Worldwide, breast cancer (BC) is the most common malignancy in women and the leading cause of cancer death. It is estimated that 1.5 million new cases of BC diagnosed annually with odds of getting BC is one in eight women    . Generally, high body mass index (BMI), low fruit and vegetable intake, lack of physical activity, tobacco use, and alcohol abuse are the five behavioral and dietary risks leading cause of 30% of cancer deaths    . International variation in female BC incidence and mortality rate could be attributed to differences in sociodemographic factors, reproductive patterns, lifestyle, and other hormonal factors    . Moreover, family history and age of women are the most two individual critical BC risk factors   .
In low-income countries, BC cases tend to young women with median age of 49 - 52 years whereas 63 years in high-income countries  . Early detection of BC would improve treatment and recovery, limit the complications and reduce the risk of mortality    . High BC mortality rate, particularly in developing countries, is due primarily to the detection of late-stage BC   . Therefore, the American Cancer Society recommended that women should have the opportunity to begin annual BC screening around the age of 40 years and should be encouraged to discuss their family history and medical history with a clinician. Also, they should be provided with information on BC risk factors and risk reduction  .
According to the Palestinian ministry of health (MOH), BC is 31.3% of women’s cancers in Gaza Strip and it is the second leading cause of female death after cardiovascular disease. Since the total number of reported BC cases between 2009 and 2014 was 1283 cases, out of them, 1207 were females and 76 were males. Furthermore, as has been estimated, the incidence rate of BC among Gaza’s females was about 83.9 per 100,000 women between 2009 and 2014, which was increased to 154.2 per 100,000 women in 2015  .
To the best of our knowledge, there was limited documented research on the extrinsic risk factors for women BC in Gaza strip. Therefore, the objective of this case-control study was to identify the distinct associations between extrinsic risk factors and developing BC among women in the Gaza strip. Understanding such associations is important to further our understanding of disease etiology and to provide personalized prevention and treatment measures.
2. Materials and Methods
2.1. Study Design and Setting
The present hospital-based case-control study was conducted between January and August 2018 with a representative sample of BC women. The study sample was compromised of 105 BC patients and 210 controls. Data about the study cases were collected in the only two oncology day-care clinics in the two main hospitals in Gaza strip “Al-Shifa hospital in Gaza governorate and European Gaza hospitals in Khanyunis governorate”.
2.2. Study Tool and Sampling
In this study, patients and controls were interviewed by well-trained interviewers. The interviewers used a structured and a validated questionnaire to collect information on sociodemographic characteristics and potential risk factors, such history of exposure to toxic gases, radiation and pesticides, body anthropometric measurements, history of medical conditions, history of maternal and reproductive health, lifestyle, and dietary habits.The computer program Epi Info version 6.04d was used to calculate the sample size using 5% precision with 95% confidence interval from the study population comprised of 1207 breast cancer women to be 105 patients.
Patients and controls were questioned about age at breast cancer diagnosis and history of cancer and breast cancer among their first and second-degree relatives. No proxy interviews were conducted. Smokers were defined as subjects who had smoked ≥100 cigarettes during their lifetime. Obesity measured by body mass index (BMI), a participant’s weight (in kilograms) divided by the square of her height (in meters). A participant with a BMI of 30 kg/m2 or more is considered obese. The dietary habits in our study contain a list of the 19 most common food groups; based on the results of the previous study  . Also, Participants were asked about the number of daily meals.
2.3. Eligibility Criteria
The case subjects were confirmed BC women by a histopathology test and recorded in one of the two above mentioned oncology day-care clinics. Whereas, the control subjects were healthy women and genetically unrelated family members of BC patients. The reason behind excluding family members of BC patients, as controls, is to avoid induction of selection bias. Control subjects were recruited from the vaccination departments at primary health care clinics, where women take their children for vaccination. Controls and patients were recruited simultaneously. The cases and controls were frequency matched by age group, marital status, governorate of residence, and nature of housing area.
