Labeling index ki 67. Immunohistochemical study (ER, PR, her2neu, ki67, p53, etc.)

Immunohistochemical study in oncology, this is a type of tissue examination using special reagents antigen-antibody principle.

When using reagents that contain antibodies marked with special substances.

An antibody is a protein that binds in tissues with certain molecules - antigens, after which a reaction occurs. If there are no such molecules, then there will be no reaction.

On this basis, one can judge whether an interesting molecule is present in the tissue or not. This is similar to applying colorless glue to a white table. It is practically invisible to the naked eye on a white background, but as soon as fine sand is poured on the table, the glue becomes visible due to the adhering grains of sand.

According to the rules immunohistochemical study for cancer always carried out in a specialized laboratory. For its implementation, tumor tissue obtained as a result of or an operation is necessary.

An immunohistochemical study is performed to determine the presence in tumor cells different points applications, such as the presence of estrogen receptors (ER) and progesterone (PR). Also, immunohistochemistry is performed to determine the Ki-67 index (index of proliferative activity of tumor cells), overexpression of the Her2neu protein, VEGF ( vascular factor growth), p53.

Immunohistochemical study for cancer is performed in order to understand what drugs can be used to treat a malignant tumor, and to which types of drugs it is sensitive.

The most common analysis, determined when immunohistochemical study, this is the presence of receptor sensitivity to hormones in the tumor.

1. ER / PR (Estrogen and progesterone receptors, ER-estrogen receptor, PR-progesterone receptor)

ER and PR- protein receptors on the surface of tumor cells.

The human body constantly produces hormones - estrogen and progesterone. These hormones affect ER and PR receptors, which leads to the stimulation of the growth of tumor cells.

Determination of estrogen and progesterone receptors is one of the most important points that determine the sensitivity of a tumor to hormonal therapy.

Most often, the presence of ER / PR receptors is determined when. Their presence makes it possible, in addition to standard treatment methods, to apply hormone therapy.

With hormone-positive breast cancer, drugs are prescribed: Tamosxifen, Exemestane (Aromasin), Letrozole (Femara), Anastrazole (Arimidex), Hexestrol (Sinestrol) and others. It is also believed that hormone-dependent breast cancer is calm and rare.

The sensitivity of tumor cells to hormone therapy expressed in points from 0 before 10 ... The tumor is considered hormone-dependent, starting from 2 points. and requires addition of hormone therapy to treatment.

2. Her2Neu (from the English Human Epidermal Growth Factor Receptor 2)

Her2Neu is a receptor for epidermal growth factor of cancer cells. This is a gene that acts on the membrane receptors of the cell, and stimulates it to increase its division.

In some tumors (most often), overexpression (increased activity) is present Her2Neu, which causes rapid division of the tumor cell and its increased activity.

The effectiveness of hormonal therapy is also reduced. Because of this, tumors with Her2neu positive status are distinguished by an aggressive course.

There are two methods for determining the presence of the Her2neu gene in a tumor:

The results of the immunohistochemical study are expressed in points:

0-1 means that the tumor is not overexpressed by Her2neu.
3 means that a tumor with overexpression of Her2neu.

2. FISH method (Fluorescence in situ hybridization)

Unlike immunohistochemical studies, in which proteins are determined, with FISH method the presence of genes encoding Her2neu proteins is determined. Depending on their presence, overexpression is determined. Her2neu.

Determination of overexpression of the Her2neu receptor in breast tumors is very important for further treatment.

In modern oncology, overexpression Her2neu is determined to understand if it is necessary to add inhibitors to the treatment Her2neu. For the treatment of tumors with overexpression of the Her2Neu receptor, Trastuzumab (Herceptin), Pertuzumab (Perjeta), Trastuzumab-emtansine (Kadsila), Beyodaim (Trastuzumab + Pertuzumab) are actively and successfully used. These drugs specifically block Her2neu receptors, thereby stopping the active growth of tumor cells and increasing their sensitivity to chemotherapy. The addition of targeted therapy to standard chemotherapy in the treatment of Her2neu-positive tumors significantly increases overall survival and the outcome of anticancer treatments.

3. Ki-67

Ki-67 is a marker of the proliferative activity of a tumor cell. This parameter is estimated as a percentage and shows how many percent of tumor cells are actively dividing.

If Ki-67 less than 15%, the tumor is considered mildly aggressive, with an indicator Ki-67 from 30 to 50%, the tumor is considered aggressive, and with an indicator Ki-67 above 50%, the tumor is highly aggressive.

Also Ki-67 is a predictor of the course of tumor disease and tumor response to chemotherapeutic treatment. Determined by this in a simple way: the lower the indicator Ki-67, the worse the tumor responds to chemotherapy treatment. And vice versa - the higher the indicator Ki-67 the better the tumor will respond to chemotherapy.

4. Protein p53

P53 protein is a transcription factor that regulates the cell cycle. An increase in concentration was found in rapidly dividing cells protein p53 in comparison with cells that divide slowly, which is due to the high risk of their oncogenicity.

P53 protein prevents the formation of malignant tumors in our body. Normal, anti-oncogen p53 is in an inactive state, and when DNA damage occurs in a healthy cell, it is activated.

Function protein p53 consists in removing those cells that are potentially oncogenic. This is called induced apoptosis, the destruction of a potentially dangerous cell.

With an immunohistochemical study, an increased content squirrel p53 is found in 50% of malignant cells, which allows them to divide unhindered and avoid apoptosis (destruction).

Quantity squirrel p53, is determined in addition to the indicator Ki67, in order to understand how aggressive the tumor is and to determine the further course of the disease. If the level squirrel p53 high, which means the tumor is not aggressive and is not prone to metastasis and rapid growth. If, however, the indicator squirrel p53 low, it means that the tumor is aggressive and prone to rapid growth in the surrounding tissues and metastasis.

5. VEGF (Vascular Endothelial Growth Factor)

VEGF Is a signaling protein produced by cells for the active growth of new vessels in the already existing vascular system.

There are several types of VEGF protein, and each acts on a specific VEGFR (Vascular endothelial growth factor receptor). In order to actively divide, the tumor needs nutrition, and this requires the vessels through which this nutrition will flow. It is for this reason that tumor cells contain an increased content of the VEGF protein - in order to short time build vascular networks.

