hereditary risks of developing oncological diseases. Hereditary forms of tumors account for 1-2% of all oncopathologies, and here special treatment regimens and surgical intervention. An important goal of identifying familial tumor syndromes is to identify still healthy relatives of the patient who have pathogenic mutations. As a result, it is possible to develop a set of measures aimed at preventing an unfavorable outcome of oncopathology.

An example is heard: American actress Angelina Jolie, who has a mutation in the BRCA1 gene that increases the risk of developing breast cancer, went for a radical operation to prevent the occurrence of a malignant tumor.

Scientists of the Republican Molecular Genetic Laboratory of Carcinogenesis are working on this pathology.

On a grant from the Belarusian Republican Fund fundamental research in 2015–2017, the work “The system of allelic discrimination of the mutational status of the BRCA1 and BRCA2 genes in malignant neoplasms of the human breast” was completed. A population study was conducted, and it turned out that the frequency of mutations in the BRCA1 and BRCA2 genes is approximately 2.5% among women (the frequency spectrum of mutations differs from that observed in residents of neighboring countries).

Each population has its own spectrum of genetic disorders. Knowing the characteristic mutations, you can first test them, and then look for other options. The result of the scientific project was the development of a system for allelic discrimination of the mutational status of the BRCA1/BRCA2 genes using real-time polymerase chain reaction. 5 main mutations that are found in Belarusian women have been identified.

Oncology genetics specialists are also testing a large panel of markers to assess the risk of developing ovarian, endometrial, thyroid gland, kidney, colorectal cancer, melanoma, polyposis syndromes.

Today, there are new international classifications of brain tumors and lymphomas that require mandatory molecular genetic studies. Therefore, in the departments of genetics and cellular technologies, an algorithm for diagnosing such diseases using biomarkers is being developed.

"We can rarely give up our beloved
clinical hypothesis and continue to treat patients in such a way that
how they have been treated for many decades ...
Meanwhile, it is time to change the existing paradigms.”

Richard Schilsky, ASCO President

“For the most serious illnesses, the most strong medicines, accurately applied ... "
Hippocrates

The prognosis for cancer treatment depends on the clinical stage of the disease (TNM), the biology of the tumor, and the treatment performed. Modern achievements clinical oncology undeniable. And yet, despite the obvious progress in the development of new anticancer drugs, every day thousands of cancer patients take drugs that do not help them. For some patients, empiric treatment will be beneficial and safe. However, for many other patients, therapy can be both useless and toxic.

By the end of the 90s. XX Art. cytotoxic chemotherapy has reached its limit. The development of molecular biology and the focus on personalized medicine have led to a fundamentally new approach to treating patients using new generation molecular targeted drugs. Blockade of proliferation cancer cell was achieved by selective inhibition of its main signaling pathways - ligands, membrane receptors, intracellular proteins.
However, despite the obvious successes of the new approach, at the end of the first decade of the post-genomic era, there was an urgent need to revise this new therapeutic paradigm, which was due to large quantity clinical failures due to the development of acquired tumor resistance.

Targeted therapy targets and mechanisms of resistance
The most holistic view of the development and evolution of cancer was presented in two textbook articles by D. Hanaan and R. Weinberg (Cell, 2000, 2011). Based on the characteristics, the targets of therapy should not only be cancer cells with their unstable genome, special type metabolism, active neoangiogenesis, and the acquired ability to evade growth signals, circulate in the circulation, and metastasize. Therapy targets should also be the tumor microenvironment, cancer stem cells, and all components of the metastatic cascade.
Obviously, it is simply impossible to implement such a program within the framework of a treatment protocol for a particular patient, even when using a combination of several targeted drugs. A single drug, even with a unique molecular mechanism of action, cannot be effective in the treatment of a genetically heterogeneous progressive tumor in which multiple resistance mechanisms emerge and become established.
Particular mechanisms of resistance to various targeted drugs are well studied. These include activation of alternative EGFR pathways that promote cell survival in response to drug damage, formation of an oncogenic bypass and autocrine loop, loss of the extracellular domain of the membrane receptor (formation of a truncated receptor - truncated), kinome reprogramming, autophagy, epithelial-mesenchymal transition, epigenetic mechanisms, etc.
During progression and under the influence of therapy, additional oncogenic mutations appear in the tumor, its molecular landscape changes, and genome instability develops, which is commonly called genomic chaos today (W. George, Jr. Sledge, 2011).
Not only cancer cells are characterized by individuality and variability. In addition to epithelial cells, changes also occur in the tumor-associated stroma. Stromal cells are also subject to molecular evolution, although they are a genetically more stable component. solid tumor.
microenvironment of benign stromal cells immune system and inflammatory cells, also affects the evolution of the malignant clone and the formation of secondary resistance to therapy.