2.4. Ethical Consideration
Approval to conduct the study was gotten from the Palestinian ministry of health. Also, written consent from participants was obtained after explaining the aim of the study. Great care was taken to ensure privacy and confidentiality.
2.5. Data Analysis
Data were analyzed using the Statistical Package for Social Science (SPSS) version 22 (IBM Corp, Armonk, NY, USA). Frequencies and percentages were calculated for all variables. Odds ratio (OR) with a 95% confidence interval was used to investigate the strength of association between the determinant factors and the outcome variable. Univariate logistic regression analysis was used to identify risk factors associated with the incidence of BC at p < 0.05 and 95% CI without controlling confounders. Multivariable logistic regression analysis was employed to examine the association between risk factors and BC incidence under controlling of potential confounding factors.
3.1. Sociodemographic Characteristics and Their Association with Breast Cancer
As shown in Table 1, a total of 105 BC cases and 210 controls were enrolled in this study. In both cases and controls Gaza Governorate had the largest number of cases (n = 48, 45.7%) as well as controls (n = 96, 45.7%). Age groups were divided into five groups since the age of the majority of the study participants was above 40 years (80%). Eighty-one (77.1%) of the cases were married. Regarding the educational level of the cases, 22 (21%) hold a university degree and 19 (18.1%) had a primary degree. Most of cases and controls, (n = 81, 77.1%) and (n = 162, 77.1%), respectively were married. Approximately 81 breast cancer women (52.4%) were diagnosed with BC at the age between 30 and 40 years, (n = 81, 17.1%) were diagnosed at the age less than 30 years, and (n = 32, 30.5%) were diagnosed at the age more than 40 years. Among the presented sociodemographic features presented in Table 1, the difference between the two groups reached a statistical significant level (p < 0.05) only in three factors, namely: number of family members, number of children, and kind of family house, indicating that they affect the chance of getting breast cancer disease and classified as one of the risk factors that affect breast cancer disease among women in the Gaza strip.
3.2. Risk Factors Associated with Breast Cancer in Univariate Analysis
The binary logistic regression analysis was applied to define the association between the potential risk factors and incidence of BC among women in the Gaza strip. The strength of association was achieved using the crude odds ratio (OR) at 95% CI confidence interval. As presented in Table 2, a number of risk factors related to the history of exposure to toxic gases, radiation, shells and pesticides, anthropometric measurements, and history of medical conditions found to be significantly associated with the incidence of BC (p < 0.05) without controlling for confounders. Regarding exposure to medical radiation, 74.3% from the 105 cases indicated that they exposed to medical radiation previously compared to 58.1% from the 210 controls. The difference between the two groups reached a statistically significant level (COR = 2.2; 95% CI: 1.3 - 3.7), which means that this factor has the ability to develop breast cancer among women two times more likely. Likewise, the increase of body mass index (BMI) more than 30 kg/m2 was significantly associated with getting breast cancer (p < 0.05) and 3.6 times more probable to cause breast cancer (COR = 3.6; 95% CI: 1.8 - 7.5). Additionally, hypertension showed a positive association with the developing of BC (p < 0.05). The chance of getting breast cancer among women who had high blood pressure was three times more than women who did not have hypertension (COR = 3.0; 95% CI: 1.5 - 6.0). Diabetes was found to be positively associated with BC and it was a risk factor for developing BC (COR = 2.3; 95% CI: 1.3 - 4.4). However, no significant association was found for the other factors (p > 0.05).
The results in Table 3, present that women age at first pregnancy was significantly associated with BC (p < 0.05) and a difference between the two groups was shown since the age between 19 and 24 years old was protective factor (COR = 0.5; 95% CI: 0.3 - 0.9) while the age of more than 24 years old was risk factor for developing BC (COR = 1.3; 95% CI: 0.6 - 3). Also, last pregnancy time showed a statistical significance (p < 0.05). Furthermore, prolonged breastfeeding between 13 and 24 months displayed a statistical significance (p < 0.05) and protecting factor (COR = 0.3; 95% CI: 0.2 - 0.6). Likewise, reaching menopause was significantly associated with BC (p < 0.05) and 3.6 times more likely to develop BC among women in the Gaza strip (COR = 3.6; 95% CI: 2.2 - 5.9). Nevertheless, the other factors showed no significant association with BC.
Table 4, indicated that a statistically significant relationship between the history of BC in the family and getting BC (p < 0.05) with 2.7 times more likely to cause BC (COR = 2.7; 95% CI: 1.7 - 4.4). As well, getting BC was 3.8 times more probable in the case of a history of incidence of BC in one of the first-degree relations (COR = 3.8; 95% CI: 1.4 - 10.3). The daily walking exercise was a protective factor of BC (COR = 0.6; 95% CI: 0.3 - 1.2) and (COR = 0.4; 95% CI: 0.2 - 0.7) for daily waking minutes less than 20 and between 20 and 40 minutes, respectively.
As revealed in Table 5, among the included 19 food groups, only sex factors were significantly associated with the incidence of BC among women in the Gaza strip (p < 0.05), namely: vegetable oils, snacks, fruit, beans and legumes, sugar, sweets and desserts, and vegetables. Moreover, the number of daily meals also was significantly associated with BC.
3.3. Risk Factors Associated with Breast Cancer in Multiple Logistic Regression Analysis
Variables with p < 0.05 in the univariate model were inserted into the multivariate model. Many variables missed their association with BC in the multivariate model under adjustment for all confounders. Table 6, shows that woman with BMI more than or equal 30 kg/m2 are under risk of getting BC 2.9 times greater than those have BMI less than 29 kg/m2 (AOR = 2.895; 95% CI: 1.305 - 6.423). Analysis of risk according to reaching menopause showed that the estimated AOR was greater among those reached menopause (3.137, 95% CI 1.824 - 5.395) than among those did not reach menopause. The risk of developing BC in the case of a history of BC incidence in the family was more than two times higher (AOR = 2.632, 95% CI 1.528 - 4.535) than in case of the history of a free family of BC.
Table 1. Sociodemographic features of the study population.
n = Frequency; Ref = Reference category; COR = Denotes crude odds ratio using 95% confidence interval in univariate logistic regression analysis; CI = Confidence interval; p < 0.05 = significant on univariate analysis; NIS = Denotes New Israeli Shekel, the local currency (1 USD ≈ 3.63 NIS).
Table 2. History of exposure to toxic gases, radiation, shells and pesticides, anthropometric measurements, and medical conditions risk factors and BC among women in Gaza strip.
Table 3. Maternal and reproductive health risk factors and BC among women in Gaza strip.
Table 4. Family history of cancer and life style risk factors and BC among women in Gaza strip.
Table 5. Univariate model of dietary habits and their association with breast cancer among women in Gaza strip.
Table 6. Multiple logistic regression model of risk factors and BC among women in Gaza strip.
AOR = Denotes adjusted odds ratio using 95% confidence interval in multivariable logistic regression analysis; B = slope; CI = Confidence interval; p < 0.05: Significant, p > 0.05: Not significant.
The primary purpose of knowing the risk factors related to breast cancer is to take precautionary measures to prevent the incidence of breast cancer. Therefore, we investigate potential risk factors for breast cancer among women in the Gaza strip, Palestine. The outcomes of this study, in the multivariate model, have indicated three risk factors associated with the incidence of BC among Gazan’s women namely: high BMI more than or equal 30 kg/m2, reaching menopause, and history of BC incidence in the family. On the other hand, in the univariate model, several factors seemed to be risk factors for BC.
Previous epidemiological studies have reported that premenopausal obesity is generally protective for breast cancer  , while postmenopausal obesity is associated with increased risk  . Our case-control analysis revealed that patients with a BMI of 30 kg/m2 or more had more chance for getting disease compared with patients with a BMI below 29 kg/m2 (p < 0.001). Our findings in this regard are in line with the results of former research in other countries    . Moreover, there is no evidence that the assumption of a simple linear or a log-linear relationship between BMI and BC risk is real, in particular when BMI is less than 25 kg/m2  . The mechanisms underlying the relationship between high BMI and BC in women was discussed in the literature and it was primarily the result of the associated increase in estrogens, particularly bioavailable estradiol   .
With respect to menopause age and risk of breast cancer in women, findings of the present study also indicated that reaching menopause was significantly associated with developing of breast cancer among women in Gaza strip. Similar outcomes were reported in previous studies stated that breast cancer is a disease of older women and its incidence increases with age, and it is rare below the age of 20 years     . More than half of patients in our study were between the third and fourth decade of their life, in contrast to the western countries where only 23% of women younger than 40 years presented with breast cancer  .
The significant association between the family history and BC among women in Gaza strip indicated to imply a genetic predisposition  . We herein, recommend more investigation to find out what gene linked to BC. In any case, the literature indicates a family history of BC in any first-degree relative is known to increase a women risk of disease onset     . In addition, these results are consistent with the work of Buxton et al.,  , Caruso et al.,  , Silk et al.,  , Aljohani et al.,  , and a meta-analytic review by Katapodi et al.,  all of whom found an association between risk perception and family history of breast cancer. In developed countries, about twenty-five percent of inter-individual differences mainly due to genetic causes of BC  . Our finding regarding the significant association between the exposure to ionizing radiation and the initiation of breast carcinoma was compatible with the results of previous research   .
According to the results of previous research, exposure to ionizing radiation after 40 years of age does not significantly influence the genesis of breast cancer, but exposure to radiation before 20 years of age significantly influences the initiation of breast carcinoma  . An investigation indicated that exposure to diagnostic radiation is accountable for 29 BC cases per year in women in the UK, aged up to 75 years  .
Our study indicated that there is no association between breast cancer and exposure to pesticides, although there is growing scientific evidence of a link between exposure to pesticides and increased incidence of breast cancer  .
The present study findings in the univariate model revealed that diabetes and hypertension were a risk factors for BC, this results were consistent with the conclusion of the Boyle et al., meta-analysis found a significantly increased risk of breast cancer among women with diabetes, furthermore, the mechanisms that could increase the breast cancer risk were discussed  . Though our study had limited power, our result warrants further investigation and future studies should stratify their analyses by menopausal status particularly because of the increase of chronic diseases epidemics such as hypertension and diabetes among Palestinian population  . The potential for an increased risk of BC in women with hypertension has been the subject of a great deal of recent research. A strong correlation between hypertension and BC in women has concluded in some earlier studies     , however weak relationship was reported in other research   . Furthermore, several studies showed that the association was confounded by obesity and high BMI   .
In this study, the association between BC and intake of different food groups such as vegetable oils, snacks, fruit, beans and legumes, sugar, sweets and desserts, and vegetables. However, other studies revealed that intakes of cereals and grains, vegetables and beans are associated with the reduction in risk of early-stage breast cancer among young women  . High risk was shown for all types of meat and fish intake, whereas intakes of eggs and milk were associated with a decreased risk of breast cancer  .
Knowing the risk factors for breast cancer may help take preventive measures to reduce the likelihood of developing the disease. Our survey shows that women with body mass index, reaching menopause, and history of BC in the family are the three main risk factors of BC among women in Gaza strip. Here, educational programs target at women living in Gaza to make them aware and address the misconceptions of the BC risk factors. Moreover, campaigns to promote the concept of screening for breast cancer among both public and healthcare sectors are critical to improving the rates of early detection of breast cancer in Gaza in order to be able to save lives and for reinforcing societal positive attitudes towards breast health care, including support from family and friends.
Some patients did not respond to questionnaire and reject to participate in the study.
SY and MY participated in the design of the study and data collection. MD and AM performed the statistical analysis and drafted the manuscript. SA supervised the study and participated in draft review. All authors have read and approved the final version of the manuscript and agree with the order of presentation of the authors.
The authors are grateful to the Palestinian Ministry of Health for giving us a permission to conduct the study in Gaza strip. Also, women who participated in our study are thanked.