Availability protein VEGF in a tumor speaks of the possibility of using drugs such as Bevacizumab (Avastin), Ramutsirumab (Tsiramza), Aflibercept (Saltrap). They rebuild the vasculature of the tumor, thereby depriving it of nutrition.

6. Determination of the expression of proteins PD-1, PDL-1 and PDL-2

In order to select patients for whom immunotherapy is indicated, the presence of expression of PD-1 and its ligand PDL-1 and PDL-2 is determined, by fluorescence in situ hybridization (FISH)... In the presence of expression of PD-1 and its ligand PDL-1 and PDL-2, the use of immunotherapy with drugs is indicated Pembrolizumab (Keytruda), Nivolumab (Opdivo), Atezolizumab (Tecentrik).

In modern oncology, immunohistochemical research plays a very important role, since with the help of this study, oncologists determine the presence of certain factors in the tumor, which make it possible to competently and adequately draw up further patient treatment and talk about the prognosis of the disease.

Breast cancer is known to be a heterogeneous disease. This means that the same manifestation of the disease can be caused by mutations in different genes or different mutations within the same gene. There are many subtypes of the disease that can be determined through genetic testing or based on methods using immunohistochemical analyzes.

In multigenic tests, proliferation (cell proliferation) has a significant effect on predicting the risk of disease recurrence. In addition to determining the usual histological parameters, the assessment of proliferation is one of the most important factors for making decisions about treatment in breast cancer patients.

A wide range of methods are available to assess the proliferation of tumor cells, in particular, the calculation of mitotic figures in the segments of stained tissues, flow cytometry analysis to determine the proportion of cells in the growth phase of the cell cycle, consideration of the thymidine-marking index of proliferating cells with nuclear antigens.

Ki-67 is a nuclear protein associated with cell proliferation. It was originally identified in the early 1980s in the study of a murine monoclonal antibody directed against the nuclear antigen of Hodgkin's lymphoma. The most common test for Ki-67 antigen is immunohistochemical evaluation.

It was found that the Ki-67 nuclear antigen is expressed at certain phases of the cell cycle. Gene expression is the process of converting information from a gene into final product- RNA or protein. Using immunological staining with monoclonal antibodies Ki-67, it is possible to estimate the proportion of growth in the population of tumor cells and to reveal the prognosis of the course of the disease.

Detection methods

Ki-67 is cancer antigen, which is found in growing, dividing cells, but is absent in the resting phase of cell growth. This characteristic makes Ki-67 a good tumor marker. The analysis is performed on a sample of tumor tissue to help predict the prognosis of tumor growth.

The Ki-67 test is not recommended as mandatory for histological examination of breast tumors. But for aggressive forms of cancer, the doctor may order this test to see the effect of Ki-67 on tumor growth. The analysis is done in conjunction with other studies. Based on the general results of all the analyzes received, a treatment plan is developed.

Positive analysis Ki-67 gives a higher risk of recurrence and worse survival rates in patients with early stages of breast cancer. In everyday clinical work Ki-67 is widely used as an adjuvant factor in decision-making for adjuvant (complementary to surgical and radiation) treatment strategies.

Breast tumors with high Ki-67 scores are made up of cells that divide and grow rapidly. Chemotherapy drugs are highly effective for targeting cells that grow beyond their normal rate. Therefore, tumors with higher Ki-67 levels respond well to chemotherapy. Knowing the Ki-67 level will help the clinician more accurately determine which treatment will work best in a particular case.

Preparation for the analysis of Ki-67 does not require any special conditions. Standard methods of material preparation for histological examination of breast tissue are used.

The assay is performed by staining to measure the percentage of tumor cells that are positive for Ki-67. The more positive cells, the faster they divide and form new cells.

During the analysis, the following methods are used:

immunohistochemical staining of malignant cells of the Ki-67 nuclear antigen is performed. The result is assessed quantitatively and visually using light microscopes;
tumor marker value is calculated as the percentage of positively labeled malignant cells using the anti-human Ki-67 monoclonal antibody MIB1, which is one of the most commonly used antibodies and is considered the "gold standard";
the percentage of Ki-67 is defined as the percentage of positively stained tumor cells among the total number of malignant cells. The result does not depend on the color intensity;
The Ki-67 cut-off point of 15% was determined in accordance with the experience of various pathologists, as well as generally accepted national and international medical recommendations;
the result is calculated taking into account the section of the entire tumor.

The value of the Ki-67 marker in breast cancer

In breast cancer, a Ki-67 result of less than 10% is considered low, 10-20% borderline and 20% high.

Table 1 shows the average Ki-67 values depending on the stage of the disease, tumor size and other parameters.

Table 1 - Average Ki-67 indicators depending on various indicators of the disease

Characteristic Absolute mean value Ki-67 (± differentiation)

Menopause stage
premenopausal	24.1 (± 20.4)
postmenopausal	19.3 (± 17.3)
Tumor size
pT1	17.7 (± 16.3)
pT2	24.1 (± 20.3)
pT3	20.7 (± 15.7)
pT4	20.1 (± 16.6)
Nodal status
N0	18.9 (± 17.9)
N1	21.6 (± 18.6)
N2	23.4 (± 17.9)
N3	24.4 (± 17.0)
Histology
Flowing	21.8 (± 18.7)
Lobular	13.3 (± 10.7)
Other	14.5 (± 17.5)
Profiling
G1	9.7 (± 8.2)
G2	16.2 (± 12.7)
G3	37.4 (± 22.1)
Lymphatic invasion
L 0	18.2 (± 17.3)
L 1	24.3 (± 18.9)
Vascular invasion
V0	19.7 (± 17.9)
V1	27.8 (± 19.9)
Extrogenoreceptors
positive	16.8 (± 14.1)
negative	16.8 (± 14.1)
Progesterone receptor
positive	16.5 (± 13.8)
negative	33.5 (± 24.1)
HER2 / Neu
positive	27.5 (± 19.0)
negative	18.7 (± 17.5)
Receptor status
ER + PR +	16.1 (± 13.2)
ER + PR-	21.9 (± 19.1)
ER- PR +	40.6 (± 27.4)
ER- PR-	41.9 (± 23.8)

The lack of positive dynamics of the tumor marker index in the course of treatment indicates an unfavorable course and prognosis of the disease.

Ki67 serves as an indicator of the prognosis of residual risk in breast cancer patients receiving endocrine therapy with Letrozole or Tamoxifen. Endocrine therapy use is directly correlated with Ki-67 levels. The indicator of a tumor marker after taking medications is considered as an index of residual (residual) disease after treatment.

