Molecular portrait of the tumor. List of used literature. B. Checking for a mutation in the K-RAS-Test is suitable for patients with metastatic colon and rectal cancer

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

To understand how molecular diagnostics works and what place it occupies in oncology, one must first understand the mechanisms that occur in a 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, 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 choice can be from potentially efficient schemes treatment.

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 the tumor resistant to a particular treatment, or genetic features that are associated with increased toxicity and require individual selection of the dose of the drug.

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 indicated surgery. 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 advise oncologists or patients and suggest whether a test is needed in this case.

Precision Medicine and Clinical Research

Usually in medical practice apply general strategies 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 medications and chemotherapy (pharmacogenomics), to know the main biomarkers.

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

Targeted drugs are on the rise and have two major 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 implementing precision oncology in 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 by type malignant neoplasms, and then take into account genetic mutations.

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 with 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 get more full information about the disease. The patient was biopsied and tissue samples sent for analysis. As a result of diagnostics, several important genetic disorders were found in the tumor:

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 metabolism anticancer drug"Cisplatin".

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

The BRAF inhibitors (Vemurafenib) may be potentially effective, moreover, the presence of an NRAS mutation may 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.

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

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 It 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 full list articles:

One of the most modern and high-tech methods for diagnosing cancer is genetic (molecular) tests. These studies make it possible not only to determine the hereditary predisposition to certain oncological diseases, but also to assess the feasibility of prescribing chemotherapy and determine the degree of cancer aggressiveness.

In the first medical center Tel Aviv conducts the most effective and proven genetic research of more than 900 existing on this moment. At the same time, a remote testing service is provided when the patient does not need to fly to Israel. It is enough to send a sample of the material by mail (after a puncture or operation), following some rules, and wait for the results of the study.

Oncotype DX

This molecular study is applied in breast cancer. Depending on the objectives of the study, the type of tumor and individual features patients distinguish between several types of Oncotype DX.

Oncotype DX Breast

The test is used to determine the degree of differentiation of breast cancer tumor cells (the probability of recurrence is determined accordingly). It is used after surgery to remove the tumor to determine the advisability of prescribing chemotherapy. The study is suitable for estrogen-positive tumors (ER+), invasive cancer breasts without metastasis to regional The lymph nodes.

Standard signs for the choice of treatment tactics after surgery are:

Before the advent genetic tests, these three signs were the only source information, on the basis of which the tactics for the further appointment of chemotherapy was determined. However, the aggressiveness of cancer cells and, accordingly, the likelihood of a distant recurrence does not always correlate with the size of the tumor and the presence of metastases in the lymph nodes.

Today, in world medicine, the Oncotype DX genetic test is the gold standard and the leading criterion for choosing treatment tactics for breast cancer. It allows both to prevent the recurrence of the disease, and to avoid unnecessary prescription of chemotherapy and all the side effects associated with it.

Fish test for Herceptin receptors

It is an immunohistochemical study that detects specific receptors (HER-2, PR, ER) on cancer cells, which make it sensitive to targeted drugs. Such, in particular, is the drug Herceptin, belonging to the class of monoclonal antibodies. It has long been successfully used in the treatment of breast cancer in Israel and has shown nice results to prolong life and prevent recurrence, even in advanced stage and the presence of metastases.

In about 1 in 4 cases of breast cancer, the tumor is sensitive to Herceptin therapy and this can be determined by a molecular test for specific receptors. Treatment advantage biological preparations compared to standard methods(radio and chemotherapy) is the absence of harmful side effects.

Molecular test of the CYP2D6 gene

It is used exclusively in cases of hormone-dependent breast tumors. These cancer cells have receptors for the hormones estrogen and progesterone, making them sensitive to the effects of hormone therapy(especially in women during menopause).

Studies have shown that the hormone used replacement drugs converted in the liver to active active substance thanks to a special enzyme CYP2D6, encoded by the gene of the same name. On average, up to 10% of people have a mutation of this gene, due to which a full transformation of hormones is impossible.

