Вплив іонізуючого випромінювання на розвиток раку молочної залози

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Державна установа «Національний науковий центр радіаційної медицини Національної академії медичних наук України», м. Київ

ДНП «Національний інститут раку» МОЗ України, м. Київ,

Інститут клінічної радіології ННЦРМ, м. Київ, Україна

Вплив іонізуючого випромінювання на розвиток раку молочної залози

Базика Димитрій Анатолійович

доктор медичних наук, професор, академік НАМН України

генеральний директор ННЦРМ, м. Київ, Україна

Литвиненко Олександр Олександрович

доктор медичних наук, професор

завідувач відділу радіоіндукованих онкологічних захворювань

Литвиненко Олександр Олександрович

доктор філософії

Анотація

радіоіндукований пухлина молочний залоза

Рак молочної залози (РМЗ) є однією з актуальних проблем охорони здоров'я, що обумовлена постійною тенденцією до зростання. Одним із факторів ризику розвитку РМЗ є іонізуюче випромінювання (ІВ). Численні епідеміологічні та експериментальні дослідження показали високу чутливість молочної залози (МЗ) до цього чинника. Розгляд моделей абсолютного та відносного ризиків виникнення радіоіндукованих пухлин МЗ в опромінених осіб показав значущість таких факторів, як вік у момент опромінення, кратність, частота опромінення, рівень дози та супутні непухлинні захворювання молочної і щитоподібної залози (ЩЗ). Надлишкові радіаційно зумовлені випадки раку МЗ виявлені серед опромінених жінок після атомного бомбардування Хіросіми і Нагасакі. Детально представлені епідеміологічні особливості розвитку РМЗ під дією ІВ, що є одним із факторів зовнішнього середовища, який бере участь у формуванні сучасної канцерогенної ситуації. У зв'язку зі значною чутливістю МЗ до канцерогенної дії ІВ, ця форма новоутворень привертає особливу увагу після Чорнобильської аварії. Дія малих доз опромінення після Чорнобильської катастрофи призвела до хвилеподібних змін захворюваності на РМЗ в певні періоди років, а радіаційно-індукована захворюваність на дану патологію може відбуватися у вигляді спонтанної.

Ключові слова: рак молочної залози, радіаційний ризик, іонізуюче випромінювання, забруднена радіонуклідами територія, радіаційна дія, канцерогенний ризик, радіочутливість.

Dymytriy A. Bazyka - Doctor of Medical Sciences, Professor, Academician of NAMS of Ukraine, General Director of NRCRM, Kyiv, Ukraine

Oleksandr O. Lytvynenko - Doctor of Medical Sciences, Professor, Head of the Department of Radio-Induced Cancer Diseases, Clinical Radiology Institute of the NRCRM, Kyiv, Ukraine

Oleksandr O. Lytvynenko - Doctor of Philosophy, National Institute of Cancer of the Ministry of Health of Ukraine, Kyiv, Ukraine

State Institution «National Research Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine», Kyiv

Nonprofit Organization National Cancer Institute of Ministry of Health of Ukraine, Kyiv

Influence of ionizing radiation on the development of breast cancer

Abstract

Breast cancer (BC) is one of the urgent problems of health care, which is due to a constant trend of growth. One of the risk factors for the development of breast cancer is ionizing radiation (IR). Numerous epidemiological and experimental studies have shown the high sensitivity of the mammary gland (MG) to this factor. Consideration of models of absolute and relative risks of the occurrence of radio-induced tumors of the MG in irradiated persons showed the importance of such factors as age at the time of irradiation, multiplicity. frequency of exposure, dose level and concomitant non-neoplastic diseases of the mammary and thyroid gland (TG). Excess radiation-induced cases of cervical cancer were found among irradiated women after the atomic bombings of Hiroshima and Nagasaki. Epidemiological features of the development of breast cancer under the influence of IV are presented in detail, which is one of the environmental factors involved in the formation of the modern carcinogenic situation. In connection with the significant sensitivity of the MG to the carcinogenic effect of IR, this form of neoplasms attracted special attention after the Chornobyl accident. The effect of small doses of radiation after the Chornobyl disaster led to a wave-like change in the incidence of breast cancer in certain periods of the year, and the radiation-induced incidence of this pathology can occur spontaneously.

Key words: breast cancer, radiation risk, ionizing radiation, territory contaminated with radionuclides, radiation effect, carcinogenic risk, radiosensitivity.

Breast cancer (BC) is the world's leading oncological disease in prevalence among the female population and accounts for about 25 % of all oncological diseases to which the female population is prone [1--4]. About 30 % of the disease occurs in women of reproductive age. Every eighth woman in the world suffers from breast cancer in different age ranges. According to the WHO, in 2020, more than 2.3 million new cases of breast cancer and more than 685,000 deaths from breast cancer were diagnosed in the world [3]

According to the National Cancer Registry of Ukraine, 12,736 new cases of breast cancer were registered in 2020, and the incidence varies from 35.3 to 82.0 cases per 100,000 women in different regions of the country. 4,960 people died from this disease.

At present, about 60 risk factors are known that contribute to the development of neoplasms in the mammary gland, as well as a number of factors that have been associated with an increased risk of devel-oping breast cancer (breast cancer).

In most cases of breast cancer, it is impossible to clearly explain its cause, and it is precisely because of this that it is impossible to accurately predict in whom it may develop. The regularities of the development of breast cancer are probable, and to predict such a possibility, it is more likely to use an assessment of the risks of the development of the disease than to rely on a precisely known cause [9].

