Impact of risk factors on the development of breast cancer in women from Kyrgyzstan

Introduction and Aim: Breast cancer (BC) is the world's leading oncological disease in terms of prevalence among females and accounts for 25% of all oncological diseases affecting the female population, 25% of women are from the age of 50–60 years. The aim of the study was to determine the risk factors affecting the development of BC in women from Kyrgyzstan (well–known, specific, and protective). Methods: This is a retrospective study that analyzed medical records and outpatient records of 1024 patients with BC treated at the National Center of the Oncology and Hematology of the Ministry of Health of Kyrgyzstan from 2016–2021. Results: Regression analysis showed that out of numerous BC risk factors, only five factors are significant: spontaneous miscarriages (RR = 5.0, p<0.007), preterm birth (RR = 5.0, p<0.007), kidney disease (RR = 5.2, p<0.002), severe anemia (RR = 6.1, p<0.002) and severe postpartum bleeding (RR = 6.9, p<0.002), as indicated by a RR of 0, CI <1, and p<0.001. Conclusion: Based on regression analysis, the presence and influence of specific risk factors for the development of BC in women from Kyrgyzstan were proved: spontaneous miscarriages, premature birth, kidney disease, severe anemia, and severe postpartum bleeding.


INTRODUCTION
reast cancer (BC) is the world's leading oncological disease in terms of prevalence among females and accounts for 25% of all oncological diseases affecting the female population (1), 25% of women are from the age of 50-60 years.The reproductive age of women accounts for about 30% of diseases.In most European countries, two out of 1,000 women a year develop BC among women over the age of 50, and about 15 have a high risk of developing BC (2).One of the leading risk factors for BC is age.In 2010, the prevalence of BC in the Russian Federation was 355.7 per 100,000 people.Mortality in the first year after diagnosis was 9.1% (3).In Kyrgyzstan, BC is one of the most common oncological diseases among women and ranks 2nd in terms of prevalence, and 3rd in mortality.In more than 40% of cases, BC is detected at a late stage, which complicates both the course of the disease and its treatment (4).
BC can occur because of simultaneous, complex, and long-term action of various factors such as socioeconomic, geographical, environmental, genetic, constitutional, reproductive, endocrine-metabolic, psycho-emotional, occupational, and dietary factors (5)(6)(7)(8).A risk factor is more of an epidemiological concept than an etiological one since it is based on the greater prevalence of the BC or the greater likelihood of its development in an individual.The established risk factors for BC can be both general and independent for cancer and fibrocystic breast disease (8).
Currently, many studies adhere to the following classification of risk factors (9-12): 1. Factors that characterize the functioning of the reproductive system • menstrual, sexual, childbearing, and lactation • hyperplastic and inflammatory diseases of the ovaries and uterus 2. Hereditary i. Endocrine and metabolic • excessive fat intake • Some studies also identify the following groups of risk factors for development of BC ( 13): • Low-risk factors (the risk is two times higher than in the population): Use of oral contraceptives, hormone replacement therapy, high-fat foods, and termination of the first pregnancy.The risk of BC is assumed to be primarily associated with genetic and hormonal-metabolic characteristics of the body.According to World Health Organization experts, the main risk factors for BC are the late age of the first birth, high-fat content in the diet, being overweight during menopause, and the presence of breast cancer in blood relatives (8,14,15).
The aim of the study was to determine the risk factors affecting the development of BC in women from Kyrgyzstan (well-known, specific, and protective).The obtained data are presented as the n (%).Statistical data analysis and mathematical processing were carried out using Excel.XLSTAT v2020.1 (Microsoft, Addinsoft, France), and calculating logistic regression analysis by Statistica 8.0 application package.For the determination of risk factors, relative risk (RR), and 95% confidence interval (95% CI) was carried out.The analysis of factors that characterize the functioning of the reproductive system of the body was carried out.The Mann-Whitney U-test was used to assess the statistical significance of the differences.Differences were considered statistically significant at p<0.05.

MATERIALS AND METHODS
Well-known risk factors for the development of BC that characterize the functioning of the reproductive system in the control group was presented in Table 1.Protective factors for the development of BC in women from the control group were presented in Table 3.To determine the risk factors leading to breast cancer and compare them with the control group, we conducted an epidemiological study of 1024 women with a diagnosis of BC.
Well-known risk factors for the development of BC that characterize the functioning of the reproductive system in patients with BC was presented in Table 4. Specific risk factors for the development of BC in women from the control group were presented in Table 5. Protective factors for the development of BC in patients with BC were presented in Table 6.