A genetic test makes it possible to identify this mutation and thus determine whether effective treatment hormonal drugs and assess the risk of relapse. Tel Aviv First Medical Center this study carried out with material from the patient's saliva.

Oncotype DX Colon

A molecular study that is used in colon cancer to comprehensively weigh the risk of recurrence and the degree of tumor progression. The essence of the test lies in the analysis of complex software 12 DNA genes cancer cell, which are responsible for the degree of differentiation, atypicality and gene aberrations. The result of the analysis is converted into a numeric form and has a value from 0 to 100.

The Oncotype DX Colon study is indicated for patients with stage 2 colon cancer after surgery to remove the primary tumor and in the absence of metastases in the regional lymph nodes. About 15% of patients with colon cancer have a non-aggressive form of the tumor that is not prone to recurrence. The test allows you to assess this risk and avoid unnecessary chemotherapy.

Duration genetic testing Oncotype DX Colon in Israel is about two weeks, and the material is taken directly from the primary tumor. The assessment is made on a 100-point scale, a comprehensive conclusion is made and the further tactics treatment.

K-RAS test

A specific genetic test that allows you to determine the sensitivity of colon cancer and to targeted therapy with Setuximab. The drug is a monoclonal antibody that selectively blocks EGFR receptors on tumor cells. The aggressiveness of colon and rectal cancer directly depends on the expression of specific epidermal growth factor receptors (EGFR).

K-RAS is a protein that is involved in a cascade of reactions that control cell division intestinal epithelium. Mutations in the gene encoding this protein make treatment with Setuximab ineffective. Approximately 60% of people do not have this mutation, so a drug can be given if the test is negative.

The K-RAS test is extremely important diagnostic criterion in modern oncology. This is due to the fact that treatment with Setuximab prolongs life by 2-5 years or even leads to complete recovery of patients with advanced forms of neoplasms of the colon and rectum. Another 10 years ago metastatic cancer these sections of the gastrointestinal tract was considered incurable and patients received palliative therapy, with the introduction of biological therapy, patients got a chance for recovery.

EGFR mutation test

This genetic test is used for non-small cell lung cancer. There are two enzymes that control cell reproduction - tyrosine kinase and epidermal growth factor EGFR. Therefore, in modern methods Targeted tumor therapy uses two drugs that inhibit these enzymes, Erlotinib and Gefetinib.

According to statistics, from 15 to 20% of patients have an EGFR gene mutation, so they need to be prescribed targeted treatment in the form of monoclonal antibodies instead of second-line chemotherapy drugs. This is especially true for stages 3 and 4 of non-small cell lung cancer with the presence of metastases. Erlotinib and Gefetinib can inhibit the growth of cancer cells for years and cause a long-term remission in the patient. In addition, monoclonal antibodies do not have negative side effects, like chemotherapy (cytotoxic effect), since it does not affect healthy cells.

Comprehensive survey Target Now

Each atypical cancer cell has its own unique set of receptors and gene expression, just like each person has a unique fingerprint. The effectiveness of chemotherapy and treatment with biological targeted drugs depends on their presence or absence.

The current stage of development of treatment with monoclonal antibodies has acquired such a scope that for the maximum effective selection the drug needs to be carried out molecular tests. The Target Now methodology allows you to combine them all into one study that accurately reflects genetic code atypical cell.

First official results tests of the test were presented in 2009 at the American Association for Cancer Research conference. According to them, more than 98% of patients with an advanced form of cancer (the presence of metastases) managed to get complete picture molecular targets and select the appropriate targeted therapy. Moreover, in 30-35% of patients, as a result of modified therapy according to the results of Target Now, there was a significant improvement in the quality of life and increased life expectancy.

The test is indicated for use in patients in whom previous treatment has not been effective, or with metastases of any localization. For the study, material from the tumor tissue is needed (biopsy, or after surgery).