It has been established that IR is one of the factors of the external environment, which causes an increase in the frequency of malignant neoplasms at the population level [10, 11]. Many studies have shown that the carcinogenic effect of IR does not depend on the type and form of action. According to a number of researchers, any radiation effect (no matter how small the radiation dose) causes an additional risk of cancer in an irradiated person. This makes it clear that there is a carcinogenic radiation risk at the smallest doses regardless of the «impossibility» of its detection during epidemiological observations [12--16]. IR, regardless of the type and mode of action, is a non-specific carcinogenic factor, as it causes tumors or contributes to their occurrence in almost all mammalian tissues. Not one of the chemical carcinogens does not have such a universal effect. Irradiation does not cause specific forms of cancer, but increases the frequency of already known types of cancer. On the basis of numerous studies, conclusions have been drawn that deny the existence of a safe phase or power of IR. The obtained data show that the immune system is not able to extinguish all radiation-induced tumors, including at rather low doses and radiation power, which refutes the concept of safe IR doses [17--20].

According to the Scientific Committee on the Effects of Atomic Radiation of the United Nations (SCEARUN), breast cancer is one of the main indicator risks of human exposure to radiation. Breast cancer is the most common localization of cancer among women in most countries of the world [21]. The «dose-effect» relationship for this localization is stably determined and has a linear form in a wide range of doses. Numerous radiation-epidemiological studies of the effect of IR on the population of the cities of Hiroshima and Nagasaki (irradiation as a result of the bombing in 1945) made it possible to reveal the relationship between the frequency of BC and the received radiation dose. The current Recommendations of the International Commission - on Radiological Protection (ICRP) of 2007 and the World Health Organization (WHO) contain prognostic models of the radiation risk of breast cancer identified on cohorts that were exposed to external radiation [22--25].

Data from various studies report that MG is particularly sensitive to the action of IR. An increase in the risk of malignant neoplasms (MNS) of the mammary gland was shown in women who were exposed to IV for medical purposes -- multiple fluoroscopy to monitor the results of tuberculosis treatment [26, 27]; multiple diagnostic exposures or exposures for the treatment of benign diseases in childhood [28--31]; acute postpartum mastitis [32]; benign MH diseases [33], Hodgkin's disease [25, 34, 35], as well as in women who survived the atomic bombings in Hiroshima and Nagasaki [22, 36].

In clinical and epidemiological studies conducted by Japanese and American researchers on cohorts of residents of Hiroshima and Nagasaki, affected by the atomic bombings in May 1945, the oncological effects of IR were reliably established for the first time [35, 37]. An outbreak of breast cancer in Japanese women was noted. In the female population irradiated between the ages of 10 and 19 years, the risk of the disease became significantly higher than in those who were exposed at the time older than 35 years [38, 39].

A study of the health of Japanese women showed that the risk of breast cancer is exceptionally high only for early cases detected many years ago. A strict linear dependence on radiation dose was found, with a high excess relative risk among women whose age at the time of the bombing was less than 20 years. A less pronounced dosage dependence was observed among women after 40 years [40, 41].

When studying the fate of 77,752 Japanese who survived the bombing of Hiroshima and Nagasaki, it was found that by 2002, 14,048 developed the 1st primary cancer, including 970 cases of breast cancer, and 1,088 were diagnosed with 2nd primary malignant tumors, including 61 cases of breast cancer. When exposed to a dose > 2Gy, the relative risk (RR) of the development of breast cancer was 6.42 (95 % CI: 4.40--9.39), the HR of the 2nd breast cancer was 7.33 (95 % CI: 2.61-20.59) [42]. There are data that BC can be induced by doses lower than 0.5 Gy [43]. The dose-effect relationship is linear. The excess frequency of breast cancer for both cities was 40.5 and 30.8 cases per 100,000 women per year per 1 Gy, respectively [44].

The fact that an exposure dose of 100 rads increases the risk three times indicates the direct impact of IR on the risk of developing breast cancer. At the same time, the age at which the patient is exposed to radiation is very important: the period up to 30 years is especially dangerous (15--18 years are the most dangerous) [34, 35]. One of the most frequent causes of IR exposure to healthy MH is radiation therapy in the treatment of Hodgkin's disease, while MH may receive a radiation dose of > 20 Gy. Women who were treated in this way before the age of 30, at the age of 40--45, in 13--20 % of cases, develop breast cancer, and after 20--30 years of observation, the probability of developing the disease is 12--26 %. Henderson T O. and co-authors [46] believe that this is a very significant increase in morbidity, as only 1 % of women in the general population under the age of 45 are affected. With smaller doses of radiation on the MG, the risk of the disease on the MG is lower, but still significantly higher than in the absence of irradiation. Thus, with an irradiation dose of 1.3--9.9 Gy (median - 4.4 Gy) BP 1.9 (95 % CI: 0.7-5.4), with a dose of 10.0-19.9 Gy (median -- 14,5 Gy) HR 6.5 (95 % CI: 2.3--18.5) [47]. According to L.B. Travis et al. [48], a chest radiation dose of > 40 Gy at the age of 25 years led to the development of breast cancer at the age of 35, 45 and 55 years in 1.4; 11.1 and 29 % of cases, respectively.