The dynamics of the change in the index during the course of chemotherapy helps to make a decision about its appropriateness in a particular case. A decrease in Ki-67 levels occurs in any case of neoadjuvant chemotherapy. The absence of a drop in the level of tumor marker is a harbinger of an unfavorable prognosis of the disease.

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Dlyagrudi.ru

ki67 in breast cancer: indicators of norm and pathology

Ki-67 is a specific protein, cancer antigen. This substance is formed only during cell division; it is not produced at rest. This property of the protein allows it to be used as an indicator of carcinoma behavior.

The study is carried out on pieces of mutated tissue taken during a biopsy or surgery. To process the obtained biological material, either an immunohistochemical study or a set of tests to assess genomic activity is used.

The ki67 protein is found in tumor tissues, but it is not detected in the usual histological examination of a biopsy. Currently, the definition of this protein is used mainly in the diagnosis and management of patients with breast carcinomas. But the effectiveness of this study has also been proven in oncopathologies of other organs, therefore, the study for this protein is not considered specific for breast cancer.

Indications for the purpose of the study

The doctor will prescribe an examination for ki67 in the following cases:

suspicion of the aggressive nature of the neoplasm;
control of treatment and identification of the risks of relapse of the disease;
to select a method for the treatment of carcinoma.

At the same time, the hormonal status of the tumor and the likelihood of the appearance of secondary foci in the lymph nodes and other organs are determined.

Norms, indicators and prognosis for breast cancer

The amount of ki67 protein in breast cancer is a factor determining the further management of the patient. Research on the content of this protein is relevant, because it helps to reveal the latent potential of carcinoma cells to divide. Excess normal performance is a criterion when choosing a method of treatment - chemotherapy or irradiation of the affected tissues.

Analysis results and preliminary conclusions:

The rate is less than 10% - the prognosis is 95%. If the result is from 10 to 15%, 85% of patients with breast carcinoma will successfully overcome the five-year mark.
The norm of ki 67 in breast cancer is up to 15%. In this case, the prognosis is favorable. The appointment of a course of treatment with hormonal drugs is shown.
The indicator is 30% - the cells of the neoplasm are actively dividing, but the carcinoma will respond well to chemotherapy. Medicines actively work only if the tumor is in the stage of active growth. Therefore, the higher the ki values of 67, the better the carcinoma cells will respond to treatment.
The result is 90% - the prognosis is unfavorable, the survival rate is practically zero.

It has been experimentally proven that with sensitivity of carcinoma to hormonal drugs and the absence of secondary foci in other organs and lymph nodes, but at high values of ki 67, the probability of a new round of the disease is very high.

In case of relapse, 2 variants of the development of events are possible - the appearance of secondary neoplasms in other organs or the appearance of tumors in the regional lymphatic collectors, in the area of the surgical suture, in the tissues of the mammary glands.

If, with a relapse of the disease, the indicators of the tumor marker are higher than in the primary tumor, then the secondary neoplasm is more aggressive. Therefore, it will require the appointment of a combined treatment, possibly more traumatic than at the first stage of the disease.

Knowing the indicators of ki 67, the oncologist will offer the patient the best treatment option for breast carcinoma.

onkoexpert.ru

Ki67 indications in breast cancer: rate and survival

The ki67 marker and its performance

The Ki 67 marker is an indication of the division rate cancer cells... It is evaluated as a percentage. Ki 67 is predictive. A Ki 67 level of 30% in breast cancer indicates that the tumor is developing rapidly enough to respond to chemotherapy. At levels below 30%, treatment can be carried out with hormone therapy.

Important! The definition of this marker is relevant because it allows one to determine the latent proliferative potential of a malignant tumor. A positive Ki-67 response is predictive of chemotherapy and radiation therapy choices.

According to scientists, at a Ki 67 level below 10%, the survival rate is almost 95%, and at a level above 10%, the overall 5-year survival rate is about 85%. Based on this, we can say that at a Ki level of 67 90% in breast cancer, the survival rate is virtually zero.

Predicting the disease

Since Ki 67 is a marker that determines the process of cell division, there is no expression in the G0 phase. This type of protein was identified in the 80s and scientists had to determine the possibility of its use in medicine and its significance.

After conducting multiple studies, to study this indicator, it can be said that a high Ki 67 level suggests an unfavorable outcome at the stage early development cancer. It is also open to the question of which level can be considered high and which low for a given marker.

Prediction of Ki-67 in breast cancer when prescribing chemotherapy. Detection of this antigen is possible in all phases of the cell cycle, except for G0.

A large number of studies have not provided an accurate answer about the relationship between the choice of therapeutic methods of treatment and the level of Ki-67. Therefore, experts do not yet have a common opinion on this matter.

therapycancer.ru

Ki67 indications for breast cancer

The development of oncological diseases is now quite common. For this reason, it is necessary to periodically undergo examinations by a specialist mammologist. In the field of the study of tumor processes, there are many indicators, according to which, the specialist draws a conclusion about the development of the tumor and its characteristics. One of these is ki67 indications in breast cancer. This indicator indicates the process of active development of a malignant neoplasm.

Research for detection of tumors and markers

Special reagents are required to conduct a study of the patient's tissues. Such a study is called immunohistochemical. During it, reagents are used that contain antibodies labeled with special substances.

This diagnostic test is based on an antibody-antigen response. When an antigen is introduced into the body, it begins to produce antibodies, which will subsequently help it overcome the disease.

During the immunohistochemical study, sera are used that contain antibodies. After introducing them into the body, a certain reaction occurs, by which it is possible to judge the presence of a malignant formation.

When conducting a large number of studies, scientists have come to the conclusion that in cancers there are a number of factors associated with the prognosis of the disease and the choice of therapy. These include:

ER (Estrogen Receptor) is a marker that predicts clinical outcome and promotes the choice of antihormone therapy.
PR (Progesteron Receptor) is a progesterone receptor. The value is the same as ER, but more stable.
pS2 is an estrogen-induced protein that indicates the sensitivity of the formation to antihormone therapy.
Bcl-2 - shows the degree of apoptosis block. Taken into account when choosing an effective cancer chemotherapy.
c-erbB-2 (Her-2 / Neu) - a marker indicating the frequency of metastasis.
P53 - shows the malignant potential of the tumor process. Influences the choice of chemotherapy method.
Ki-67 is an indicator indicating the malignancy of the formation. Indicates the proliferative activity of tumor tissues. The norm for ki 67 in breast cancer is up to 15%. It indicates a favorable prognostic sign.