Mamma Print

This genetic test is designed to determine the risk of recurrence after breast cancer. According to the recommendations of the American Food and drug administration (FDA), the test is indicated for patients with any form of breast cancer younger than 60 years old, without metastatic lesions of the lymph nodes, and provided that the tumor is less than 5 centimeters in size.

The essence of the study lies in the molecular analysis of the expression of 70 genes of a cancer cell, followed by an assessment of the aggressiveness of the tumor and the derivation of the final risk of recurrence using mathematical formula. The result allows you to choose the tactics of treatment and determine the feasibility of prescribing chemotherapy to patients.

The difference between Mamma Print and similar genetic tests lies in the fact that the study is carried out on a sample of “fresh” tissue, so the patient must stay in Israel for a puncture or operation. You need to wait about a week for the result, but after the procedure you can go home and get an answer in writing.

Fill out an application for treatment

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. These modern knowledge 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 be used in the first place 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 minimum quantity the material under study.

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, one of the alleles in the tumor can be lost (loss of heterozygosity (LH), which reflects the presence of chromosomal deletions underlying the inactivation of suppressor genes.

The most common of all types. The tumor resembles a fern leaf. This type belongs to highly differentiated tumors. This means that the cells look like normal cells, and it is not so easy to immediately determine the presence of the disease.

This species occurs in 80% of cases. Basically everything happens smoothly and slowly. The disease does not pose a particular danger if you start to eliminate it in time. This type of cancer is not capable of metastasizing and is perfectly treatable.

If you examine the thyroid gland healthy person, then 10% can be found to have tiny tumors. They do not grow and do not manifest themselves in any way. But in some cases, they still reach large sizes, it is then that high-quality treatment should be prescribed.

This problem is more common in men than in women aged 30-50 years. People who applied to the hospital on time and underwent a course of therapy live for more than 25 years. Therefore cancer thyroid gland in this case has a favorable prognosis.

Medullary thyroid cancer

Medullary thyroid cancer is quite rare form diseases. It occurs in 5-8% of all cases. This is mainly due to parafillicular cells, which are produced by the hormone calcitonin. It is he who regulates the level of phosphorus, calcium, as well as bone growth.

This tumor is much more dangerous than others. It is able to grow into a capsule in the trachea and muscles. In this case, the disease is accompanied by a feeling of heat, redness of the face and intestinal upset. The disease occurs in people aged 40-50 years. It affects both men and women equally.

Medullary cancer is often accompanied by other glandular disorders. internal secretion, multiple endocrine neoplasms are also not excluded. The cells of this tumor do not absorb iodine, so therapy with it does not bring a positive result.

Only surgery can eliminate this type of thyroid cancer. It is necessary to completely remove the gland and cervical lymph nodes. Patients over 50 years of age have an extremely poor prognosis.

Follicular thyroid cancer

Follicular thyroid cancer is represented by the presence of a tumor with vesicles. Often the disease occurs in older people, especially in women. It occurs in 10-15% of cases and does not pose a particular danger. Quality therapy provides positive effect and the person is on the mend.

In extremely rare cases the tumor does not grow blood vessels and surrounding tissues. In addition, it does not metastasize, which is why it is called minimally invasive. The remaining 70% of cases of follicular cancer are more aggressive and require a serious approach to fixing the problem. Cancer can spread not only to the vessels, but also to the lymph nodes. In addition, distant organs are affected, including bones and lungs.

Metastases in this case respond well to treatment with radioactive iodine. The prognosis of the course of the disease is favorable, especially in patients under the age of 50 years. In older people, thyroid cancer of this type may be complicated by metastases.

Anaplastic thyroid cancer

Anaplastic thyroid cancer is the rarest form of the disease. It is characterized by the development of atypical cells in the thyroid gland. They do not have any functions and can only share. This type of tumor occurs in 3% of cases.