In Scotland, a group of women (243 patients) were examined, who, during the treatment of tuberculosis, were repeatedly subjected to X-ray examination of the chest cavity (CC), in which the beam passes in the direction from the chest to the back, that is, the patients were turned to face the source of radiation. The amount of the absorbed dose to the breast gland in one session was equal to an average of 7.5 Gy. The time between sessions was days or weeks. At the same time, the total absorbed dose for the breast was approximately 8.5 Gy. The incidence of breast cancer in this group exceeded the expected by more than 6 times [49--51].

In order to control the radiation loads during screening X-ray examinations of individual contingents of the population, methods of biological, namely, cytogenetic dosimetry, based on the recording of radiation-induced chromosome aberrations in the culture of human peripheral blood lymphocytes (LPK) were used (in vitro and in vivo studies) [51, 52]. In this case, biodosimetric information was obtained by simulating irradiation conditions on a tissue-equivalent phantom. In the studies, the data of biological (cytogenetic) indication of radiation action and physical dosimetry were compared under the conditions that during fluorography of the chest cavity organs, bottles with donor blood were placed in experimental points in the area of the thyroid, thymus, and chest glands of tissue equivalent factor «Alderson» during mammography on the upper and lower surfaces of the breast phantom. In order to indicate the degree of radiation exposure, test-systems of the culture of LPK of conditionally healthy persons with metaphase analysis of chromosome aberrations were used. Physical dosimetry was performed using an automated ALNOR thermoluminescence system [53--55]. As a result of the work, it was established that during fluorography of CC in the front straight and right-side projections, the total number of chromosome aberrations at the experimental point on the inner surface of the left breast (which was located closer to the source of IR) at the equivalent dose value of 3.25 mSv was 9.5 ± 2,1 per 100 cells, which was 3 times higher than the spontaneous level of chromosomal aberrations [56, 57].

During mammography in two projections (direct and lateral), the total number of chromosome aberrations at the experimental point on the upper surface of the breast gland at the value of the equivalent dose of 6.08 mSv reached 13.0 ± 2.5, which exceeded the spontaneous level by more than 4 times [54, 57, 58].

The presented results make it possible to state that with multi-projection fluorography of the CC and mammography, radiation-induced damage can develop in the tissues of the breast cancer, which potentially increases the risk of developing breast cancer of radiation genesis [51, 58]. When conducting X-ray studies of CC (low doses of local radiation), the number of chromosome rearrangements in the blood cells of patients increases significantly, this may determine the future development of radiation- associated cancer among people who have undergone preventive fluorography [59].

Thus, low (above-background) doses of IR during radiological examinations can induce an increased level of chromosome aberrations in the cells of irradiated tissues. During fluorographic and mammographic screening, there is a risk of developing radiation-induced instability in the cells of the breast gland, which is relevant when examining the female population of Ukraine living in areas contaminated with radionuclides. Repeated radiation exposure to these cells can be a promoter of carcinogenesis [51, 57]. There are other data that even at the lowest doses of IR (1 cGy and less) during X- ray examinations of the CC, esophagus and stomach, an increased level of chromosomal aberrations is registered in the LPK of the examined persons. The circulation of a part of aberrant lymphocytes in the bloodstream decades after diagnostic irradiation was noted [60, 61].

It is important to note that radiologists represent a unique professional group associated with chronic exposure to low dose rates. A significant increase in the risk of breast malignancy associated with daily exposure to low doses of occupational exposure over several years was found in a cohort of female radiologists in the United States [62--64] and among radiologists in China [65].

When examining British female workers who applied a luminescent compound (radium-226) to the dials of measuring devices, the total dose to the mammary glands of the female workers was 0.5 cGy per week, and the total absorbed dose was 40 cGy. Among women whose age before the start of work was 20 years, breast cancer was subsequently observed 2 times more often than the expected frequency [66--67].

In persons who underwent therapeutic irradiation of the thymus in childhood, after 30 years, an increase in the frequency of intractable gland cancer (RGC) was noted, 83 % of the diseases are represented by fibroadenomas [68].

IR is one of the etiological risk factors for the development of BC with a latent period of 10 or more years. in patients who were subjected to repeated fluoroscopy of the CC, the risk of developing RHZ increased as the number of these diagnostic procedures increased. The average dose per GH during a single mammographic examination was 0.015 Gy, the average cumulative dose was 1.5 Gy. At the same time, the average latent period of the development of RGZ was equal to 24.4 years. The advantage of the linear component is characteristic for the dose dependence of the formation of BC [58, 69].

The results of a meta-analysis of the incidence of breast cancer among female flight attendants show a significantly increased risk of breast cancer as a result of occupational exposure to cosmic radiation [70]. Rafnsson V. et al. [71] also determined an increased risk of malignant neoplasms (MN) of the breast among flight attendants: 26 cases of SMA per 1690 women (standardized incidence ratio (SIR) = 1.5), despite the fact that the average annual dose in this group was approximately 3 mSv, and according to the authors is too low to cause an increase in risk.

An increase in breast cancer, the risk factor for the development ofwhich is IR, has been noted in Finnish doctors who work with sources of IR. A 1.7-fold increase (95 % CI: 1.0--3.1) in the frequency of development of breast cancer was revealed in comparison with doctors of other specialties [72, 73]. However, it has been shown that even among medical workers of diagnostic departments who have contact with IR, the potential risk of cancer due to occupational exposure varies depending on gender and occupation [74].

A study was conducted to assess the role of the polymorphism of the p53 tumor suppressor gene in the formation of a predisposition to malignant transformation in the case of long-term low-intensity radiation exposure, with the inclusion in the study of oncological patients working at the Northern Chemical Plant (NCP), who were under individual dosimetric control. The workers were exposed to external and internal radiation. The range of external radiation doses was from 2.28 mSv to 1605.1 mSv, the median was 40.3 mSv, the interquartile range was 10.1-70.1 mSv. The average duration of exposure was 17.63 years. All indicated doses of IV belong to the range of «small» doses. It was established that in women who had contact with sources of IV, a tendency to increase the frequency of breast cancer by 1.5 times was found (42.8 and 28.2; p = 0.08). It was also shown that IR has a carcinogenic effect, which is carried out including by increasing the general mutational background in the cell and mutations in the p53 gene. The mutated p53 gene loses its tumor suppressive functions and acquires the properties of a dominant oncogene. When the mutation background increases under the influence of IR and increases the probability of the occurrence of mutated protein p53 with oncogenic properties, the presence of an allele with high activity is a risk factor for MN, and the protective effect of the heterozygous genotype is eliminated [75].

Analysis of the incidence of MN among the staff of the Siberian Chemical Plant (SCP) who experienced long-term external exposure to low-intensity occupational activity (up to 200 mSv), in which all cases of morbidity and death due to OSA among the staff were studied for the period from 01.01.1970 to 31.12.2015 including, in addition to the data on the number of patients when assessing the risk of onco- logical morbidity of the staff, information on the number of accumulated person-years (APY) in the studied cohort during the observation period was used. The results of the calculations showed that among women the incidence of gastrointestinal diseases was the highest (69.7 cases per 100,000 APY), while the highest incidence rate was observed among female workers aged 40--49 (95.1 cases per 100,000 APY). The second place among all higher education institutions in terms of female staff was occupied by BC (63.5 cases per 100,000 APY). This APY occurred most often among women aged 40--49 years (133.5 cases per 100,000 APY) [76].

The form of dose dependence and magnitude of radiation risk have been described in many analyzes from the above cohorts. The excess relative risk per 1 Gy obtained from the pooled analysis was 0.86 (95 % CI: 0.7--1.04), and the range of risks for each cohort separately was between 0.06 and 1.94. Based on the research data, it was concluded that the mammary gland is one of the most radiosensitive organs and that the action of IR plays a role both at the stage of initiation and promotion of the process of development of breast cancer. The most common types of cancer caused by radiation are thyroid and breast cancer. About ten out of a thousand irradiated people develop thyroid cancer, and ten out of a thousand women develop breast cancer [58, 77, 78].

A large volume of epidemiological and clinical research was carried out in the region of the Semipalatinsk nuclear test site. It was established that the increase in the frequency of general oncological morbidity and prevalence of breast cancer was fixed 20--30 years after radiation in women. An increase in the incidence of oncology was also found in the descendants of irradiated persons. So, for the period from 1990 after 2005 a more than 2¬fold increase in the total incidence of breast cancer by region was observed [79]. A significant increase in the frequency of this pathology was noted in people who lived in the territories that were most actively contaminated by radioactive fallout [80]. The level of cancer incidence was recorded among persons whose radiation dose (effective equivalent dose) exceeded the value of 250 mSv or more. The relative risks of cancer incidence indicators exceeded the indicators of control groups, both among persons who were directly exposed to radiation and among their descendants [81].

The risk of developing radiation-induced breast cancer increases in women who were exposed to radiation during hormonal changes in the body (menarche, menopause, pregnancy and lactation) [44, 80]. According to the analysis of 61 cases of BC among 5,000 women who were irradiated in connection with atmospheric precipitation after nuclear tests in Kazakhstan (average effective dose 634 mSv), the obtained estimate of excess relative risk (RR) was equal to 1.09/Sv (95 % CI: 0.05--15.8), and the highest risk was noted in women with doses > 750 mSv compared to women who received doses < 20 mSv [82].

Genetic factors that lead to the development of breast cancer are usually associated with family forms, as well as with national and population forms [83]. The effect of adverse environmental conditions can be one of the factors that increases the frequency of mutations of any of the genes in the relevant population [84, 85]. The most dangerous in terms of genetics is the radiation factor [86, 87]. The radiation-unfavorable territory of the Semipalatinsk nuclear test site is characterized by the residence of a large number of directly exposed women and their descendants at an age in which breast cancer often develops. In many cases, they have a family history of cancer [88, 89]. This is of great interest in the possibility of a relationship between the exposure factor, family radioecological and tumor anamnesis, and the histological structure of malignant neoplasms of the MH. Thus, a group of authors conducted a study to determine the morphological features of breast cancer associated with the presence of BRCA1 and TR53 gene mutations in women with radioecological and family cancer history. The study includes data obtained from 190 women aged 40 to 78, ethnic Kazakhs, with breast cancer, distributed depending on the presence of a family history of the disease, personal and family radioecological history. In the study, the existence of a relationship between the histological characteristics of breast cancer and family history and the presence of BRCA and TP53 gene mutations was revealed. Individuals with a mutant genotype of all clinical groups showed an increased frequency of relatively rare histological forms of the disease. The authors believe that the first generation with a family history of breast cancer may also be related to the effect of radiation, since most of the mothers of women in this group lived in radiation risk zones during dose-forming explosions [89].

Separately, with the involvement of these groups of patients, studies were conducted to determine the frequency of the 5382 insC polymorphism of the BRCA1 gene in patients with familial breast cancer in the first and second generations of irradiated patients. As a result of the study, a difference in the frequency of the 5382 insC polymorphism of the BRCA1 gene in women with breast cancer in the indigenous population of Eastern Kazakhstan was found, which is associated with the presence of family and radioecological anamnesis. A significant excess of the frequency of this polymorphism was registered in patients with family and radioecological anamnesis over the control group and breast cancer patients with family history without radioecological history and without family and radioecological anamnesis, which testify to the leading role of the radiation factor in the accumulation of the 5382 insC mutation of the BRCA1 gene in the population [90].

In the fifties of the 20th century, as a result of the activity of the «Mayak» enterprise, which produced plutonium, a large amount of radioactive waste entered the Techa River, which caused a long period of exposure to the residents of the coastal strip in the range of low and medium power doses. In order to study the assessment of the risk of breast cancer, case histories of 9,899 women living in this region were analyzed. A statistically significant risk of BC was established per 1 Gy in women who were exposed to long-term radiation exposure in the range of low and medium doses. The greatest radiation risk for the development of BC was noted in women who were less than ten years old before the start of irradiation [91]. According to the results of an epidemiological study, among the personnel who started working at the factories of the manufacturing association (MA) «Mayak» in 1948--1958 and were exposed to radiation in doses that exceeded the permissible level, an increase in the incidence of BC by 15 % was found [92].

When studying the evaluation of the carcinogenic risk among the first generation of descendants of workers of the «Mayak» vocational school, who underwent prolonged preconceptional radiation at work, it was established that during the period 1949--2018, among the first generation of descendants of 1949--1990, one of the leading nosological forms in the structure Among the women of the main group (MG), the most common cancer is the most common cancer of the mammary gland. The analysis of cancer incidence rates in the offspring also indicates that among MG women, the incidence of MG was 2.3 times higher than the data for the comparison group (41.4 vs. 17.7 per 105 person-years). An analysis of the relative risk of breast cancer revealed a more than two-fold increase in risk among female offspring of MG at all dose intervals [93].

Somatic and hereditary variants of the TP53 gene are of great importance in the development of malignant neoplasms. The group of authors conducted studies to determine the spectrum, frequency, structural features, and functional significance of TR53 gene variants in irradiated women of the Techa cohort with and without breast cancer. Individual doses of action on the red bone marrow ranged from 0.003 Gy to 4.6 Gy. The examination included 57 women from the Techa cohort. In the group of patients with breast cancer, 2 variants of the TR53 gene were found, which were absent in the control group. The authors believe that the continuation of research on larger groups will provide an opportunity to draw reasonable conclusions in the future regarding the role of variants in the TR53 gene in the development of BC induced by IR [94].

The radiation factor can act directly on organs and tissues of the reproductive system or through organs and systems (nervous, immune, endocrine, humoral) that ensure the functioning of the reproductive system. The Chornobyl accident created an exceptional opportunity to study and understand the mechanism of carcinogenic long-term effects of small doses of radiation. The generalization of data on the main trends in the dynamics of the incidence of malignant tumors in general and in the period after the Chornobyl disaster in particular, the assessment of the magnitude of the radiation risks of this pathology have not only practical, but also theoretical significance. Such studies are carried out in a number of countries, therefore it is important to compare the obtained data [95--97].

Analyzing the incidence of BC in the regions of Belarus that were significantly affected by the accident at the Chornobyl nuclear power plant, it was noted that already in the period from 1977 to 1994, a 1.5-fold increase in incidence was observed in Gomel and 1.9-fold in Mogilev regions. It should be noted that the initial level of the incidence rate in the Gomel region in 1977 was 20.0, and in Mogilevska -- 16.7. In the post-accident period, there is a significant increase in the incidence of breast cancer in relation to the pre-accident period. The average standardized index increased from 20.5 ± 0.58 to 28.7 ± 1.39 in Gomel Oblast, from 19.8 ± 1.15 to 29.1 ± 1.31 in Mogilev Oblast [98].

The United Nations established the Chornobyl Forum in 2003 to study and understand the medical, economic, and socio-economic consequences of the accident. According to the expert group «Health» of the UN Chornobyl Forum, the study of breast cancer is of great interest and concern for two reasons: 1) this type of cancer is of great importance in health care and 2) it is known that breast cancer is sensitive to cancer induction under the action of some types of IR. The relative risk of breast cancer in women who were exposed to external radiation in childhood and adolescence is one of the highest, along with the risk of leukemia and thyroid cancer. For women living in polluted areas, the value of the standardized incidence rate (SIR) of breast cancer, obtained when compared with the incidence rates of the female population of Ukraine, was 1.50 (95 % CI: 1.27--1.73) for the period 1993--1997. For female evacuees from the 30-km zone, the SIR value for 1990--1997 was 1.38 (95 % CI: 1.06--1.70), and for female liquidators in 1986--1987, it was only 5 % of the entire cohort of liquidators, the SIR value for the period 1990--1997 was 1.51 (95 % CI: 1.06--1.96). In Russia and Belarus, a descriptive epidemiological study was carried out with the participation of the International Cancer Institute and the Cancer Registry of Finland. The preliminary results of the study indicated a significant increase in the incidence of breast cancer in pre-menopausal women who were exposed to radiation before the age of 45 and lived in the most polluted areas (with an average accumulated dose of 40 mSv or more) compared to women who lived in less polluted areas [99].

In order to identify the peculiarities of the frequency and dynamics of the incidence of BC among women of the Gomel region who received different doses of radiation as a result of the Chornobyl disaster and live in areas with different densities of 137Cs contamination, as well as to determine the main risk factors for the development of BC after exposure to IR, the women were divided into three subgroups: group 1 -- who live in territories with a pollution density of 137Cs --185 kBq/m2; group 2 -- who live in territories with a pollution density of 137Cs 185--555 kBq/m2; group 3 -- who live in areas with a density of 137Cs contamination greater than 555 kBq/m2 [100]. As a result of the research, it was established that the maximum level of morbidity in residents of the territory with a density of cesium pollution > 555 kBq/m2 is statistically significantly higher than similar indicators in the control group and in territories with a pollution density of 37--185 kBq/m2 and 185--555 kBq/m2.

The peak incidence of BC in territories with a pollution density of 37--185 kBq/m2 and > 555 kBq/m22 occurs 15 years earlier than in controls and corresponds to the age group of 55--59 years. Among women who received a dose load of more than 50 mSv, a statistically significant excess of the relative risk is noted, which makes it possible to assign them to the group of high risk of developing breast cancer [100].

A study of the spontaneous and radiation-induced incidence of BC in the post-Chornobyl period (1986--2005) in the Belgorod Region revealed a 164.5 % increase in the pre-accident level of BC. A characteristic feature of this pathology is a more intense increase in morbidity in all age groups after a short latent period [101].

The assessment of the dynamics of breast cancer incidence and the identification of a possible screening factor for breast cancer among the population of the Bryansk and Oryol regions, which experienced pro-longed exposure as a result of living in areas contaminated with radionuclides after the accident at the Chornobyl nuclear power plant, was carried out based on the analysis of information on 127,104 women during the observation period from January 1, 1986 to 31.12.2011. For the population of the most polluted areas of these regions, a statistically significant screening effect was established in the process of registration of diseases for breast cancer in the period 2006--2011, which is an increase of 40 % in comparison with regional rates of incidence of breast cancer and by 24 % in comparison with the all-Russian level [24].

In the period after the Chornobyl disaster (1986--1994), the incidence of BC as a whole in the state of Belarus increased statistically significantly compared to the period before the disaster (1977-1985) - respectively 29.9 ± 1.11 and 20.9 ±0.77 (per 100,000 female population). The age indicators of this disease also changed significantly after the disaster - the incidence in people after 45 years increased significantly. The number of diagnosed cases of primary multiple breast cancer in the Gomel region since 2001 significantly exceeds that of people living in Belarus. The incidence of breast cancer in the territories contaminated by 137Cs at the level of > 555 kBq/m2 in 1997-2003 was significantly higher than in these territories in 1990-1996. In more radiation-contaminated territories, the level of morbidity and its rate of growth over the years is higher than in less polluted ones. In the period 1990-2003, BC occurred on average significantly more often in the more radiation- contaminated territories of the Gomel region. This difference became apparent starting in 1995 and significantly increased 12 years later [100, 102]. In women of rural areas of the Gomel region the growth rate of the incidence of breast cancer is statistically significantly higher than that of women from rural areas in the less radiation-contaminated Vitebsk region [102, 103]. From 1986 to 1999, the incidence of breast cancer increased from 1,745 to 2,322 cases per year. In the most radioactively contaminated territories, this growth was more significant. In the Mogilev region. among women aged 45--49 in 1993--1996 four times compared to the period 1989--1992, and in the country as a whole -- 2.6 times in 2002 compared to 1982 [104, 105].

Starting from 1995 in the Bryansk region, the incidence of BC in the southwestern regions of the region, contaminated with 137Cs at a level of > 5 Ci/km2, became statistically higher than the average for the region. According to the Russian National Epidemiological Register, the frequency of additional «Chornobyl» cancers of the Ministry of Health in the more radioactively contaminated areas of the Bryansk region after the disaster reaches 10 % of the total number of this disease. A comparison of the age profile of the incidence of breast cancer in the five- year period before the disaster and five and fifteen years after the disaster in the Belgorod region shows that starting from the age of 39, there is a noticeable increase in the rate of manifestation of this type of cancer, more expressed after 15 years [101, 102].

In a significant number of domestic and foreign publications, about 60 risk factors contributing to the development of MG neoplasms are considered. All these factors have a pathogenetic tendency: the functioning of the immune system is disturbed, the activity of the body's hormonal systems and home-ostasis changes. For example, obesity leads to an increase in the total pool of estrogens due to the conversion of androstenedione into estrone, which is associated with the realization of the carcinogenic effect. To assess the impact of somatic diseases that precede the occurrence of BC, the database of the State Register of Persons of Belarus, who were exposed to radiation as a result of the Chornobyl nuclear power plant disaster, was used. A cohort of women who took part in the liquidation of the accident at the Chornobyl Nuclear Power Plant in 1986--1987 was formed from the persons registered in the State Register. The number of the cohort is 17,661 persons, among whom, as of the end of 2002, 156 women with a diagnosis of breast cancer were identified. Among breast cancer patients, the incidence of breast cancer per 100,000 was established, the relative risks and the frequency with which somatic diseases occur in women were calculated. Relative risks were calculated as the ratio of the incidence rate of breast cancer in women with some groups of somatic diseases to the incidence rate of breast cancer in the cohort. The incidence rate of breast cancer in the cohort was 883.3 per 100,000 women The most common pathology preceding the onset of breast cancer was thyroid disease, benign breast cancer neoplasms, and non-cancerous breast cancer. In the presence of these diseases, the risk of developing breast cancer is quite high: the relative risk ratio is 1.43-2.01. The values of the given coefficients are indicative, since one and the same patient may have several diseases from the list under consideration. It should be taken into account that the study was conducted with a contingent that was exposed to IR, and IR, depending on the dose load, has a carcinogenic effect [106].