Important! All of the above factors are contained in the neoplasm, but may not be detected by a simple histological examination.

ID: 2015-06-1276-A-5298

Original article (free structure)

Maslyakova G.N., Ponukalin A.N., Tsmokalyuk E.N.

State Budgetary Educational Institution of Higher Professional Education Saratov State Medical University named after IN AND. Razumovsky Ministry of Health of Russia

Summary

Keywords

Crayfish Bladder, tumor marker

Article

Introduction. Bladder cancer (Bladder cancer) is the most common cancer of the urinary system. In 2011 in Russian Federation 13784 cases of bladder cancer were diagnosed, while the increase in this disease over the past 10 years was 15.26%. Mortality from bladder cancer in the first year after diagnosis is 19.5%. , therefore, the diagnosis and treatment of patients with bladder cancer (BC) is one of the urgent problems of urology.

According to the clinical course, muscle non-invasive (Tis, Ta, T1), muscle invasive (T2-T4) and metastatic bladder cancer are distinguished. Superficial and muscle-invasive tumors of the urinary bladder in 90-95% are represented by urothelial carcinoma, but differ in a number of molecular genetic, morphological and immunohistochemical signs.

Muscle-invasive bladder cancer (MIBC) is a potentially fatal disease, as patients die within 24 months without treatment. In 50% of patients with MIBC, radically operated on, relapse develops, which is associated with the morphological stage of development of the primary tumor and the state of regional lymph nodes. The most common localization of metastases of urothelial cancer is regional The lymph nodes(78%), liver (38%), lungs (36%), bones (27%), adrenal glands (21%) and intestines (13%), less often (1% - 8%) metastases develop in the heart, brain , kidneys, spleen, pancreas, meninges, uterus, ovaries, prostate and testes. It should be noted that during the first year of the development of the disease, the MIBC group will be replenished by another 15-30% of patients with superficial bladder cancer, who develop a tumor recurrence with muscle invasion.

In Russia, in 2011, among the newly diagnosed patients registered, 45.8% of cases were diagnosed with I - II, 37.6% - III and 16.6% - IV stage of bladder cancer. In most cases, organ-preserving treatment can be carried out only in the T1-T2 stages of the disease. In T3-T4 stages, cystectomy or palliative treatment is performed. Correctly chosen treatment tactics is a fundamental point for the patient's future life. So, after removal of the bladder, the quality of life of patients is significantly reduced, and they are established 1 - 2 groups of disability. At the same time, unreasonably long conservative treatment can lead to the death of patients.

Today, the influence of more than 30 prognostic factors on the course of bladder cancer has been studied and it has been established that only the stage of the tumor and the lesion of regional lymph nodes with metastases are independent factors influencing overall survival (EAU-2009).

The results of bladder cancer treatment are directly related to the stage of the disease. Thus, the five-year survival rate at stage T1 is 90-80%, at T2 - 70-63%, at T3 - 53-32%, and at T4 - 28-5%. At the same time, the frequency of errors in the preoperative period in determining the stage of bladder cancer reaches 73%. Even a morphological study can give an error in determining the depth of tumor invasion of 20-50%.

Preoperative diagnosis of metastases in regional lymph nodes is unsatisfactory. CT scan allows to identify only 35-40% of metastatically affected lymph nodes, and fine-needle aspiration biopsy only slightly improves the diagnosis, since its sensitivity does not exceed 60%, and this procedure is performed only with enlarged lymph nodes.

Regional lymph node involvement in invasive bladder cancer is an extremely poor prognostic factor. It has been shown that after cystectomy, 50% of patients die within 12 months with regional metastases to the lymph nodes and 87% within 24 months; the five-year survival rate is less than 7%. Extended lymph node dissection and systemic chemotherapy significantly improve the survival rate of these patients, therefore, preoperative diagnosis of metastasis to the lymph nodes can significantly affect the choice of treatment tactics in this group of patients.

In addition to the depth of tumor invasion and metastatic lesions of the lymph nodes, the prognosis of MIBC is influenced by the degree of malignancy of transitional cell carcinoma. However, in muscle-invasive bladder cancer, as a rule, there are no urothelial tumors with low malignant potential or highly differentiated (G1) carcinomas. In all cases, ureteric cancer of a high degree of malignancy is determined (G2 or G3 according to the WHO classification, 1973). In this regard, further differentiation of MIBC does not carry any prognostic information.

Errors in disease staging based on clinical and routine histological examinations stimulated interest in immunohistochemistry, which makes it possible to predict the nature of the course of the disease in each specific patient based on the study of molecular markers. The most studied genes involved in the regulation of the cell cycle are tumor suppressor genes p53 and p21. The p53 gene regulates the cell cycle and apoptosis, and controls the integrity of the genome. Activating in response to a variety of adverse effects, p53 simultaneously activates the bax gene and suppresses the bcl-2 gene responsible for apoptosis at the transcriptional level. With the development of neoplasias, including transitional cell carcinomas, somatic mutations of the p53 gene are often noted. P53 mutations in urothelium carcinomas are detected in 29-53% of cases, however, the authors' opinions on the prognostic value of this indicator are contradictory.

Cell proliferative activity can be assessed using various techniques. These include counting the number of mitoses of Ki-67-positive cells, detection of proliferating cell nucleus antigen (PCNA), P63. Antibodies to Ki-67 are used to assess the proliferative activity of many neoplasms. Its predictive value has been proven in superficial bladder cancer. The Ki-67 study allows predicting the rate of tumor growth and the tumor's response to chemotherapy. Ki-67 is also an independent predictor of recurrence in high-risk patients with superficial bladder cancer [ 6]. The data on the effect of Ki-67 on the prognosis in patients with MIBC are contradictory and insufficiently studied.

Purpose of the study: to conduct a comparative assessment of the effectiveness of various immunohistochemical markers in determining the stage and prognosis of muscle-invasive bladder cancer.

Material For the study, we used the surgical material of 80 patients with neoplasms of the bladder who were treated at the Research Institute of Clinical and Fundamental Uronephrology of the SSMU and in the control group (Table 1).

