Investigation Risk Factors for Breast Cancer in Women: A Case–Control Study in Arak, Iran


 BackgroundBreast cancer is the most common malignant in women globally. In Iran, breast cancer incidence rate is continuously increasing. This study aimed to investigate the risk factors for breast cancer in Iranian women.MethodsA hospital-based case-control study was conducted between September 2016 and July 2019 in Arak, Iran. The sample size was 400 breast cancer patients and 400 healthy women. Demographical records and risk factor related data were collected. Logistic regression analysis used to calculate odds ratios (ORs) and 95% confidence intervals (CIs).ResultsData showed that among various factors, urban life (OR = 1.361, 95% CI 1.025–1.808, P = 0.033), height (OR = 3.347, 95% CI 2.0443–5.480, P = 0.000), BMI (OR = 0.397, 95% CI 0.273–0.577, P = 0.000), education level (OR = 7.048, 95% CI 3.985–12.467, P = 0.000), awareness level (OR = 0.507, 95% CI 0.349–0.736, P = 0.000), job status (OR = 0.321, 95% CI 0.122–0.846, P = 0.022), economic status (OR = 4.333, 95% CI 1.424–13.184, P = 0.010), early menarche (OR = 2.815, 95% CI 1.745–4.541, P = 0.000), Stillbirth status (OR = 1.935, 95% CI 1.087–3.446, P = 0.025), family history (OR = 10.281, 95% CI 3.628–29.134, P = 0.000), behavioral habits (OR = 0.554, 95% CI 0.386–0.796, P = 0.001), and second-hand smoking (OR = 1.472, 95% CI 1.108–1.955, P = 0.008) significantly were associated with an increased risk for breast cancer.ConclusionThe data suggest that lifestyle may have more impact on the incidence of breast cancer in Iranian women, suggesting change unhealthy lifestyle and screening for preventing breast cancer.


Abstract Background
Breast cancer is the most common malignant in women globally. In Iran, breast cancer incidence rate is continuously increasing. This study aimed to investigate the risk factors for breast cancer in Iranian women.

Methods
A hospital-based case-control study was conducted between September 2016 and July 2019 in Arak, Iran.
The sample size was 400 breast cancer patients and 400 healthy women. Demographical records and risk factor related data were collected. Logistic regression analysis used to calculate odds ratios (ORs) and 95% con dence intervals (CIs).

Conclusion
The data suggest that lifestyle may have more impact on the incidence of breast cancer in Iranian women, suggesting change unhealthy lifestyle and screening for preventing breast cancer.

Background
Cancer is one of the main global health issues, with an estimated 10 million incidents and 6 million annual mortality rates, and this gure is estimated to reach 11 million by 2030 [1]. Breast cancer is the most prevalent cancer and the leading cause of death among women globally [1,2]. The incidence of breast cancer and mortality rates differs in various centuries, the highest incidence rate belongs to the USA and the lowest reported in Asia. Nevertheless, the incidence is increasing in Asian countries [3]. In Iran, breast cancer is one of the most frequent cancers in women and its incidence rate is continuously increasing. Incidence age in Iranian women is in the fourth and fth decades of life, which is a decade younger than the global age of incidence [4]. Breast cancer is a multifactorial disease that caused due genetics, hormones, environmental, sociobiology, physiology, reproductive, dietary and lifestyle-related risk factors [5][6][7]. Identifying risk factors can play an important role in reducing/preventing the risk of breast cancer which, in turn, results in reducing mortality rates, improving the health of women, increasing the quality of life, and reducing the economic and social costs [1]. When risk factors are well understood, healthcare providers can supply women with more accurate information regarding their risk of developing breast cancer [8]. Worldwide, numerous studies have sought to know the risk factors for breast cancer. However, there has been no consensus because of differences in sample sizes, races that comprised study populations, and local customs [9,10]. Besides, the risk factors of breast cancer may vary among different populations [11]. Currently, national monitoring data on risk factors among the Chinese general population are limited. The aim of this study was to investigate the risk factors for breast cancer in Iranian women in Arak. Risk factors determined in our study will help to identify Iranian women who have an increased risk of breast cancer and support effective early detection and disease prevention interventions.