After the accident at the Chornobyl nuclear power plant, the study of the incidence of BC was mainly conducted within the framework of descriptive epidemiological studies regarding the study of possible stochastic effects in the affected population groups. A number of studies have established that among the groups most affected by the accident at the Chornobyl nuclear power plant (liquidators, evacuees, people living in the areas most contaminated with radionuclides), 12 years after the accident, there is a significant increase in the incidence of BC. This trend continued in the following years with the most pronounced growth rates among women liquidators [107-109].

In the most polluted areas, the incidence of BC in 1980-1992 was relatively stable, compared to the indicators for Ukraine, it was somewhat lower. In 1991-1995, a significant increase in the frequency of this pathology in women living in polluted areas led to the fact that its indicators became close to the indicators of large areas and exceeded, in particular, the incidence rate in the Zhytomyr region. During the period 1993-1977, these indicators increased significantly. The actual level of SIR compared to the expected was 150.3 % (95 % CI: 127.1-173.4 %) [110, 111].

Epidemiological analysis of the combined data for Belarus and Ukraine revealed a significant two-fold increase in the incidence of breast cancer in 1997-2001 in women living in the areas most contaminated with radionuclides compared to those living in less polluted areas. In regions of Ukraine, where the average accumulated dose was 40 mSv or more, the relative risk was equal to 1.78/Sv (95 % CI: 1.08-2.93) [109, 112, 113]. Since women did not directly participate in emergency work, but provided the work of communal services and medical assistance, the doses they received are much smaller and can be compared with the doses of evacuees. The average effective dose of external radiation of evacuees is estimated at 10-30 mSv, but it should be doubled due to internal radiation [109].

In women from among the liquidators of 1986-1987, in 1994-1997 and in general for 1990-1997, a statistically significant increase in the number of cases of breast cancer was noted in comparison with the expected. The expected incidence rate in 1990-1997 was exceeded by 37.7 % [110]. In 1994-2007, morbidity rates in this group of victims exceeded the expected level by 1.5 times. This is due to a significant increase in morbidity in persons who were 21-45 years old at the time of the accident (SIR - 160.2 %; 95 % CI: 106.4-214.1 %). In the age group older than 45 years, at the time of the accident, the incidence did not differ from the expected rate (SIR - 110.2; 95 % CI: 52.4-167.6 %) [109]. In 1994-2010, the SIR value was 164.3 % (95 % CI: 145.3-183.4 %) among participants in the liquidation of the consequences of an accident [111]. 30 years after the Chornobyl disaster, the incidence rate of breast cancer in female liquidators was significantly higher than national indicators [114]. Morbidity rates among residents of radionuclide-contaminated territories and evacuees were significantly lower. When analyzing the possible causes of this phenomenon, one should take into account the fact that these groups of victims before the accident at the Chornobyl Nuclear Power Plant lived in the territories where the incidence rate of BC was one of the lowest in Ukraine [111, 113]. There is data that in the period 2011-2017, in the territories contaminated with radionuclides, there is a significant increase in the incidence of breast cancer, which reaches the level of incidence of this pathology in the female population of Zhytomyr region. A comparative analysis of the amount of radiation doses and the morbidity rate of the female population of polluted areas did not establish a statistically significant relationship between factorial (irradiation dose) and outcome (incidence of breast cancer) characteristics [115].

A study of the incidence rate of malignant neoplasms among the population living in cities where nuclear power plants are located showed that the incidence rate of all forms of malignant neoplasms in cities with nuclear energy complex enterprises is significantly higher than the national level -- 113.0 % (CI: 110.7--115.3 % ), the incidence rate of breast cancer also significantly exceeds the national and regional level and is 114.6 % (95 % CI: 106.5--122.7 %) [116, 117].

As noted by some studies, the effect on people of IR in a dose close to 1 Sv makes it possible to esti-mate an increase in the incidence of breast cancer by 13.2 % [109, 118]. Numerous epidemiological, as well as experimental and clinical studies, testify to the high sensitivity of MG tissue to the carcinogenic effect of radiation. The given data indicate a relative increase in the frequency of BC in all cases of radio- ecological disasters, starting with the atomic bombings of Hiroshima and Nagasaki and ending with the Chornobyl accident. Summarizing the given data, it should be noted that in the spectrum of etiological factors of the occurrence of malignant neoplasms MG, IR has a significant role. In publications related to breast cancer in women working in contact with IR, studies indicate the presence of an association between the risk factor being studied and the development of breast cancer. The most common cancer, which is caused by radiation, along with thyroid cancer, is breast cancer. Approximately 10 out of 1,000 irradiated people develop thyroid cancer, and 10 out of 1,000 women develop breast cancer. Analysis of the «dose--response» relationship revealed a statistically significant linear trend of an increase in the risk of BC with the soft tissue irradiation dose, which is in the range of small and medium doses of IR.

Рак молочної залози (РМЗ) є провідним у світі онкологічних захворювань за розповсюд- женістю серед жіночого населення і становить близько 25 % від усіх онкологічних захворювань, до яких схильне жіноче населення [1--4]. При цьому близько 30 % захворюваності на РМЗ припадає на репродуктивний вік жінок. У різних вікових проміжках кожна восьма жінка у світі хворіє на РМЗ. За даними ВООЗ у 2020 році у світі діагностовано понад 2,3 млн нових випадків РМЗ і понад 685 000 випадків смертності від РМЗ [3].

За даними Національного канцер-реєстру України, у 2020 році загальна кількість випадків захворювання на РМЗ складала 12 736, у різних регіонах держави захворюваність варіює від 35,3 до 82,0 випадків на 100000 жінок. Померло від цього захворювання 4 960 жінок [5].

Натепер відомо близько 60 факторів ризику які сприяють розвитку новоутворень в молочній залозі, а також відмічають ряд факторів, для яких встановлено зв'язок з підвищеним ризиком розвитку раку молочної залози (РМЗ). Одними з відомих причин виникнення РМЗ є генетична схильність і такий екологічний фактор як іонізуюче випромінювання (ІВ) [6--8].

У більшості випадків РМЗ неможливо однозначно пояснити його причину, і саме тому неможливо точно спрогнозувати, у кого він може розвиватись. Закономірності розвитку РМЗ носять вірогідний характер, і для прогнозування такої можливості скоріше можна використовувати оцінку ризиків розвитку хвороби, ніж опиратись на точно відому причину [9].

Встановлено, що ІВ є одним із факторів зовнішнього середовища, що спричиняє підвищення частоти злоякісних новоутворень на популяційному рівні [10, 11]. У багатьох дослідженнях показано, що канцерогенний ефект ІВ не залежить від виду і від форми дії. На думку ряду дослідників, будь-яка радіаційна дія (наскільки малою не була б доза опромінення) викликає додатковий ризик появи онкологічного захворювання у опроміненої людини. Тим самим це дає зрозуміти, що існує канцерогенний радіаційний ризик при самих малих дозах незалежно від «неможливості» його виявлення при епідеміологічних спостереженнях [12--16]. ІВ незалежно від виду і способу дії є неспецифічним канцерогенним фактором, оскільки призводить до виникнення пухлин або сприяє їх розвитку майже у всіх тканинах ссавців. Ні один з хімічних канцерогенів не має подібної універсальної дії. Опромінення не викликає специфічних форм раку, проте збільшує частоту вже відомих видів ракових захворювань. На підставі численних досліджень зроблено висновки, які заперечують існування безпечної дози або потужності ІВ. Отримані дані свідчать, що імунна система неспроможна загасити всі радіа- ційно-індуковані пухлини, в тому числі й при досить низьких дозах і потужності випромінювання, що спростовує концепцію безпечних доз ІВ [17--20].

За даними Наукового комітету по дії атомної радіації ООН (НКДАР ООН) рак молочної залози є одним із основних індикаторних ризиків дії на людину ІВ. РМЗ -- найбільш розповсюджена локалізація раку серед жінок у більшості країн світу [21]. Залежність «доза-ефект» для даної локалізації стійко визначається і має лінійний вигляд в широкому діапазоні доз. Численні радіаційно-епідеміологічні дослідження дії ІВ на населення міст Хіросіма і Нагасакі (опромінення в результаті бомбардування у 1945 р.) дали можливість виявити зв'язок між частотою РМЗ і отриманою дозою опромінення. Сучасні Рекомендації Міжнародної комісії з радіологічного захисту (МКРЗ) 2007 р. і sition and such an environmental factor as ionizing radiation (IR) [6--8].

Всесвітньої організації охорони здоров'я (ВООЗ) містять прогностичні моделі радіаційного ризику РМЗ, ідентифіковані на когортах, які зазнали зовнішнього опромінення [22--25].

Дані різних досліджень повідомляють, що МЗ особливо чутлива до дії ІВ. Було показано збільшення ризику злоякісних новоутворень (ЗНУ) молочної залози у жінок, які зазнавали дії ІВ в медичних цілях: багаторазова рентгеноскопія для контролю результатів лікування туберкульозу [26, 27]; багаторазове діагностичне опромінення або опромінення для лікування доброякісних захворювань в дитячому віці [28--31]; гострого післяпологового маститу [32]; доброякісних захворювань МЗ [33], хвороби Ходжкіна [25, 34, 35], неходжкінських лімфом, а також у жінок, які перенесли атомне бомбардування у Хіросімі та Нагасакі [22, 36].

У клініко-епідеміологічних дослідженнях, виконаних японськими та американськими дослідниками на когортах мешканців Хіросіми і Нагасакі, постраждалих від атомних бомбардувань у травні 1945 року, вперше були достовірно встановлені онкологічні ефекти ІВ [35, 37]. Було відмічено спалах розвитку РМЗ у японських жінок. У жіночого населення, опроміненого у віці від 10 до 19 років, ризик захворіти став значно вищим, ніж у тих, хто був на той момент старше 35 років [38, 39].

Вивчення здоров'я японських жінок показало, що ризик виникнення РМЗ є виключно високим тільки для ранніх випадків, виявлених багато років тому. Виявлена чітка лінійна залежність від дози опромінення з високим надлишковим відносним ризиком серед жінок, які на момент бомбардування були молодші 20 років. Менш виразна дозова залежність спостерігалась серед жінок старше 40 років [40, 41].