Heterogeneity as a reason for the ineffectiveness of anticancer therapy

The main reason for the low efficiency empirical therapy is tumor heterogeneity.
For decades, histologists have classified cancer according to morphological features describing different types cancer cells and their relationship with the tumor stroma.
Methods of molecular analysis, especially rapidly developing in the post-genomic era, have shown the true extent of tumor heterogeneity.

Individual (intertumoral) heterogeneity
Microchip technology for analyzing the level of expression of thousands of genes made it possible at the beginning (2000) to classify cancer mammary gland(BCG) to luminal A, luminal B, HER/2 and basal. Somewhat later, a refinement of molecular taxonomy with an emphasis on basal crayfish revealed additional subtypes. Among them, there are such as Claudin-low (characterized by gene expression similar to breast stem cells), subtypes of mesenchymal tumors (genes that regulate the epithelial-mesenchymal transition), subtypes of apocrine tumors with androgen receptor expression and activation of the corresponding signaling pathway, subtypes with activity genes that regulate the immune response.
Further molecular studies of breast cancer were associated with the implementation of the METABRIC (Molecular Taxonomy of Breast Cancer International Consortium) project. It has been found that molecular events such as point mutations, insertions, deletions, amplifications, duplications, translocations, and inversions can influence the tumor genomic landscape. It turned out that somatic mutations can occur both in genes not associated with carcinogenesis and in genes whose mutations occur frequently during cancer development (GATA3, TP53, and PIK3CA). In addition to genome damage in breast cancer, various epigenomic disorders (DNA methylation), damage at the level of transcription and microRNA were found. As a result of these studies, only in the luminal A subtype, another 10 different molecular integrative clusters were classified that affect the outcome of the disease. It has also been established that all four "main" subclasses and new "additional" molecular subtypes of BC have different sensitivity profiles to anticancer drugs.
Molecular genetic classifications that affect the characteristics of treatment are being created for gastric cancer, colorectal carcinoma, ovarian cancer and other localizations.

Intratumoral (intratumoral) heterogeneity
A much greater fundamental problem of oncology is intratumoral heterogeneity. The coexistence of several subclones in a tumor with different sets of molecular aberrations and different drug sensitivities makes it ineffective to suppress one cell fraction against the entire tumor. Additional unfavorable factor is a change in the biology of the tumor during its development.
Intratumoral heterogeneity is usually divided into spatial (geographic) and temporal (evolutionary).
Spatial heterogeneity suggests the presence of molecular genetic differences in certain regions of the tumor, genetic differences between the primary tumor and its metastases, as well as differences between metastases of different anatomical locations.
Depending on the level of genetic heterogeneity, monogenomic (the same genetic profiles in different geographical areas) and polygenomic tumors (different subclonal populations of cells in different departments) are observed.
Fundamental changes in the genome during tumor development occur at three time points: at the moment of transition of cancer in situ to invasive cancer, during the slow evolution of primary invasive cancer and during metastatic progression.
There are many reasons to believe that cancer behaves like an open, unstable ecosystem that depends on the pressures of environmental factors such as the immune system and hypoxia to develop. The formation of evolutionary (temporal) heterogeneity of the primary tumor is also actively influenced by ongoing antitumor treatment.
In a solid tumor, there is always a rare subclone of cells of critical importance that determines the final outcome of the disease. The death of a patient is most often observed as a result of exposure to the organism of that clone of cells, which at the moment primary diagnosis was not dominant and represented no more than 1% of all tumor cells. The presence of such cells has been proven in malignant myeloma, prostate cancer, and tumors of other localizations. Analysis of serial biopsies performed multiple times throughout the history of the disease (from the moment primary diagnosis until the death of the patient) showed that the clone of cells that survived as a result of therapy was not dominant at the beginning and developed after drug elimination of other, “basic”, rapidly proliferating clones.
The identification and eradication of this deadly cell clone leading to the death of patients is a necessary therapeutic strategy.