Methods
This hospital-based and case-control study was approved from the ethics committee of Arak University of Medical Sciences, Arak, Iran (IR.ARAKMU.REC.1395.288) and conducted between September 2016 and July 2019 at the Ayatollah Khansari Hospital in Arak, Iran. The sample size is determined using Quanto 1.2 application. That was obtained using substitution on the software with α = 0.05 and power of 80% and calculated sample size of 400 in each group [12]. A sample size of 400 cases including women with breast cancer that diagnosed with breast cancer by an oncologist with pathological tests and 400 controls including healthy women without breast cancer was found to be adequate to test the signi cance. Control samples were prepared by women in the same hospital. Cases and controls were age-matched. Socio-demographic, reproductive, behavioral habits and chronic diseases data as probable risk factors data were collected from both groups using a questionnaire face to face. The questionnaire consisted of details including socio-demographic data such as name, age, height, weight, location, education status, job status, economic status, awareness of breast cancer and reproductive information including age at menarche, age at menopause, nulliparous status, number of births, marital status and rst childbirth status, stillbirth, abortion status, oral contraceptives status, breastfeeding, and behavioral habits information like diet (lack of consumption of vegetables and fruits and consumption of food highfat, fried food and fast food), smoking, physical activity, second-hand smoking and chronic diseases information including hypertension, diabetes mellitus, family history of breast cancer ( rst and second degree relatives). BMI (kg/m 2 ) was categorized as; normal range 18.5 to 24.9 kg/m 2 , overweight 25 to 30 kg/m 2 and obese ≥ 30 kg/m 2 [13,14]. Statistical analysis was done using the software SPSS version 16. Binary logistic regression analysis was performed to evaluate the association of various risk factors with the risk of breast cancer, displayed as odds ratios (OR) with 95% con dence intervals. P < 0.05 was considered statistically signi cant.

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Risk factors for breast cancer in a statistical population that total of 800 women, including women who have been diagnosed with breast cancer (cases, n = 400) and women who don't have breast cancer (controls, n = 400), were studied. Socio-demographic characteristics and their association with risk of breast cancer for the case and control groups are shown in Table 1  We found a signi cant difference in the height value of controls (158.6 ± 4.2 cm) and cases (161.4 ± 5.3 cm) (P < 0.05). The mean weight of controls was 70 ± 7.5 kg and that of cases 68 ± 7.3 kg (P > 0.05).
In addition, 37% of the cases and 44.5% of the controls lived in the rural area. 7.25% of cases lived in the urban area, which was higher than of controls; there was statistical signi cant difference between location statuses and breast cancer in two groups (OR = 1.361, 95% CI 1.025-1.808, P = 0.033) ( In keeping, we studied the association between reproductive factors and breast cancer ( Table 2). We found that the mean age of menarche was 12.9 for cases and 13.3 for controls. There was signi cant statistical difference between the age of menarche in statuses < 12 (OR = 2.815, 95% CI 1.745-4.541, P = 0.000) and 12-13 (OR = 2.013, 95% CI 1.485-2.729, P = 0.000) with risk of breast cancer. Early menarche is associated with increased risk of breast cancer. Furthermore, menopause status (yes or no) and age were studied, which can be seen in Fig. 3. Mean age of menopause was 47.7 for cases and 47.5 for controls. There was no signi cant association between risk of breast cancer and menopause status as well as age (Table 2). Marital status was investigated in two groups ( Table 2). The frequency of single and married individuals in both groups did not differ much, thus, we found no association between the marital statuses and breast cancer.
Having children (yes or no) and number it (< 2 or ≥ 2) was investigated in two groups. Our nding indicated that there was no relationship between the numbers of children and breast cancer. In addition, data from Table 2  Through Table 3, we presented the association between risk of breast cancer and either chronic diseases or behavioral habits. There was no signi cant association between breast cancer and the hypertension (OR = 1.252, 95% CI 0.737-1.304, P = 0.306) as well as diabetes mellitus (OR = 1.332, 95% CI 0.638-2.781, P = 0.445). However, we showed a statistically signi cant association between the family history and breast cancer ( rst-degree relatives, OR = 10.281, 95% CI 3.628-29.134, P = 0.000) and (seconddegree relatives, OR = 3.324, 95% CI 1.403-7.874, P = 0.000).