It mostly manifests itself in people over the age of 65. Moreover, women are more likely to suffer from such a tumor than men. The disease is characterized fast growth and spread of metastases. Unfortunately, this species cancer is difficult to treat. Eliminate the tumor is almost impossible. Therefore, out of all existing species cancer, anaplastic has the most unfavorable prognosis.

Unfortunately, it is impossible to save a person. But, and the disease manifests itself not so often. The whole problem lies in the fact that metastases spread at a special speed, which does not allow for high-quality treatment. It is impossible to eliminate all the consequences of this tumor because of the speed of the process. thyroid cancer on this stage almost never eliminated.

Squamous cell thyroid cancer

Squamous cell thyroid cancer is extremely severe course. Metastases begin to appear early and in large numbers. The prognosis is unfavorable. At the initial treatment of the patient, a common process can be seen. The tumor can occupy the entire thyroid gland and even spread to surrounding tissues and organs.

Microscopic tumors have a typical structure of squamous cell carcinoma. Often they are accompanied by the formation of horn pearls. Sites of such metaplasia can occur in papillary and follicular adenocarcinomas. This can exacerbate the course of a different type of malignant tumor.

If possible, immediate surgical treatment. After all squamous cell carcinoma refractory to other species therapeutic effect. There are chances for improvement, but they are extremely small. This is the most complex type of tumor, which is not so easy to eliminate. Thyroid cancer at this stage is dangerous because of its complexity and almost impossible to eliminate.

Hidden thyroid cancer

Latent thyroid cancer may manifest itself as clinically regional metastases in the jugular region. The primary tumor of the thyroid gland is determined exclusively by means of ultrasound. In some cases, a microscopic examination is performed.

It is worth noting the fact that the hidden focus is able to have different histological structure. In almost 80% of cases, it is represented by papillary cancer.

Clinical signs of the disease can be safely divided into 3 groups. So, the first notes the symptoms associated with the development of a tumor in the thyroid gland. The second group is represented by symptoms that have arisen in connection with the germination of the tumor in the tissues surrounding the gland. The third group of symptoms is due to regional and distant metastasis.

The first group is characterized by rapid growth of the node, moreover, a dense consistency and tuberosity appear, as well as uneven compaction. If the tumor extends beyond the thyroid gland into the surrounding tissues, there may be hoarseness, difficulty breathing, swallowing food, and an enlarged vein on the anterior surface of the chest.

The third group of signs is directly related to regional and distant metastases. In the neck, you can see the defeat of the deep jugular chain, less often the lymph nodes. Thyroid cancer can be diagnosed at this stage with the help of ultrasound.

Molecular thyroid cancer

Molecular thyroid cancer is the second name papillary variety. It is the most widespread of all existing ones. If you look closely at the tumor itself, then according to its external data, it is very similar to a fern leaf.

This type cancer education is one of the highly differentiated tumors. This suggests that the cells are very similar to normal, and it is extremely difficult to understand that these are cancerous foci.

A malignant neoplasm of this type occurs in 80% of cases. The disease does not pose a particular danger if the elimination process is started in a timely manner. This type of cancer does not allow metastases, which allows you to qualitatively remove the tumor and prevent it from developing strongly.

Even a healthy person can see small tumors on the thyroid gland. They do not grow and do not pose a particular danger. If suddenly their size begins to increase rapidly, everything is removed by means of high-quality therapy. This type of thyroid cancer is more common in men than in women.

Differentiated thyroid cancer

Differentiated thyroid cancer is characterized by relatively slow growth and late metastasis. That is why it is much easier to remove without any complications. To differentiated cancer include papillary and follicular appearance.

These types of malignant tumors are among the most common among both men and women. In view of some features, eliminating them is easy. The main thing is that a person seeks help in time.

On the initial stages cancer does not particularly manifest itself, and only after a certain period of time will it begin to “interfere” with the patient. He will feel some discomfort, there will be difficulties in eating, breathing and physical activity. But the thing is that these types of cancer practically do not give metastases. Therefore, it can be eliminated even with pronounced symptoms. radioactive iodine helps to get rid of all the consequences this disease. Thyroid cancer in this case is not particularly dangerous.