Surgical and biopsy materials were fixed in a 10% solution of neutral formalin and embedded in paraffin. Sections with a thickness of 5-7 μm, stained with hematoxylin and eosin, were subjected to an overview morphological analysis, in which the stage of cancer was determined in accordance with the TNM classification, and the degree of differentiation of tumor cells was assessed in accordance with the WHO recommendations, 2004. The study of preparations was carried out using binocular microscope "Micros MC100" at 600x magnification (objective - 40x, binocular attachment - 1.5x, eyepieces - 10x). The material was divided into groups based on the clinical stage of the cancer. A total of 94 samples were examined.

Investigated 3120 sections, stained with hematoxylin and eosin, and for 12 different markers.

For immunohistochemical studies, 12 commercial monoclonal antibodies were used, divided into groups according to their functional significance:

markers of proliferative activity - Ki67, PCNA, p63,
tumor suppressor - p53,
apoptosis marker Bcl2,
epidermal growth factor receptor - EGFR,
cytokeratin profile - TsK7, TsK8, TsK10 / 13, TsK17, TsK18, TsK19.

Immunohistochemical staining technique

Immunohistochemical reactions were performed on serial paraffin sections (5 μm) using the streptavidin-biotin method. The LSAB2 System, HRP (K0675), Dako was used as a detection system, and diaminobenzidine (Dako) was used as a chromogen.

The intensity of reactions localized in the cytoplasm (cytokeratins 7, 8, 13, 17, 18, 19) and on cell membranes (EGFR) was assessed semi-quantitatively on a point scale from 0 to 3 using a microsMC100 light binocular microscope, taking into account the severity of the reaction and its localization: 0 - no reaction, 1 - weak reaction, 2 - moderate reaction, 3 - strong reaction.

The results of reactions with antigens having nuclear localization (PCNA, Ki67, p53, p63, bcl2) were evaluated by counting the number of stained nuclei per 100 nuclei in 3 fields of view, expressing the results obtained as a percentage.

The results of reactions with antigens with nuclear localization (PCNA, Ki67, p53, p63, bcl2) were assessed using the histochemicalscore system. The counting system includes the intensity of immunohistochemical staining on a 3-point scale and the proportion (%) of stained cells and is the sum of the products of percent reflecting the proportion of cells with different intensity of staining per point corresponding to the intensity of the reaction. Color intensity 0 - no coloration, 1 - weak coloration, 2 - moderate coloration, 3 - strong coloration.

The calculation formula is as follows: histochemicalscore = ∑ P (i) x i,

where i is the intensity of staining, expressed in points from 0 to 3. P (i) is the percentage of cells stained with different intensities. The maximum value of the histo count should be 300.

Statistical analysis was performed using the SSPS 13.0 for Windows statistical processing software package.

Results. In an immunohistochemical study of 12 tumor markers, it was found that to establish the stage of bladder cancer and prognosis of the disease, it is rational to use only 4: markers of proliferative activity Ki67, p63, tumor growth suppressor - p53 and epidermal growth factor receptor - EGFR. Table 2 provides a comparative assessment of the effectiveness of immunohistochemical markers for determining the stage of bladder cancer.

Table 2 shows that all these markers do not give positive expression in the comparison group, which can be used in differential diagnosis.

Bladder cancer and other neoplasias. In addition, the percentage of expressing cells of these markers allows one to judge the degree of bladder cancer invasion, which is important points to determine the stage of the disease, and therefore the prognosis. That is why Ki 67 can be used very promisingly for differential diagnosis between T2 and T3-T4, which is very important, since the exit of the tumor outside the organ indicates a poor prognosis. It can be used as a prognostic one, capable of influencing the choice of treatment tactics in patients with MIBC.

When analyzing the expression indicators of markers in each of the stages of bladder cancer, presented in Table 3, it was found that the Ki 67 marker showed 100% expression in patients with bladder cancer stages T3 and T4, while at the T2 stage its expression was only 56. 5%, which is a significant difference.

In order to study the prognostic value, we studied the long-term results of treatment of 27 patients with bladder cancer, whose fate was traced over 5 years. In all patients, during immunohistochemical examination of tumor tissue, Ki 67 gave a positive expression.

Of the 27 patients with bladder cancer, 11 patients underwent organ-preserving, complex treatment, including transurethral electroresection of the bladder wall together with the tumor and systemic chemotherapy according to the M-VAC scheme (methotrexate, vinblastine, doxorubicin, cisplatin). Cystectomy was performed in 13 patients, and 6 patients were recognized as inoperable; they received only symptomatic therapy.

Table 4 shows that of 27 patients with bladder cancer, 16 (59.2%) died. Of these, 10 (62.5%) - in the first year. Of the 10 who died in the first year, 9 (90%) patients had a Ki 67 expression ≥ 30%. All 9 patients had the stage of the disease Tzb-T4N0-1M0-1.

At the same time, out of 11 patients with bladder cancer who lived for more than 5 years, in 70% Ki 67 expression was< 30%. Стадия заболевания у выживших больных, была Т1N0M0- 4; Т2N0M0- 6; Т3N0M0-1.

Thus, regardless of the method of treatment, with a reliability of 81.2% Ki67 can predict an unfavorable outcome of the disease within 24 months.

With muscle invasive bladder cancer T2N0M0-T3-4N0-1M0-1 (22 patients), 14 (62%) died in the first 24 months. Ki 67 expression in these patients ranged from 30 to 80%.

During organ-preserving treatment of patients at stage T1-T2 (11 patients), 5 (45.4%) patients died in the first two years, in whom Ki 67 expression was ≥30%. After cystectomy (n = 13), 8 died (61.5 %), 7 (87.5%) of them had Kj 67> 30%. Of 11 who lived for 5 years or more, only in two cases Kj 67 was> 30% (34 and 44), the rest - 9 (82%) had Ki67 less than 30%.

Conclusion. A comparative assessment of the effectiveness of various immunohistochemical markers in staging and prognosis of muscle-invasive bladder cancer showed that the most effective marker is a marker of proliferative activity - Ki 67.

Ki 67> 30%, regardless of the method of treatment, with a reliability of 81, 2%, a relapse of the disease is possible and fatal outcome within 24 months. At the same time, at Ki67< 30% пятилетняя выживаемость составляет 70%.

Thus, the marker of proliferative activity - Ki 67 can be an auxiliary prognostic factor when choosing the volume surgical treatment(organ-preserving surgery or cystectomy).