Discussion
In Iran, along with worldwide, breast cancer is one of the most frequent cancers [4]. We performed a casecontrol study involving 800 Iranian women to evaluate the relationship between breast cancer and such risk factors as socio-demographic, reproductive, chronic diseases, and behavioral habits.
As shown in Table 1, we found that more than 48% of patients were younger than 50 years, patients were between 41-50 years, which is in line with results of Akbari et al. study [4]. This con rms breast cancer patients in Iran are relatively young and breast cancer occurs a decade earlier in Iranian women in comparison with women of western countries [15]. In addition, our study provides additional support for a great risk factor for patients living in urban regions, a nding that is consistent with previous studies [16,17]. Breast cancer shows a large urban-rural difference worldwide [18]. Due to differences in lifestyle, dietary choices, and the environmental pollution in urban life, it was considered as a risk factor for breast cancer incidence in contrast to rural life factor [14,19,20]. In contrast, in a study conducted on Chinese women by Liu et al. the converse results were reported, where the rural life was considered as a risk factor for breast cancer [11].
Weight gain increases the risk of breast cancer [21]. Weight loss in early adulthood and after menopause is related to reduced breast cancer risk [22,23]. In contrast, it was con rmed that excess body weight protects against premenopausal breast cancer risk [24]. Our study showed no signi cant relationship between weights and breast cancer. Besides, previous studies showed that taller women have a higher risk of breast cancer than shorter women [25,26]. But in our study, there was a signi cant association between height status of short and the risk of breast cancer. Further studies are needed on the association between height and the risk of breast cancer. High values of BMI are associated with increased risk of breast cancer after menopause [27,28]. Similar to previous reports, we found an association between increasing BMI and the risk of breast cancer [11,13]. This is probably due, in part, to higher estrogen levels because fat tissue is the largest source of estrogen in postmenopausal women [22].
The ndings of various studies on the relationship of levels of education and breast cancer risk are controversial, but some studies have suggested an association [29,30]. We found a correlation between low levels of education with an increased risk of breast cancer. In contrast, it was reported that there is no relationship between education status and risk of breast cancer [13,31]. In keeping, in consistent with Liu et al. [11], we also showed a statistical signi cance difference between awareness level with risk of breast cancer. The high level of awareness about risk factors related to breast cancer and screening may help to prevent/ reduce the risk of breast cancer [32]. Women's job is another factor that we involved in our study and showed a signi cant association between job status and breast cancer, supporting the results of previous studies [33,34]. Women in professional and managerial jobs have 1.4-2.0 times greater risk of breast cancer than women in lower-status jobs [35]. A case-control study conducted by Chatchai et al. [36] reported an increased risk of breast cancer in women who worked in manufacturing, transport equipment operators and laborers. There was a signi cant association between the job status of the employee and the risk of breast cancer. In another word, the job status of the employee is associated with a reduced risk of breast cancer. Researchers believe that employee women generally have higher income and are more likely to use health insurance and spend the most on healthcare [37]. However, it seems that the association of job status with risk of breast cancer remains unknown or controversial [38,39]. This needs further investigation. It was suggested that higher economic status is associated with increased breast cancer risk [40]. In contrast, our result suggested an association of the economic status of the poor with breast cancer that is consistent with data of Liu and co-workers [11].
The association between reproductive risk factors and breast cancer has previously been reported [41]. As can be seen in Table 2, we found the early menarche increased risk of breast cancer. Correlation between early menarche and increased breast cancer risk may be attributed to the earlier exposure and higher levels of estrogen experienced by women who had early menarche [42]. The results of our study on the age of menarche are consistent with other studies [42,43]. Breast cancer risk increases with later menopause [44]. Women who experience menopause at age 55 or older have about a 12% higher risk compared to those who do so between ages 50-54 [45,46]. In our study, we found no signi cant association between breast cancer risk and late menopauses. This is in good agreement with previous studies [29,31]. In case of the marital status, in consistent with previous reports [13,33], we demonstrated that there was no relationship between the marital status with the risk of breast cancer. However, others found a signi cant correlation between marital status and breast cancer [47].
A growing body of evidence showed that single women have a higher risk of breast cancer than married women [48]. Married, divorced, and widowed women have no inherent differences in their risk of breast cancer than with single women, and that the apparent protective effect of marriage maybe because of the age of their rst pregnancy and childbirth [31,49]. Nulliparous women are more at risk to attain breast cancer than those who have given birth many times. Women having children have 30% reduced risk compared to nulliparous women, in other words with each full-term pregnancy, the risk falls overall by 7% [50]. But in our study, as shown in Table 2, there was no association between the number of children (having or not having children) with breast cancer, which substantiates previous ndings in the literature [13,29]. These ndings signi cantly differ from previous results reported in the literature [11,31].
