There is an international variation in incidence of breast ca whose reason remains unclear. These variations were seen between countries with high and low income. Many of the risk factors for breast ca have been investigated but still there is a need to examine these factors in the various nations.
In this study we examined a broad spectrum of risk factors for breast ca including the women’s reproductive factors. The reproductive risk factors for breast ca identified for Palestinian women are shown to be similar to those observed in other studies. This study provides clear evidence that late menarche poses additional risk for breast ca. Early marriage and having children early in life were shown to increase the odds of having breast ca, which is still very popular in the Palestinian community. The roles of using oral contraceptives and hormonal replacement therapy on women’s health were shown evidently. Therefore, there should be a rational use of hormone whether as a birth control tool or in therapy. Having children proved to be protective against breast ca, but since most married women in Palestine are shown to breastfeed their children, we could not show the breastfeeding as a protective factor from breast cancer among this study group. However, we can still emphases on the role of breastfeeding on breast ca protection. Therefore, more in-depth investigations are needed to identify the relation of various factors especially of the protective role of having children and breastfeeding practices on breast ca protection in Palestine. Special attention should be considered for the special social and cultural factors related to sexual and reproductive issues among women in Palestine.
Several studies reported that women in the high socioeconomic status (SES) are at risk for breast ca , with an overall estimation of 20% increased risk . This positive association was clearer among Hispanic and Asian women , and not only for breast ca, but also for other cancers such as colon, ovary and melanoma cancers . Our study found that breast ca was more common among more educated than in less educated ladies and among women having less family income compared with women with higher family income. In the Northern area of Palestine, a previous study showed that there was an increased risk for breast ca by 4 folds among highly educated women , which was also reported among Egyptian women . However, among European women, a direct dose response relationship was seen between education level and postmenopausal breast ca incidence . Considering type of living place in our results, it was found women living in an apartment had significantly less risk of getting breast ca when compared to those living in a separate home that are assumed to be from a higher SES. In the United States, a study showed a significant trend of higher incidence with increasing SES . Other studies showed that the lower SES increased the risk of breast ca, as females had less awareness toward screening techniques and diagnosis . Our results could have the explanation that women generally who have more family income are able to afford health insurance and is more willing to spend money on their health with better medical care access. Also, the increased awareness among educated in having a mammography screening test compared to less educated women is very clear in Palestine. It is worth mentioning that screening in Palestine is free of charge for all women over 40 years of age. Another possible explanation is that the more the woman is educated the later they get married, have late pregnancy age, practice less breastfeeding periods, and have a lower parity which are the characteristics of women from higher SES. Indeed, socio-economic inequalities could affect the time of diagnosis, survival or mortality due to cancer despite improved knowledge, reduction of risk factors for cancer, early diagnosis and treatment .
Consanguinity is becoming a very strong factor for many diseases such as cancers and other genetic diseases in many countries [8,44]. Our study showed that daughters of unrelated parents showed a decreased breast ca risk, whereas those with first degree relative parents had increased risk by 2.5 folds. Similar finding was reported in United Arab of Emirates (UAE) in which unrelated parents of the subjects decreased the risk to the half (RR=0.5, 95%CI: 0.27- 0.93). This genetic issue was investigated in a study conducted in Palestine, which showed a real genetic mutation among breast ca females who had related parents, but the study revealed that although the consanguinity rate is high in the Palestinian population, no significant difference exists between consanguinity in breast ca and controls, but the sample size was very low . However, a study among Israeli Arabs who are Palestinian in origin, showed an increase in diabetes and duodenal ulcer . Consanguineous practices in populations might affect the gene frequency in these populations, which could lead to a major effect on the carrier rate of such genes. Therefore, in countries with high consanguinity, the incidence of several diseases and syndromes should be monitored with caution. Although some studies showed that there is a trend of decreasing breast cancer incidence with an increasing consanguinity rate [46,47].
It is believed that up to 10% of breast ca cases in Western countries were due to genetic predisposition  with a threefold increase in the risk of breast ca among those with family history of breast ca . The consistent increase in the risk was when the relative is a mother or a sister . In our study, women with a family history of breast cancer had a 4 folds increased risk to have breast ca. In Qatar, a country with high consanguinity marriage, a study showed that consanguinity was lower in breast cancer patients than in Controls, but family history of breast cancer was significantly more often in breast cancer patients . The relative risk of breast ca ranged from 1.5 to 3.6 in a pooled analysis depending on the relative degree, with the highest risk was reported among women who had a mother or a sister with breast ca . Furthermore, women living in the Gaza Strip and who had a positive family history of breast ca showed an increased the risk for breast ca (OR=2.7, 95%CI: 1.04-7.20). Similar results were reported among Moroccan women (OR=11.15, 95%CI: 2.54-49)  and among Algerian women where the odds for breast cancer was 4 times among those with a family history of breast ca (95%CI: 2.22-7.77) . These two factors, i.e. consanguinity and family history of breast cancer, might have a synergistic effect in such studies and the risk might be greater if combined in these women.
Early age at menarche, late age at menopause, and late age at first full-term pregnancy are linked to a modest increase in the risk of developing breast cancer [22-24]. Also, parity and age of marriage are amongst the most known extrinsic factors that modulate breast cancer risk. It is well documented that parity has a dual effect on breast cancer risk with an increased risk during 5 to 10 years after pregnancy, followed by a strong and life-long protective effect [18,54].
In several studies, older age at menarche was inversely associated with breast ca risk. The high risk groups were females with menarche before age of 12 years (OR 1.5) , or 11 years . On the other hand, the protection was in females who had menarche after 14 years (OR=0.84, 95%CI: 0.65-1.09). Furthermore, it was found among 117 studies that breast ca risk was increased by a factor of 1.050 for every year younger at menarche , and a delay of 2 years at menarche had led to a 10% reduction in breast ca all around the world . This protection applied for all cancer subtypes (OR=0.72) . Older age at menarche in our study was shown to be associated with increased risk of breast ca. The risk was significantly increased by three folds by menarche at the age of 13 or more. Similar results were found among Moroccan women, where age at menarche of less than 13 was significantly associated with breast ca [52,52]. Also, in the North area of the West Bank, and estimated risk of 6.5 increased the risk for breast ca too. The protective results of older age at menarche was explained by decreasing in the cumulative number of ovulatory cycles, which is negatively associated with the risk, so with younger age at menarche, and with older age at menopause, a female would have more cycles, and so increased risk [58,59]. Consistent to our findings, was a Chinese-Vietnamese study which showed a slight increase in the risk of breast ca with older age at menarche .
According to the Palestinian Center Bureau of Statistics (2016), the mean age for the first marriage was 19.8 years in the southern region of Palestine . Consequently, many women might have their first pregnancy and first delivery at a young age (below age 18 years). Women with breast ca in our study had a mean age of marriage of 20.4 years (SD=5.44). Our multivariate results showed an inverse association between age at first marriage and age of first pregnancy with breast ca. We could not see a difference whether a women had her first child before age of 18 years or after. In contrast, a study in the North region of the West Bank showed that there was a 10% increase in the risk of breast ca when the first marriage was below 20 years of age . Another study in Gaza Strip showed that women who had their first pregnancy after the age of 35 years had an significantly increased for breast cancer by 11 folds . Our results may be different from these studies due to the inconsistency in the cutoff point. In addition, multi-parity was shown to be protective among Moroccan women .
Our results revealed no significant association between full term pregnancies and the risk of breast ca. However, number of full term pregnancies was negatively associated with BREAST CA risk in almost all studies, even in the western world. This result was consistent not only for one type, but all subtypes of breast ca, for pre and post-menopausal women . The reduction in the risk ranged from 18% to 60% [25,56,63]. Even in the Northern region Palestine, a 50% decrease in the risk was reported among women with 4 full term pregnancies or more .
One of the well established protective factors against breast ca is breastfeeding . In our results, almost all women who had children had practiced breastfeeding, but the protective effect in our analysis wasn’t in breastfeeding itself, but in its period. Previous studies found that breastfeeding itself was protective; A Saudi study reported that never having breastfed had doubled the risk (OR=1.89, 95%CI: 1.19-2.94) . Furthermore, breastfeeding decreased the risk of having breast ca by almost 60% in an Israeli study in our region, (OR=0.39, 95%CI: 0.26-0.59) . Similar result was reported in Morocco with a 35% risk reduction (OR=0.65, 95%CI: 0.55-0.78) . Other results even in USA confirmed this association with 14% increased risk among women who had never breastfed, (RR=1.14, 95%CI: 0.17-1.38) . Breastfeeding has been proposed to protect against breast ca through hormonal mechanisms that include postponing the resumption of ovulatory menstrual cycles after a pregnancy , reducing estrogen levels in the breast , and having fully differentiated breast tissue which is less susceptible to the hormones . In addition, it has been proposed that breastfeeding also has a direct mechanical effect by which carcinogenic agents are excreted from the breast ductal tissue .
Upon examining period of breastfeeding, results of studies were inconsistent. A study that summarized findings from developed countries showed that for every year a woman breastfed, her risk of developing breast ca was reduced by 4.3% . Similar results were reported in an American study for different age and ethnic groups . In China, the risk was reduced to the half in those who breastfed more than 3 children compared to those who never lactated (OR=0.53, 95%CI: 0.27-1.04) . An article review showed that OR was 1.37 for never breastfed compared to 16 months or more of breastfeeding . In our study, a very clear inverse dose response relationship was found, with AOR=0.39 for the group of 9 years or more of breastfeeding, compared to never breastfed, with a decrease the risk by 25% to 30% for additional 3 years of breastfeeding. Among Palestinian women in the north, the risk for those who never breastfed was doubled compared to those who had lactated for 4 years or more . It was found that the reduced risk was only for hormone negative disease. On the contrary, no association was found between breastfeeding period and the risk of breast ca , either in developed or developing countries .
With regards to the use of hormonal contraceptive pills (OCP) and their association with breast Ca, our study showed that oral OCP past use for more than two months significantly doubled the risk for breast ca (AOR=2.22), but could not show the duration effect on the risk of using OCP on breast ca. Similar result were revealed among Jordanian females [73,74]. The regular use of OCPs in Jordanian women was shown to be associated with increased risk of breast cancer in (OR = 2.25, 95% CI 1.34-2.79; p = 0.002), while the duration of OCs use was not associated with the increased risk of breast cancer (p > 0.05) . However, many studies found a slight increase in the risk . Other studies reported that the increased risk was only for the next 10 years just after the last OCP use . Some studies on the other hand, found a decreased risk among women but at least after 10 years of the last use of OCPs . A study in Iran showed that long term OCP use (>/=10 years) (OR = 3.17, 95% CI: 1.27-7.95, P = 0.01) increase the risk for breast ca . On the contrary, some studies showed a protective role of OCP from breast ca. A study in Central African Republic showed a decrease in the risk for breast ca (0.62) . In Palestine, 54.8% of married women aged 15–49 years reported using contraception and 44.0% of women of reproductive age used modern contraceptives .
Hormone replacement therapy (HRT) was very strongly associated with risk of breast ca in our results (AOR=3.97). Similar results were reported among Saudi and Jordanian women, (OR=2.25, 95%CI: 1.65-3.08) [66,73]. A population based study in Korea showed that the risk of breast cancer in HRT users was 1.25 [95% CI, 1.22-1.29] compared with HRT nonusers, and as the duration of use increased the adjusted hazard ratio (HR) increased (adjusted HR for 2 to <5 years was 1.33 and was 1.72 for ≥ 5 years) . In our study, 77% of women use the HRT for less than 5 years (mean 3 years, standard deviation 2.61 years) with no significant difference between the study cases and Controls. The increased risk among HRT users was shown in most studies. Martino et al. showed a 30% increase risk for breast ca in past users compared to 60% in current users, revealing a dose response relationship with duration of use . Nevertheless, it was reported that HRT therapy using estrogen alone had reduced breast ca risk in young women but increased the risk in older women . In our study women could not tell which type of HRT they used and the exact duration of its use.
Some limitations must be considered to explain the findings of this study. Firstly, the study was carried out on patients living in the south area in Palestine; therefore known risk factors may be different in the general population. Secondly, information (recall) bias from self-reporting of information of some variables; for example, age of menarche, age of menopause, breastfeeding practices, abortion experiences, and others. Also, women could not report which type of OCP and HRT they used and the duration of its use. Third, using women who came for screening of breast ca as controls introduced some selection bias in the study. However, the results and limitations of the study are very useful due to the fact they contribute to the ongoing research in the field of breast ca among Palestinian women. In addition, this study was conducted in an Arab developing country where changes in lifestyle can provide other important information about breast ca risk factors.