Literature

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Tables

Table 1 Characteristics of the studied patients

Indicator	Number of patients

The total number of RMP
Average age, years


Stage of the disease
T0N0M0 - comparison group

Prognostic and predictive value of Ki-67 in triple-negative breast cancer
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5058740/

This study was to investigate the prognostic role of Ki-67 in the further classification of triple negative breast cancer (TNBC) and to test whether high Ki67 expression could predict a benefit from carboplatin. From January 2004 to December 2012, 363 patients working for TNBC were identified through the institutional clinical database. After a median follow-up of 34 months (5.2-120.0 months), 62 patients (17.1%) had relapses, and 33 patients (9.1%) died of breast cancer. On univariate analysis, a high Ki-67 score as well as larger tumor size and lymph node involvement were associated with shorter disease-free survival (DFS) and overall survival (OS). In multivariate analysis, a high Ki-67 is an independent risk factor for DFS (hazard ratio, RR: 2.835, 95% confidence interval, 95% CI: 1.586-5.068, P

Triple negative breast cancer (TNBC) is a subgroup of breast cancers lacking estrogen receptor (ER) receptor and progesterone receptor (PR) expression, and amplification of human epithelial growth factor receptor 2 (HER2). From a histological point of view, TNBC is a common immunohistochemical (IHC) status for a number of tumors with heterogeneous clinical manifestations... Recent research has identified six TNBC subtypes that exhibit unique profiles. Given the biodiversity in TNBC, it is necessary to identify subtypes with a better prognosis, which can be used for intensive adjuvant therapy, as well as for those in need of more aggressive shelves.

Tumor activity, an important cellular function, is closely related to the behavior of tumors in breast cancer. Various methods have been developed to assess the rate of proliferation, including mitotic counting, assessment of the cell fraction in the S-phase of the cell cycle, and determination of IHC associated with proliferation of antigens. Ki-67 is one of the most widely used IHC proliferation antigens and has been confirmed as an independent prognostic and prognostic factor early cancer breast. The Ki-67 value is an important parameter when subclassing translucent tumors into good predictive subgroup Luminal A and subgroup Luminal B with poor prognosis according to the International Expert Consensus in St. Gallen. Although the predictive value of the Ki-67 level in TNBC is unclear.

TNBC treatment has been challenging. TNBC is generally considered to exhibit more aggressive clinical behavior and a higher risk of tumor recurrence and mortality than its nontrippentive counterparts. In addition, the lack of well-defined molecular targets makes it worse, and cytotoxic agents are the only treatment strategy. Platinum salt is one of the new agents in the treatment of TNBC. Many researchers have investigated the role of cisplatin and carboplatin in the treatment of TNBC in neoadjuvant and metastatic settings, while early-stage carboplatin supplementation is still lacking conclusive evidence. One important question is whether all TNBC patients should be exposed to carboplatin, with its toxic effects and high discontinuation rates; or all TNBC patients will get similar results from the platinum salt.

The aim of this study was to investigate the role of Ki-67 in further categorizing TNBC into subtypes with different prognosis and whether the expression level of Ki-67 could predict the advantage of TNBC over carboplatin in the setting of adjuvant therapy.

The study included 363 patients with TNBC. The median age was 55 years (range 23-86). Two hundred seventy-five patients (75.8%) underwent mastectomy; 324 (89.3%) patients underwent chemotherapy. Chemotherapy regimens included EC (Epirubicin 100 mg / m2 IV day 1, Cyclophosphamide 600 mg / m2 IV day 1, cyclically every 21 days for 4 cycles), EC-T (Epirubicin 100 mg / m2 IV day 1, Cyclophosphamide 600 mg / m2 IV day 1, cyclically every 21 days for 4 cycles, followed by docetaxel 100 mg / m2 IV on day 1, cyclically every 21 days for 4 cycles), TEC (docetaxel 75 mg / m2 IV day 1, epirubicin 75 mg / m2 IV day 1, cyclophosphamide 600 mg / m2 IV day 1, cyclically every 21 days for 6 cycles), TC (docetaxel 75 mg / m2 IV day 1, cyclophosphamide 600 mg / m2 IV day 1, cyclically every 21 days for 4 cycles), EC-wPCb (epirubicin 100 mg / m2 IV day 1, cyclophosphamide 600 mg / m2 IV day 1, cyclic every 21 days for 4 cycles followed by paclitaxel 75 mg / m2 IV day 1, carboplatin area 2 0 under the curve, cyclic weekly for 12 cycles) and wPCb (paclitaxel 75 mg / m2 IV day 1, area of carboplatin 2 0 under the curve, cyclically to every week for 12 cycles). Both anthracycline and taxane regimens were used in 177 patients (48.8%) and 58 (16.0%) patients received the platinum-containing regimen. One hundred seventy one patients (47.1%) received radiation therapy.

Of 363 triple negative tumors, 317 (87.3%) were histologically identified as invasive ductal carcinomas, 17 (4.7%) as apocrine carcinomas, 9 (2.5%) as medullary carcinomas, 7 (1.9% ) as metaplastic carcinomas, 2 (0.6%%) as invasive lobular carcinomas, 3 (0.8%) as neuroendocrine carcinoma, 3 (0.8%) as invasive papillary carcinoma, 2 (0.6% ) as adenocystic carcinoma, 1 (0.3%) as myoepithelial carcinoma, 1 (0.3%), tumors of malignant phyllodes, and 1 (0.3%) as mucinous carcinoma.

The average expression level of Ki-67 was 40%. With 40% as a Ki-67 cutoff index, 196 patients (54.0%) were classified as low Ki-67 expression and 167 patients (46.0%) as high expression. Patient characteristics combined with Ki-67 expression are described in Table 1. High TNBC expression of Ki-67 was more prevalent in IDC than in non-IDC (p

After a median follow-up period of 34.0 months (5.2-120.0 months), 62 first events (17.1%) were observed, 24 (12.2%) in the low Ki-67 group and 38 (22 , 8%) in high-level expression (X2 = 11.372, p = 0.001). The first 62 events included 53 relapses with 30 locoregional relapses and 44 distant metastases and 9 other events with 6 contralateral breast cancers. All local recurrent lesions and contralateral breast lesions were proven using either a fine aspiration needle or a needle core biopsy. Thirty-three patients (9.1%) died during follow-up, and patients with high Ki-67 expression had a higher mortality rate (13.2% versus 5.6%, X2 = 13.368, p

(A) 3-year DFS was significantly better in the low Ki-67 group than in the high Ki-67 group (90.8% versus 78.4% log rank p = 0.001) and (B). Poor 3-year OS was also found in the high Ki-67 group (98.0% versus 90.4% log p = 0.000).