Use oral contraceptives pills has been associated with increased risk of breast cancer in young women [51,52]. The International Agency for Research on Cancer came to deduction that there was su cient evidence to support combined estrogen-progestin oral contraceptives carcinogenicity in humans, with an increased breast cancer risk [53]. In our study, there was no association between the use the oral contraceptives pills and breast cancer that is consistent with previous reports [54][55][56][57]. Similarly, we found no association between abortion and breast cancer, which is consistent with previous studies [11,54]. To best our knowledge, few studies have been conducted on the association between stillbirth and breast cancer. In a study, a signi cant association between stillbirth and reduced risk of breast cancer was reported [58]. We also found an association between the stillbirths and increased risk of breast cancer [58]. Breastfeeding has a protective role against risk of breast cancer [59]. In the 47 studies in 30 countries, the risk of breast cancer was reduced by 4% for any 12 months of breastfeeding [59].
Breastfeeding considered as an uncertain protective factor due to indecisive results [60]. But we obtained different results so that, there was no signi cant association between breastfeeding and breast cancer.
Our results share a number of similarities with previous ndings [11,54]. It may discuss that marital status by itself is not a decisive factor for reduced or increased breast cancer risk.
We also investigated an association between chronic diseases and behavioral habits and risk of breast cancer. As shown in Table 3, the hypertension was not associated with breast cancer risk. Our data is consistent with studies conducted by Wang et al. [61] and Sun et al. [62]. One cohort study, one nested case-control study and ten case-control studies showed that hypertension is associated with increased risk of breast cancer [63]. In addition, in our study, in contrast with literature, there was no signi cant association between the risk of breast cancer and either diabetes [64][65][66] or the physical activity [33,67] and or the smoking status [33,68]. But we found a signi cant association between the second-hand smoking and breast cancer, which shares similarity with ndings of Reynolds et al. [69]. The majority of studies have shown that a family history of breast cancer is one of the major risk factors [24,25]. In our study, we demonstrated that the family history of breast cancer, in the rst degree relatives and seconddegree relative was associated with the susceptibility to breast cancer.
We investigated behavioral habits as a risk factor for breast cancer ( Table 3). The positive association between unhealthy dietary patterns (low or no consumption of vegetables and fruits, high consumption of high-fat food, fried food and fast food) and breast cancer has been reported [68]. In our study, we found that a healthy dietary was associated with a reduced risk for breast cancer risk, while an unhealthy dietary pattern was increased the risk of breast cancer. Our nding is consistent with previous reports [70,71]. Increased consumption of fatty, fried, and fast foods should be replaced with an increase intake of fruits and vegetables so that, it is necessary to raise awareness about healthy diets and reduced risk of breast cancer. In some studies, the role of alcohol carcinogens and its association with breast cancer has been addressed [72,73]. Numerous studies show that alcohol consumption increases the risk of breast cancer in the female by about 7%-10% for each 10 grams of alcohol consumed per day on average [74,75]. We found a non-signi cant relationship between alcohol consumption and breast cancer so that consistent with some studies conducted [11,76].
Our study has some limitations; since the present study is a hospital-based case-control study rather than population-based, it may make selection bias. In addition, it is notable that this hospital treats a part of the breast cancer cases in Arak, Iran. Most of the data were recorded from the women's self-reports, thus bias was more possible; thus participants history records were checked.

Conclusion
In the present study, we showed that breast cancer patients in Iran are relatively young. We found a signi cant association between risk of breast cancer and urban life, height, BMI, awareness level, job status, economic status, early menarche, second-hand smoking, family history, and behavioral habits. However, we showed that there was no a signi cant association between breast cancer and such factors as weight, education level, late menopauses, marital status, the number of children, the oral contraceptives pills, abortion, chronic diseases, alcohol consumption, and breastfeeding. It seems that lifestyle factors exhibit a greater risk than the effects of chronic diseases and reproductive factors for breast cancer of women in Arak, Iran. Therefore, various modi able factors may participate in the prevention of breast cancer risk in women in Iran. Determining and identifying the risk factors of breast cancer can play an important role in preventing the incidence of this disease so that a screening plan for high-risk female must be put on the agenda.

Declarations
Availability of data and materials The primary data for this study is available from the authors on direct request.