RESULTS
Kyrgyzstan is characterized by a variety of climatic and geographical factors that have a particular impact on the woman's body.Thus, the harmful effects of increased sun exposure, high-altitude hypoxia, sharp fluctuations in temperature, and atmospheric pressure on the course of diseases such as arterial hypertension, stroke, coronary heart disease, myocardial infarction, skin cancer, and melanoma were observed.
Despite the well-known risk factors for BC, there is very limited data about the features of the development and course of BC in various climatic and geographical zones.In particular, the impact of wellknown risk factors on the development of BC has not been studied and specific risk factors for the development of BC for women from the control group in Kyrgyzstan have not been identified.
We also studied the influence of the main prognostic and risk factors for BC and determined the probability of protective influence of several factors specific to women from the control group in Kyrgyzstan.
To determine the risk factors for the development of BC, we conducted an epidemiological study of 1024 women with a verified diagnosis of BC. 453 women without a diagnosis of BC were analyzed as a control group.This study determined the causal relationship between the occurrence of BC and risk factors.
A comparative analysis of the prevalence of comorbidities and the reproductive function of women in the observation groups was carried out.In the patients with BC, 68.1% suffered from chronic pyelonephritis, and exacerbations of the disease were recorded 2-3 times a year.While in the women from the control group, only 43.9% had kidney disease.
When analyzing the features of labor, it was found that in the patients with BC, 38% of deliveries were complicated by postpartum bleeding, for which 16% of women underwent uterine extirpation without appendages.Subsequently, 70% of patients with BC developed neuro-endocrine obesity after postpartum hemorrhage.
It is important to note that 21% of women were observed by a gynecologist for infertility on the background of hyperandrogenism and received dexamethasone for a long time.
In European and American countries, protective factors that determine reproductive behavior are clearly defined: childbirth before 20 years, prolonged breastfeeding, birth parity of more than 2, and childbirth after 35 years.The presence of protective factors in women reduces the cause of BC and excludes them from screening studies.It is known that in Kyrgyzstan there are traditions that determine the reproductive behavior of women.The reproductive behavior is not determined by two children, and childbirth before the age of 20 and after the age of 35 is widespread.Long-term breastfeeding is an integral rule and one of the methods of contraception.Despite positive trends in women's reproductive behavior, the incidence and mortality of BC remain high.Therefore, it is doubtful whether these factors are really protective for women living in Kyrgyzstan, or whether this category of women also requires close attention to their inclusion in BC screening programs.
This study analyzed the protective factors in the development of BC such as childbirth before 20 years, long-term breastfeeding, birth parity of more than 2, and childbirth after 35 years in women from the control group and patients with BC (Table 9).As can be seen from table 9, 37.2% of patients with BC had their first pregnancy before the age of 20 years, which ended in childbirth.It is important to note that 21.1% of patients with BC delivery were observed after 35 years.
Coming to breastfeeding, 89.2% of women from the control group were focused on breastfeeding and successfully implemented it.At the same time, 31.1% of these women breastfeed a child up to 2 years, 28.4% up to 1 year, and 26.2% up to 8 months.14.6% of women refused to breastfeed, 4.5% separation of the child due to the transfer of the child to the parents, and 4.2% due to illness.In the group of women with BC, 79.3% of women were breastfed, and the duration of breastfeeding up to 2 years was observed in 34% of women, 27% up to 1 year, and 24% up to 8 months.The reasons for refusing to breastfeed were similar to those of women in the control group (15.1%).
When analyzing the parities of labor in the studied women, we identified the following features.In the control group, 87% of women were pregnant, 65% of them were in labor, and 38.9% had 2 or more deliveries.84% of patients with BC had a pregnancy, 71% of them gave birth, and 15% of them reported premature births, while in the control group, this risk factor was 8%.Two births were registered in 34.7% of women.

DISCUSSION
A meta-analysis conducted by the Collaborative Group on Hormonal Factors in Breast Cancer revealed the risk of developing BC at the age of onset of menstruation of 13 years (16).Abortions don't contribute to the development of BC and neither spontaneous nor induced abortions increase the risk of BC (17).
In postmenopausal women, weight loss of 5% or more is associated with a reduced risk of BC (RR = 0.88, 95% CI: 0.78-0.98)(18).Early childbirth before 20 years of age may be a factor in reducing the risk of developing BC, but uncommon.In women with a hereditary burden, which contributes towards increased risk.Among women who have no relatives with BC, early births are related to a minimal risk of developing BC; among women with >2 relatives with BC, early birth is related to maximum risk (19).
The frequency of hereditary BC was 5-15% (20), predisposition genes that play a key role in the occurrence of BC.In particular, the risk of developing BC in carriers of mutations in the BReast CAncer gene 1, BReast CAncer gene 2, and Checkpoint kinase 2 genes by the age of 70-80 years is 65%, 45%, and 28-44%, respectively (21,22).
Many studies have shown that the use of hormonal contraceptives leads to an increased risk of developing triple-negative BC (23).A meta-analysis by Chen et al., showed obesity had different effects on premenopausal and postmenopausal BC risk, where obesity was associated with increased risk of BC in pre-menopausal women (24).
In patients who underwent screening mammography for many years, the density of breast tissue and the subsequent influence of this factor on the development of BC were evaluated.Among women with an increased radiological density of the mammary glands, both in the reproductive and postmenopausal periods, the risk of developing BC was increased by 1.5 times, earlier (RR = 1.52, 95% CI: 1.39-1.66),and later (RR = 1.53, 95% CI: 1.44-1.64)(25).
According to a meta-analysis conducted by Dyrstad et al. (26), the presence of cysts is accompanied by a statistically significant increase in the risk of developing BC (RR = 1.55, 95% CI: 1.26-1.90),and the presence of adenosis increases the risk of developing BC by two times (RR = 2.00, 95% CI 1.46-2.74)(26).It is necessary to remove even a histologically confirmed fibroadenoma in case of detection of tumor growth; it is desirable to remove fibroadenoma when planning pregnancy.In a metaanalysis of 11 studies, it was stated that the presence of fibroadenoma significantly increases the likelihood of developing BC (RR = 1.41, 95% CI 1.11-1.80)(26).Thus, we have proved that in women, both in the control group and patients with BC, there are no significant differences in the number of risk factors, but there is a difference in the number of premature births, which suggests premature pregnancy is a risk factor for BC.General recognised tendency about the effect of protective factors of BC is not adequate for residents of Kyrgyzstan, therefore, a study should be undertaken to determine the protective factors specific to Kyrgyzstan and, of course, the inclusion of the above-mentioned contingent of women in screening programs for early detection of BC.

CONCLUSIONS
1. Based on regression analysis, the presence and influence of specific risk factors for development of BC in women from Kyrgyzstan were proved: spontaneous miscarriages, premature birth, kidney disease, severe anemia, and severe postpartum bleeding.
2. There is no influence of well-known reproductive risk factors on the occurrence of BC in women from Kyrgyzstan (early menarche up to 12 years, late menopause after 55 years, late first pregnancy and childbirth, refusal to breastfeed).3. Protective factors of BC: childbirth before 20 years of age, prolonged breastfeeding, birth parity of more than two, and childbirth after 35 years of age are not specific for women from Kyrgyzstan and do not reduce the risk of BC.

CONFLICTS OF INTEREST
None.

Table 1 :
Well-known risk factors for the development of BC that characterize the functioning of the reproductive system in the control group Specific risk factors for the development of BC in women from the control group were presented in Table2.

Table 2 :
Specific risk factors for the development of BC in women from the control group

Table 3 :
Protective factors for the development of BC in women from the control group

Table 4 :
Well-known risk factors for the development of BC that characterize the functioning of the reproductive system in patients with BC

Table 5 :
Specific risk factors for the development of BC in women from the control group

Table 6 :
Protective factors for the development of BC in patients with BC

Table 7 :
Well-known risk factors for the development of BC that characterize the functioning of the reproductive system in the control group and patients with BC

Table 8 :
Specific risk factors for the development of BC in women from the control group and patients with BC

Table 9 :
Protective factors for the development of BC in women from the control group and patients with BC