On univariate analysis, only high Ki-67 expression, larger tumor size, and lymph node positivity were associated with shorter DFS and OS, while other clinical pathological characteristics such as age, histological subtype, and tumor level did not influence prognosis. In multivariate analysis, Ki-67 is an independent predictive factor for DFS (hazard ratio, RR: 2.835, 95% confidence interval, 95% CI: 1.586-5.068, P

When analyzing 3-year DFS for Ki-67 distribution, STEPP analysis showed a possible beneficial effect of carboplatin in patients with highly proliferative tumors (Ki-67> 40%) (Figure 2A). Figure 2B and Figure 2C show the observed proportion of DFS, respectively, for patients with "high" and "low" Ki-67, stratified by treatment group. In patients with low Ki-67 breast cancer rates, carboplatin use adds little, if any, to 3-year DFS (HR: 0.608, 95% CI: 0.176-2.103). However, patients in the high Ki-67 group appear to have remarkable better 3-year DFS scores with carboplatin (HR: 0.478, 95% CI: 0.279-0.819). The interaction between Ki-67 and treatment was not statistically significant (p = 0.346).

(A) Subpopulation Effect Plan (STEPP) 3-year disease-free survival. (B) Disease-free survival in the high Ki-67 group (Ki-67> 40%) according to carboplatin treatment. (C) Disease-free survival in the low Ki-67 group (Ki-67 ≤ 40%) according to carboplatin treatment. Single p-values of the rank rating criterion and hazard ratios (HR) (carboplatin versus non-carboplatin) have been reported.

TNBC is a group of tumors with a poor prognosis due to aggressive tumor biology and lack of targeted agents. A better understanding of its biological behavior is essential to improve outcomes for TNBC patients. In this study, we retrospectively reviewed 363 patients to analyze the correlation of Ki-67 expression level with clinical pathological characteristics and prognosis of TNBC. All patients coming from the same center ensured that the quality of the pathological biomarkers test and the treatment decision were largely stable.

The use of Ki-67 as a predictive marker for breast cancer has been extensively researched, but few studies have examined it in the triple negative subgroup. Some researchers have investigated the predictive value of K-67 across the entire breast cancer cohort, but the incidence in TNBC and Her2 + was quite small and this may limit Ki-67's ability to identify clinically distinct subclasses. A study in a Korean group showed that high Ki-67 protection (≥ 10%) was significantly associated with poor relapse-free survival and overall TNBC survival, despite a higher pathological complete response rate (pCR), Munzone et al. ... reported that the Ki-67 labeling index was associated with different prognosis subgroups in negative-negative TNBC with a cutoff of 35%. Consistent with these results, our study showed that high Ki-67 expression (> 40%) significantly correlated with a worse prognosis in TNBC patients, regardless of tumor size and lymph node status.

The IHC Ki-67 measurement is an inexpensive method suitable for widespread use in clinical practice... International Ki-67 in the Breast Cancer Working Group has proposed recommendations for the analysis, reporting and use of this potentially important marker based on the available data. This study strictly followed the guidelines that ensured its value. In another retrospective study from our center, high Ki-67 expression correlated with early recurrence in Luminal B / Her2 negative breast cancer with a cutoff of 30%. This may reflect the stability and reliability of the Ki-67 test at one center.

The cut-off points for the Ki-67 index used in clinical trials and studies varied widely, ranging from 10% to 61%. Since the baseline Ki-67 values for triple-negative and HER2-positive tumors are much higher than for translucent tumors, the choice of a Ki-67 cutoff may be more obvious if considered in each subgroup respectively. In this study, we chose the median Ki-67 as the cutoff value, which has been widely used in other studies. Due to inter-observer and inter-laboratory variability, much more evidence is required to establish an appropriate Ki-67 cut-off point for TNBC.

The observation time of our study is relatively short. However, despite a mean 34-month follow-up, Ki-67 expression level shows its independent predictive value in TNBC. This may be due to early TNBC replication during the first three years of follow-up. In this study, 94.3% (50/53) relapse occurred in the first three years after surgery.

The key to using the platinum regimen would be choosing the right patient. There is a well-documented association between TNBC and BRCA germline mutations. Neoadjuvant studies have shown high rates pCR among BRCA1-associated breast cancers treated with cisplatin. However, the usual clinical application of the BRCA gene tests still has some difficulties. Although the Ki-67 test is more convenient and economical and can be a good alternative.

In the GeparSixto clinical trial, the addition of neoadjuvant carboplatin to the taxane-anthracycline regimen significantly increased the pCR fraction of TNBC patients. Subgroup analysis showed that the odds radio benefit favored carboplatin in the high Ki-67 group (> 20%) of 1.40 (95% CI: 0.968-2.02), which was higher than in the low Ki-67 group (OR: 1.09, 95% CI: 0.490 - 2.4). Likewise, our study showed a possible beneficial effect of carboplatin in patients with highly proliferative tumors (Ki-67> 40%) in an adjuvant setting. But this trend remains to be tested in future prospective, well-balanced studies with a large sample size.

One potential limitation of this study may be due to the heterogeneity of adjuvant therapy, as not all patients received the same regimen. However, we can estimate that among patients receiving chemotherapy, the majority (72.5%) received an anthracycline-containing regimen, and more than half of them (55.6%) received both an anthracycline-containing and a taxane-containing regimen.

In conclusion, TNBC appears to be a heterogeneous group with varying clinical outcomes. TNBC with a high potential for spread should be monitored most often for three years and may be a candidate for additional postoperative therapies with different mechanisms, such as carboplatin.

We have compiled information on consecutive breast cancer patients who underwent surgery on chest from January 2004 to December 2012 at Shanghai Ruijin Hospital, through the breast cancer database at the Comprehensive Breast Health Center. The protocol was approved by the Ethics Committees of Shanghai Ruijin Hospital, and all patients provided their written informed consent to a participant in this study before clinical and pathological data were collected.