Highly differentiated thyroid cancer

Highly differentiated thyroid cancer is represented by two varieties. It is papillary and follicular. The first variation is quite common in 85% of cases. Metastases usually spread through the lymphatics to regional lymph nodes. Distant metastases can affect the lungs and bones. The prognosis is favorable, despite a large number of metastases.

Follicular cancer. Occurs in 10% of all cases. At histological examination one of the features that distinguishes it from benign adenoma it is an invasion into the capsule of the thyroid gland and into the vessels. Often distant metastases affects the bones, liver and lungs. As for the prognosis, it is favorable.

Much depends on how quickly the person asked for help. Early diagnosis of the problem can lead to positive result. Thyroid cancer is eliminated simply, but only through quality treatment and not late stage the development of the disease.

undifferentiated thyroid cancer

Undifferentiated thyroid cancer is a tumor that grows from cells of carcinosarcoma and epidermoid cancer. Often given form is a malignant degeneration of perennial nodular goiter.

It is observed in people aged 60-65 years. It is characterized by fast, aggressive and heavy clinical course. For this type of cancer thyroid significantly increases in size, and quite quickly. This can cause disruption of the mediastinal organs. The tumor gradually grows into closely located tissues, organs and lymph nodes of the neck. In some cases, there is a pseudo-inflammatory form of the disease with elevated temperature, leukocytosis and redness of the skin.

Diagnosis of this type of cancer is based on an examination of the thyroid gland. In addition, there is ultrasound procedure, CT scan, magnetic resonance imaging and biochemical research. Thyroid cancer in this case requires immediate medical attention.

Cancer of the thyroid gland

Thyroid nodule cancer is a malignant neoplasm. It occurs mainly in the gland itself and, depending on the stage of development of the disease, can move to nearby tissues. Then lymph nodes, lungs and even bones are affected.

The tumor looks like a nodule, which over time can grow and bring a lot of inconvenience to a person. There is a hoarseness of voice, difficulty breathing and swallowing food. Over time, the deformation of the thyroid gland will be noticeable.

In the first stages, a small nodule is not noticeable, not visually, nor by sensations. Nothing bothers a person, discomfort appears over time, and at this stage the victim is poisoned to the hospital. With the timely diagnosis of the problem and the appointment quality treatment the problem is fixed quickly. It is important to detect it in time and start fighting the malignant neoplasm. Thyroid cancer is not a sentence, but the tumor can be eliminated only in the early stages.

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

Molecular processes in a tumor

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.

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

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 these studies are included in the new product of the Atlas biomedical holding - the Solo test. With this test, the oncologist obtains information about the molecular profile of the tumor and how it affects the potential efficacy of a wide range of anticancer drugs.

Solo experts are examining up to 450 genes and biomarkers to evaluate how a tumor might respond to more targeted cancer drugs. For some of them, biomarker analysis is dictated by the manufacturer. For others, they use data from clinical trials and recommendations from 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 provides 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 an 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 experimental treatment or inclusion of the patient in clinical trials is required.

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 lung cancer, one strategy is used, for non-small cell lung cancer, 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.

Imagine that you are an architect of Moscow. You are faced with a difficult task - to solve the problem of traffic jams during rush hour by building one bridge. Molecular mechanisms can be compared to the movement of machines, and the bridge is the main drug that should solve the main 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 the molecular processes of malignant tumors, but the current methods of bringing 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.

Molecular disorders differ not only in different patients, but also within the same tumor. Heterogeneity is 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 effects of targeted drugs - sometimes this is the only option for patients who do not respond to standard treatment with 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, several important genetic disorders were found in the tumor:

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:

The BRAF inhibitors (Vemurafenib) may be potentially effective, moreover, the presence of an NRAS mutation may 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 chance of successful treatment with 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 the possible treatment options, starting not only from the clinical parameters of the patient, but also taking into account the molecular characteristics 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.