Tumor heterogeneity at the cell level
Majority contemporary research molecular aberrations was carried out on cells representing the main tumor population. At the same time, structural changes in DNA that occur on early stages tumor development and leading to outbreaks of genomic evolution (the so-called "big mutational clock"). The disadvantage of these methods was that the research process did not take into account the presence of rare subclones with unique genetic mutations hidden in the total mass of the main cells. It is in these cells that a gradual accumulation of point mutations occurs, contributing to extensive subclonal genetic divergence (“small mutational clocks”).
Currently, attempts are being made to overcome this shortcoming (study of the tumor at the level of one leading malignant clone). Modern methods of molecular profiling make it possible to do this. It was found that the tumor contains the so-called. driver mutations and passenger mutations. Driver mutations confer a selective growth advantage on cells carrying such mutations. Passenger mutations do not have this effect.
Typically, only driver mutations have been studied as therapeutic targets. However, passenger mutations have also recently attracted the attention of researchers, since such effects as the induction of an immune response and proteotoxic stress depend on them. Passenger mutations can also be the target of anticancer strategies.
The accumulation of numerous mutations, which is characteristic of tumors with genomic and chromosomal instability, may result in a mutational crisis. When the optimal threshold of genomic instability is exceeded, there is a violation of viability and a decrease in the number of elements of the entire system.

Analysis Methods tumor tissue
The methods of molecular analysis of tumor tissue are extremely diverse and are far beyond the limits of classical histology. Today, these methods include: microarray analysis, Southern blot, Northern blot, Western blot, in situ hybridization, polymerase chain reaction (PCR), real-time reverse transcriptase PCR, immunohistochemistry, immunofluorescence microscopy, maldi-mass spectrometry.
Tumor cell analysis can be performed at the genome level (fluorescence in situ hybridization, spectral karyotyping, comparative genomic hybridization), transcription (microarray technology: gene and RNA expression profiling), proteome (2D gel electrophoresis, mass spectrometry, surface-enhanced laser desorption ionization in TOF mode: matrix technology + mass spectrometry).
Molecular tomography of tumor tissues makes it possible to visualize the spatial distribution of proteins, peptides, drug compounds, metabolites, as well as predictive molecular biomarkers.
Molecular analysis should include primary solid tumor tissues, tissues of realized hematogenous metastases (rapidly growing and clinically significant), as well as circulating tumor cells and circulating tumor DNA (an indicator of the presence of "dormant" metastases). Tumor and metastasis biopsies should be taken from different geographic locations of the same solid tumor. It is believed that a liquid biopsy is more informative (and safer).

From empiric to personalized therapy
The tumor, being an open unstable biological system, not only demonstrates individual heterogeneity, but also changes its molecular characteristics throughout evolution, and especially during metastatic progression. Both the main and non-dominant clones of solid tumor cells, as well as cells of the tumor microenvironment, undergo changes.
To suppress the proliferation of all tumor cells, a strategy is used combination therapy. The concept of combined (simultaneous or sequential) treatment was first proposed by Goldie and Coldman more than 30 years ago. The concept united such concepts as tumor growth, an increase in the frequency of mutations in it, the emergence of resistant cell clones and the development of resistance.
Today strategy modern therapy cancer involves the use of combinations of cytostatics, cytostatics and targeted drugs, and even a combination of two targeted drugs (tyrosine kinase inhibitors and monoclonal antibodies). This strategy is based on tumor suppression with drugs that act on a pool of basic, rapidly proliferating cells. Life cycle of these cells is determined by the activity of driver mutations. In general, the stability of the system is explained by many factors, including the activity of passenger mutations, the role of which is not taken into account in therapeutic protocols.
The strategy of personalized therapy, which is today the main paradigm of anticancer treatment, takes into account the constantly changing landscape of the entire "tumor field": the heterogeneity of primary solid tumor clones, the heterogeneity of circulating tumor cells, as well as the phenotypic and metabolic heterogeneity of "dormant" cancer cells in numerous metastatic niches. bone marrow and visceral organs.

Caris Molecular Intelligence Services
The idea of ​​identifying individual predictive tumor markers that could predict the results of antitumor therapy arose in 2008, when Professor Daniel D. Von Hoff created the unique Caris Molecular Intelligence Services (USA) laboratory. Today, for molecular profiling of tumor tissues in the laboratory, a combination of methods is used - IHC, CISH, FISH, Next-Generation Sequencing, Sanger Sequencing, Pyro Sequencing, PCR (cobas ®), Fragment Analysis.
For several years, molecular tomography in this laboratory has been performed on 65,000 patients with more than 150 histopathological subtypes of malignant tumors. A complex approach based on the use of not one method (for example, only immunohistochemical), but a combination of molecular methods, allows you to identify individual predictive tumor markers of a particular patient and, based on this analysis, make decisions about personalized therapy.
The expression of some proteins (or gene amplification) requires the prescription of appropriate drugs, the expression of other proteins excludes the prescription of a particular drug. Thus, TOPO1 expression is preferable for prescribing irinotecan, RRM1 expression is preferable for prescribing gemcitabine, MGMT expression is the basis for prescribing temozolomide or dacarbazine, TOPO2A expression with simultaneous amplification of HER2 allows for therapy with doxorubicin, liposomal doxorubicin, and epirubicin.
To prescribe trastuzumab, in addition to detecting HER/2 expression/amplification, in order to predict drug resistance, it is necessary to study PTEN (IHC) and PIK3CA (NGS).
On the other hand, TS expression requires the avoidance of fluorouracil, capecitabine, pemetrexed; Expression of SPARC (IHC), TLE3 (IHC), Pgp (IHC) requires the avoidance of docetaxel, paclitaxel, nab-paclitaxel.
With such a combination of tumor markers as ER (IHC), HER2 (IHC), HER2 (CISH), PIK3CA (NGS), everolimus and temsirolimus should not be prescribed.
The combination of modern methods of biological imaging makes it possible to identify molecular predictive tumor markers for each known cytosatic or targeted drug used today in clinical oncology. Such an approach, based first on conducting molecular profiling of tumor tissues, identifying individual predictive tumor markers in it, and only then on developing a treatment strategy plan, has received evidence in a number of clinical studies. One of them is the Bisgrove Study, which included TGen, Scottsdale Healthcare and Caris Dx.
The design of this study was revolutionary. Given the fact that each tumor is individual, the authors of the study design refused to randomize patients into multiple groups based on the anatomical location of the tumor or only one immunohistochemical feature. AT this study there were no comparison groups - each patient acted as his own control.
In total, 66 patients from 9 US cancer centers participated in the study: 27% - breast cancer, 17% - CRC, 8% - OC, 48% - other localizations. Before inclusion in the study, all patients received therapy for metastatic cancer according to generally accepted standards - a total of 2 to 6 lines. After the last progression continued therapy based on molecular profiling.
The results of the study showed that the time to progression in patients with BC increased by 44%, with CRC - by 36%, with OC - by 20%, with other localizations - by 16%. It should be noted that all patients at the time of inclusion in the study developed secondary resistance to drug therapy, and generally accepted recommendations for their further treatment did not have. Thus, it is concluded that for aggressive, rare tumors, as well as progressive tumors with developed resistance, there is no alternative to molecular profiling and treatment personalization.

Changing the design of clinical trials
Separately, it should be noted that the paradigm of personalized therapy in oncology is actively changing the generally accepted design of clinical trials. There are growing voices that the results of clinical trials based on randomization and stratification of patients into multiple populations and cohorts should be reconsidered to account for individual intra- and intertumoral heterogeneity. As a result, the design of modern clinical trials is becoming increasingly personalized.
An example of such latest modern designs are Master protocols, Basket trials, Adaptive trial design and, finally, N-of-1 studies. The main idea behind the new designs is as follows. The sponsors of the study are simultaneously several pharmaceutical companies that have drugs with different targets and different molecular mechanisms of action for the treatment of cancer of this localization. Patients are included in the study after a possibly complete molecular profiling of the tumor. Participating in one study, the patient, depending on the availability of appropriate target proteins, can alternately receive the most effective drugs. During therapy, an individual adaptation of the drug according to the dose can be carried out or a cocktail mix from a combination can be used. various drugs, the need for which arose during treatment. Tumor progression and toxicity are not grounds for stopping treatment, but only for changing the type of therapy. The clinical decision is influenced by the results of molecular profiling of the tumor, which is carried out immediately after tumor progression or the next course of therapy. Thus, during the study, the patient may receive a completely different drug that was originally prescribed to him.
Finally, there are already trials for only one patient - N-of-1 studies. This design is most suited to the personalized therapy paradigm. Such an approach will allow in the near future to create individual preparations for cancer therapy.
However, even today, personalized therapy protocols based on molecular profiling of the tumor are widely used in clinical practice leading cancer centers in the USA, Europe, Japan, allowing you to receive clinical results new level. Such global centers include Memorial Sloan-Kettering Cancer Center, Center for Personalized Genetic Medicine at Harvard, Institute for Personalized Medicine at MD Anderson, Center for Personalized Health Care at the Ohio State University.
Since January 2014, molecular profiling of tumor tissues based on the Caris Molecular Intelligence Services platform has been available in Ukraine. This became possible thanks to AmaxaPharma, which is the official partner of Caris Life Sciences in the field of molecular profiling of tumor tissue in Eastern Europe. Since January 2014, thanks to this collaboration, dozens of patients with rare tumors for which there are no standards of therapy, as well as cancer patients with primary and acquired chemoresistance, have already undergone Molecular Intelligence molecular profiling in Ukraine. The first results are obtained, which differ significantly from the results of the empirical approach.
The possibility of implementing molecular profiling in our country has made it possible to come close to solving the problem of personalized cancer treatment.

Conclusion
Tumor heterogeneity has profound clinical implications for cancer patients. To make the right clinical decisions, it is necessary to have the most complete picture of the biology of the cancer cell and its microenvironment. Molecular profiling of primary tumor tissues, hematogenous metastases, circulating tumor cells, and metastatic niche cells allows a major step towards the implementation of a personalized cancer treatment program.

STATS BY TOPIC Oncology and Hematology

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Source: Proceedings of the third annual Russian Cancer Conference
November 29 - December 1, 1999, St. Petersburg

PROSPECTS FOR MOLECULAR DIAGNOSIS IN ONCOLOGY. K.P. Hanson
Research Institute of Oncology. prof. N.N. Petrova

Achievements in genetics and molecular biology in recent decades have had a huge impact on understanding the nature of the initialization and progression of malignant tumors. It has been finally established that cancer is a heterogeneous group of diseases, each of which is caused by a complex of genetic disorders that determine the property of uncontrolled growth and the ability to metastasize. This modern knowledge has opened fundamentally new possibilities in the diagnosis and treatment of malignant neoplasms.

The influence of specific genetic disorders underlying tumor growth made it possible to detect specific molecular markers and develop tests for early tumor diagnosis based on them.

It is known that neoplastic transformation of cells occurs as a result of the accumulation of inherited (germinal) and acquired (somatic) mutations in proto-oncogenes or suppressor genes. It is these genetic disorders that can first of all be used to detect malignant cells in clinical material.

The most suitable substrate for molecular diagnostics is DNA, because it is stored for a long time in tissue samples and can be easily propagated using the so-called. polymerase chain reaction (PCR). This allows diagnostics to be carried out even in the presence of a minimum amount of the test material.

In addition to determining mutations in oncogenes and suppressor genes, for diagnostic purposes, changes are used that are detected in repetitive DNA sequences, the so-called. micro satellites.

When comparing paired samples of tumor and normal tissues, the loss of one of the alleles in the tumor (loss of heterozygosity (LH)) can be detected, which reflects the presence of chromosomal deletions underlying the inactivation of suppressor genes.

Breast cancer (BC) is one of the most common oncological diseases in Ukraine. According to the National Cancer Registry of Ukraine, the standardized incidence of breast cancer in 2009 is 60.5 cases per 100,000 female population. Although the incidence of malignant neoplasms of the mammary glands is constantly increasing, the mortality from them tends to decrease.

BC is a heterogeneous group of tumors that differ in morphology, clinical course, and sensitivity to treatment. However, even histologically similar tumors have a different natural history, which is due to a certain limitation of the morphological classification of breast cancer. The study of gene expression by breast cancer cells and their correlation with phenotypic manifestations made it possible to identify a number of biological subtypes of breast cancer, which determine the natural history, clinical, pathological and molecular properties of the tumor, and are also key factors that predetermine the prognosis of the course and the effectiveness of systemic drug therapy. The use of time-consuming and expensive methods of genetic analysis in everyday clinical practice is impossible. The study of the correlation between gene expression and immunohistochemical markers in the tumor made it possible to identify a number of so-called molecular subtypes of breast cancer, the determination of which is possible in routine clinical practice. Based on an immunohistochemical study of the expression of estrogen and progesterone receptors (ER and PR) and epidermal growth factor 2 receptor (Her2/neu, ErbB2) by breast carcinoma cells, breast cancer can be classified into 4 molecular subtypes that differ from each other. according to the prognosis of the course and response to drug therapy. Molecular subtypes of breast cancer, which are of fundamental clinical importance, are shown in Table. one.

Table 1. Immunohistochemical phenotype of molecular subtypes of breast cancer

There are luminal, HER2+ and triple negative (TN) molecular subtypes of breast cancer. Luminal tumors include tumors expressing ER and PR receptors, and, depending on the expression of Her2/neu, they are classified into A (do not express Her2/neu) and B (express Her2/neu). HER2+ are called tumors with Her2/neu overexpression and lack of ER and PR. Tumors that are negative for the above 3 signs are referred to as TN (basal-like) BC. It has been established that luminal types are associated with a less aggressive course and a good prognosis compared with HER2+ and TN BC. TH subtype is associated with a high mutation rate BRCA1, aggressive course, lack of response to hormone therapy and trastuzumab, low overall and disease-free survival.

The correlation between immunohistochemical markers and tumor susceptibility to drug treatment is well understood and underlies clinical guidelines for adjuvant treatment of breast cancer. However, the number of studies evaluating the relationship between molecular subtypes and clinical and biological characteristics of breast cancer is limited.

The purpose of this population study is to study the prevalence, clinical and morphological features, overall and relapse-free survival of patients with breast cancer, depending on the molecular portrait.

Materials and methods

Patient selection

The study included 350 patients with breast cancer aged 23 to 76 years (mean age 53 ± 1.7 years), who were treated at the clinic of the Department of Oncology of the National Medical University named after A.A. Bogomolets on the basis of the surgical department of the Kyiv City Clinical Cancer Center from January 1, 2005 to December 31, 2006.

All patients were recorded age at the time of diagnosis, menstrual function, determined the size, histological type and degree of differentiation of the tumor, as well as the presence of metastases in the regional lymph nodes (RLN).

Tumor size was assessed after measuring its maximum diameter and classified according to the International TNM classification (5th edition, 1997) as T1 (<2 см), Т2 (2–5 см), Т3 (≥5 см). Отсутствие менструаций у больных в течение 1 года до момента установления диагноза расценивалось как менопауза. Гистологический тип и степень дифференциации опухоли определяли в соответствии с национальными стандартами диагностики и лечения злокачественных новообразований, основанных на рекомендациях ведущих международных организаций. Для оценки метастатического поражения РЛУ из послеоперационного материала макроскопически отбирали 10 подозреваемых на наличие метастазов лимфатических узлов, из которых готовили гистологические препараты для микроскопического изучения.

Molecular subtypes of BC were determined based on the results of immunohistochemical studies of the expression of ER, PR, and Her2/neu. All tumors were divided into 4 subtypes: luminal A (Luminal A) - ER+ and/or PR+, Her2/neu-, luminal B (Luminal B) - ER+ and/or PR+, Her2/neu+, HER2+ (ER- and PR-, Her2/neu+), TH (Triple negative) - ER- and PR-, Her2/neu-.

All patients received adjuvant systemic and radiation therapy in accordance with national standards for the treatment of breast cancer. However, with Her2/neu overexpression, none of the patients included in this study received trastuzumab adjuvantly.

Immunohistochemical study

Sections of 4–5 microns thick were prepared from paraffin blocks and placed on slides pretreated with poly-L-lysine. Then the material was examined according to the generally accepted standard method using the following antibodies: ER - clone 1D5, PgR - clone 636, Her2/neu - clone CB11.

Interpretation of the results of the immunohistochemical reaction was carried out using a qualitative assessment of the nuclear reaction: negative "-", weakly positive "+", moderately positive "++", pronounced positive "+++" - and a quantitative system for evaluating the reaction in percent of stained tumor cells.

When determining the expression of Her2/neu, the severity of the color of the cytoplasmic membrane was noted: the reaction "-", "+" - the absence of overexpression, the reaction "+++" - the overexpression of Her2/neu. The presence of Her2/neu overexpression in cases of “++” reaction was assessed using the hybridization method in situ using a fluorescent label FISH (fluorescence in situ hybridization - fluorescent in situ hybridization). The studies were carried out in the pathohistological laboratory of the Kyiv City Clinical Cancer Center (head of the laboratory - Doctor of Medical Sciences L.M. Zakhartseva).

Statistical analysis

Statistical significance of differences between the clinical and biological characteristics of the molecular types of BC was assessed using a one-way analysis of variance (ANOVA). Differences were considered statistically significant at the significance level (p)<0,05.

Overall and disease-free survival was determined using the Kaplan-Meier method.

All statistical calculations were performed using the MS Excel program.

results

As a result of the study, all patients, based on the data of immunohistochemical studies of the expression of ER, PR and Her2/neu, were divided into 4 groups: luminal A - 152 (57.5%) patients, TN - 49 (26.5%), luminal B - 28 (9%) and HER2+ - 15 (7%) women.

Clinical and biological characteristics of various molecular types of breast cancer are presented in Table. 2.

Table 2. Clinical and biological characteristics of molecular subtypes of breast cancer

Notes: *lobular ductal carcinoma; **mucous, medullary, papillary carcinoma.

There were no statistically significant differences in the stage of the disease between the study groups, which indicates a homogeneous distribution of patients in groups according to this criterion.

The frequency of detection of various molecular subtypes of breast cancer statistically significantly depends on the following clinical and morphological characteristics: age and menstrual function at the time of diagnosis, histological type and degree of tumor differentiation. In patients aged 40–49 years, HER2+ and TN subtypes of breast cancer are diagnosed significantly more often (34.5 and 34% of cases, respectively). Almost half of the patients (48%) with TN of the molecular type were diagnosed in premenopause. In patients who were in menopause at the time of diagnosis, luminal A (63%) and luminal B (68%) types of BC are more common than others.

Also, statistically significant differences between immunohistochemical subtypes were observed for different histological types and degree of tumor differentiation. Lobular carcinomas were diagnosed more frequently in luminal A (19%) and TN (16%) types. Ductal breast cancer was recorded in 84 and 92% of cases of HER2+ and luminal B molecular subtypes, respectively. Lobular ductal, mucosal, medullary, and papillary carcinomas are equally common in luminal and TN types of breast cancer; however, in this study, not a single case of the above histological variants was recorded in type HER2+. In the studied groups, highly differentiated (G1) tumors are determined with the same frequency. Moderately differentiated (G2) breast carcinomas are typical for luminal A (82%) and B (86%), as well as HER2+ (80%) types. Poorly differentiated (G3) tumors were found in 28% of patients from the TN BC group.

Statistically significant interdependence between the immunohistochemical phenotype of breast cancer and the size of the primary tumor, as well as the status of RDR, has not been established, which, along with the stage of the disease, indicates a uniform distribution of patients in the study groups according to these indicators.

The results of the analysis of 5-year overall and relapse-free survival of patients with different molecular types of breast cancer are shown in Fig. 1 and 2, as well as in the table. 3 and 4, respectively.

Rice. one.

Rice. 2.

Table 3 Overall survival of patients depending on the molecular type of breast cancer

Table 4 Relapse-free survival of patients depending on the molecular type of breast cancer

Overall survival is highest in patients with luminal A (74%) type of breast cancer, and the lowest in patients with HER2+ and luminal B (58 and 57%, respectively).

5-year disease-free survival is worse in patients with luminal B and TN breast cancer (42 and 45%, respectively) compared with patients with luminal A immunohistochemical subtype.

Discussion

The results of this study confirm the variability of breast cancer, which consists in the presence of different molecular types of this nosological form. The division of breast cancer into biological subtypes, which have their own natural history, is increasingly used in everyday clinical practice, as it allows you to determine the prognosis of the course of the disease and is a key factor in choosing the tactics of systemic drug therapy. However, classification into molecular types does not replace, but rather complements, important traditional prognostic criteria, such as age and menstrual function at diagnosis, tumor size and differentiation, presence of RLN metastases, and identification of comorbidities.

Determination of molecular types of breast cancer based on immunohistochemical assessment of the expression of ER, PR and Her2/neu is inexpensive and quite informative, but at the same time a simplified diagnostic method. Due to the introduction of new markers, molecular classification is undergoing changes, which makes it possible to increase its predictive reliability. For example, at high mitotic activity of cells (Ki-67 >14%), tumors with a luminal A phenotype, according to the recommendations of the St. Gallen Congress on the treatment of breast cancer (2011), are assigned to the luminal B Her2/neu-negative molecular subtype. The need to isolate the luminal B Her2/neu-negative type of breast cancer is dictated by the natural history of these tumors, which is more similar to the natural history of luminal B than luminal A tumors. Therefore, patients with ER+ and/or PR+, Her2/neu- breast cancer with high mitotic activity of the tumor, which determines a poor prognosis of the course of the disease, are shown to undergo adjuvant polychemotherapy before antihormonal therapy.

The results obtained in this population study indicate that the frequency of detection of different molecular types of breast cancer, determined on the basis of immunohistochemical assessment of the expression of ER, PR and Her2/neu, is not the same. The most common molecular subtype of BC is luminal A (57.5%), followed by TN (26.5%), followed by luminal B (9%) and HER2+ (7%) types.

Luminal A immunohistochemical type of breast cancer in most cases is diagnosed in patients after 50 years of age who are in menopause. This variant of breast cancer is more often than others characterized by a lobular histological type and a moderate degree of tumor differentiation. The 5-year overall and relapse-free survival of patients with this molecular type of breast cancer is the highest and amounts to 74 and 62%, respectively.

TN BC is more often detected in patients aged 40 to 60 years, regardless of the state of menstrual function, it is characterized by a lobular histological type in 16% of cases, and in 28% these tumors are poorly differentiated. Compared with luminal A type, in patients with TN BC, the 5-year overall and recurrence-free survival is lower and amounts to 60 and 45%, respectively.

Luminal B molecular type, like luminal A, is more often diagnosed in postmenopausal women over 50 years of age. More than 80% of cases are moderately differentiated ductal carcinoma. Patients with luminal B BC have the lowest 5-year overall and recurrence-free survival and are 58 and 42%, respectively.

HER2+ type, like TH, occurs more often in patients aged 40 to 60 years, regardless of the status of menstrual function, and is almost always a moderately differentiated carcinoma. The 5-year overall and recurrence-free survival rates are the same at 57%.

Thus, the most favorable molecular subtype of breast cancer in terms of its prognosis is luminal A. The unfavorable clinical course of luminal B and HER2+ types may be due to the lack of trastuzumab therapy.

List of used literature

1. Bulletin of the National Cancer Registry No. 12. Cancer in Ukraine, 2009–2010, Kyiv: 2011.

2. Perou C.M., Sorlie T., Eisen M.B. et al. (2000) Molecular portraits of human breast tumors. Nature, 406(6797): 747–752.

3. Sorlie T., Perou C.M., Tibshirani R. et al. (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc. Natl. Acad. sci. USA, 19(98): 10869–10874.

4. Sorlie T., Tibshirani R., Parker J. et al. (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc. Natl. Acad. sci. USA, 14(100): 8418–8423.

5. Sotiriou C., Neo S.Y., McShane L.M. et al. (2003)Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc. Natl. Acad. sci. USA, 18(100): 10393–10398.

6. Carey L.A., Perou C.M., Livasy C.A. et al. (2006) Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA, 21(295): 2492–2502.

7. Foulkes W.D., Stefansson I.M., Chappuis P.O. et al. (2003) Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J. Natl. Cancer Inst., 19 (95): 1482–1485.

8. Liu H., Fan Q., Zhang Z. et al. (2008) Basal-HER2 phenotype shows poorer survival than basal-like phenotype in hormone receptor-negative invasive breast cancers. Hum. Pathol., 2 (39): 167–174.

9. Goldhirsch A., Wood W.C., Coates A.S. et al. (2011) Strategies for subtypes-dealing with the diversity of breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann. Oncol., 8(22): 1736-1747.

Molecular types of breast cancer, determined on the basis of immunohistochemical markers: clinical and biological features and prognosis

I.B. Shchepotin¹, O.S. Zotov¹, R.V. Lubota¹, M.F. Anikusko², I.I. Lubota²

¹National Medical University named after O.O. Bogomoltsya, Kiev

2 Kyiv City Clinical Oncological Center

Summary. Cancer of the thoracic cavity is a heterogeneous group of puffs, which are considered by their etiology, morphological picture, clinical overshoot and sensitivity to the treatment. The method of this population study led to the development of breadth, clinical and morphological features, general and disease-free survival of ailments for breast cancer in a fallow type of molecular type. 350 patients with breast cancer were treated at age 23 to 76 (middle age - 53±1.7 years), and they were treated at the clinic of the Department of Oncology of the National Medical University named after O.O. Prayers on the basis of the surgical department of the Kiev Moscow Clinical Cancer Center in 2005–2006. Statistically significant differences between the molecular type of breast cancer and clinical and morphological features, as well as: age and status of menstrual function at the time of diagnosis, histological type and degree of differentiation of swelling, as well as overall and disease-free survival were revealed.

Keywords: thoracic cancer, molecular types, prognosis of overcome, clinical and morphological features.

Molecular types of breast cancer, established on the basis of immunohistochemical markers: clinical and biological characteristics and prognosis

I.B. Schepotin¹, A.S. Zotov¹, R.V. Liubota¹, N.F. Anikusko², I.I. Liubota²

¹A.A. Bogomolets National Medical University, Kyiv

2 Kyiv municipal clinical oncological center

summary. Breast cancer (BC) is a heterogeneous group of tumors that has a different etiology, morphological pattern, clinical course and sensitivity to the treatment. The aim of this study was to investigate population prevalence, clinical and morphological features, general and disease-free survival of BC patients depending on the molecular type. The study involved 350 patients with BC aged 23 to 76 years (mean age 53±1.7 years.) They were treated in the clinic of the Department of Oncology A.A. Bogomolets National Medical University, based on the surgical department of the Kyiv City Clinical Cancer Center in 2005–2006 years. A statistically significant difference between type BC molecular and morphological features, namely age and status of menstrual function at the time of diagnosis, histological type and degree of tumor differentiation, as well as general and disease-free survival of patients.

key words: breast cancer, molecular types, prognosis, clinical and morphological features.