A total of 363 patients with TNBC were retrospectively studied. Baseline data including age, tumor characteristics (tumor size, lymph node metastases, distant metastases, tumor level, pathologic stage, ER / PR / HER2 expression, and histologic type), and surgical information. Treatment decisions for each patient were made in a daily interdisciplinary meeting attended by surgeons, medical oncologists, radiation oncologists and pathologists.

The tumors were classified histologically according to the World Health Organization tumor classification. Histological grade was scored according to the Elston and Ellis scoring system. Staining for IHC ER, PR, HER2 and Ki-67 was performed routinely using the Ventana BenchMark XT system (Ventana Medical Systems, Tucson, AZ). IHC staining was performed on 4 μm sections of tissue sections with fixed paraffin (FFPE) with primary antibodies against ER (SP1, 1: 100, Dako, Denmark), PR (PgR 636, 1: 100, Dako, Denmark), HER2 (4B5, Roche, Switzerland), K-67 (MIB-1, 1: 100, Dako, Denmark). IHC HER2 expression was assessed as follows: 0 (no or weak membrane staining), 1+ (weak membrane staining in> 10% of tumor cells, incomplete membrane staining), 2+ (weak or moderate membrane staining in> 10% of tumor cells) and 3+ (uniform, intense membrane staining> 30% of invasive tumor cells). Fluorescence in situ hybridization (FISH) test for amplification of the HER2 gene was usually ordered when HER2 was IHC 2+. FISH was performed using the PathVysion HER-2 DNA FISH Kit (Vysis Inc, Downers Grove, IL) according to the manufacturer's instructions.

All histological and IHC tumor slides were evaluated by two pathologists. Histological evaluations and all biological features were assessed on the basis of invasive components.

The cutoff for ER positivity and PR positivity was 1% nuclear-stained tumor positive. HER2 was positive for either IHC enhancement of HER2 3+ or FISH (HER2 to CEP17 ratio ≥ 2.0 or HER2 mean copy number ≥ 6.0 signals / cell). The Ki-67 index was expressed as the percentage of positive nuclear staining cells among at least 1000 invasive cells in the recruited area. The intensity of the color did not matter.

Breast cancer recurrence was defined as the first proven invasive local / contralateral breast, regional or distant recurrence anywhere. Disease-free survival (DFS) was defined as the interval from the date of primary surgery to the first recurrence, the second primary invasive breast cancer, or death attributable to any cause. Overall survival (OS) was defined as the time from the date of primary surgery to the time of death, regardless of breast cancer associated or not.

All p values less than 0.05 were considered statistically significant. All statistical tests were two-sided, with a 95% confidence interval. Chi-Square test was used for categorized variables (Fisher's exact test when Chi-square test was not available). Survival curves were constructed using the Kaplan-Meier method. The logarithmic ranking test was used to determine associations between individual variables and survival, to model logistic regression to study the relationship of tumor features with Ki-67 expression levels, and Cox proportional hazards regression analysis to identify significant predictors in TNBC. Statistical analyzes were performed in SPSS version 17.0 (SPSS, Inc., Chicago, IL).

The interaction between carboplatin use and K-67 was graphically assessed using the Pattern of Pattern of Surpopulation (STEPP) methodology. In short, STEPP uses a sliding window approach to identify multiple overlapping patient subpopulations according to a continuous covariate, such as Ki-67, and calculates the net treatment effects estimated in each subpopulation. STEPP analysis was carried out with the R software (http://cran.r-project.org/) with the "STEPP" package.

This study was funded by the National Science Foundation of China 81572581. The funders played no role in the design of the research, the collection and analysis of data, or the decision to publish or prepare the manuscript. This investigation was presented as a poster at EMSO Asia 2015 Congress, December 18-21, 2015, Singapore.

Or the mammary gland is a terrible and for some reason deadly disease, which ranks second in terms of the number of cases among both sexes.

Physiologically, cancer is most common in women, with the mortality rate in the last stages reaching 90%.

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Definition

The main difficulty in the treatment of cancer lies in its "invisibility": in the first stages - up to 2 - it is almost impossible to detect, since the development of the disease occurs without any special symptoms.

A painful condition is observed, sometimes you can feel a strange seal in the chest or specific discharge appears from the nipple, a temperature may also rise or weakness may be felt, but few of the sick pay attention to these symptoms.

When it becomes impossible not to notice the tumor at stages 2-3-4, it becomes more difficult to cure it, and the percentage of recovered also decreases: at the third stage, the percentage is 75-90%, at the fourth stage it drops to 10%.

It's important to know: to detect cancer in the early stages, it is necessary to regularly be examined by a mammologist, especially for women at risk.

Regular examination of the breast and its x-ray will help to notice the lump in time and carry out additional tests. If in doubt, the doctor should conduct an examination for tumor markers.

These are special substances that the body produces in an attempt to defend itself against cancer. Their small amount is always present in the body, and exceeding the norm in most cases indicates the presence of cancer. This helps to determine the presence malignant tumor start treatment earlier and immediately.

Tumor marker

Several tumor markers have been identified to determine breast cancer, among which the ki-67 marker is of particular benefit.

This substance can appear when different options tumors, but most often it manifests itself precisely in breast and brain cancer. Ki-67 appears in cells during division but is not observed at rest.

Since one of the main differences between cancer is its fast growth and cell division, it is quite easy to detect the ki-67 marker. The ki-67 index is the ratio of fissile into this moment cells to all cancer cells.

In this case, the substance helps not only to detect a tumor, but also to make a small prognosis: if the index is below 10%, the survival rate is up to 95%, if this number is exceeded, the survival rate decreases to 80%.

Note: the mammologist should not be limited only to the definition of ki-67: for a more accurate prognosis and determination of the nature of the cancer, additional studies on other tumor markers are necessary.

At the same time, tumors with an increased index respond better to aggressive and strong treatment, in which the impact occurs on dividing cells, which increases the effectiveness of treatment. On the other hand, increased levels of ki-67 can lead to the formation of metastases and relapses.

To obtain a substance, the doctor takes a sample from a suspicious tumor and examines it. For a more accurate determination, the sample is taken 2-3 times with an interval of several days. If the level rises, this indicates the development of cancer cells.

After that, the mammologist can begin to select the appropriate treatment. The ki-67 tumor markers are extremely useful in helping doctors identify and fight breast cancer in the early stages. The substance itself also indicates some features of the development of a malignant tumor, which is taken into account by mammologists for the selection of treatment.

The whole truth about breast cancer treatment in the following video: