The reason for international variations in the incidence of breast ca remains unclear. These variations can be seen between both high and low-income countries. Many of the risk factors for breast ca have been investigated but require further examination in individual nations.
In this study, we examined a broad spectrum of risk factors for breast ca, including female reproductive factors. The reproductive risk factors for breast ca identified in Palestinian women are similar to those observed in other studies. This study provides clear evidence that late menarche poses an additional risk for breast ca. Early marriage and having children early in life, both popular in the Palestinian community, were shown to increase the odds of breast ca. The role of oral contraceptives and hormonal replacement therapy on women’s health was also clearly shown and there should be rational use of hormones, whether as a birth control tool or for therapeutic purposes. Having children proved to be protective against breast ca but as most married women in Palestine breastfeed their children, we could not show that breastfeeding is a protective factor for breast cancer among the study group. However, we can still highlight the role of breastfeeding in breast ca protection. More in-depth investigations are needed to identify the relationship between various factors, especially the protective role of having children and breastfeeding practices on breast ca in Palestine. Special attention should be devoted to the particular social and cultural factors related to sexual and reproductive issues among women in Palestine.
Several studies have indicated that women with high socioeconomic status (SES) are at risk for breast ca with an overall estimate of 20% increased risk 27. This positive association was clearer among Hispanic and Asian women 28, and not only for breast ca but for other cancers such as colon, ovary, and melanoma cancers 29. Our study found that breast ca was more common among more educated rather than less educated women, and in women with a lower family income rather than women with a higher family income. In the north of Palestine, a previous study showed that there was a four-fold increase in the risk of breast ca among highly educated women 24; this was also reported among Egyptian women 30. In European women, a direct dose-response relationship was seen between educational level and postmenopausal breast ca incidence 31.
Our results found that women living in an apartment had a significantly lower risk of getting breast ca compared with those living in a separate home; this was assumed to be due to a higher SES. Several studies showed that lower SES increased the risk of breast ca because women were less aware of screening techniques and diagnosis 32. Our results could be explained by the fact that women with a higher family income can afford health insurance and are more willing to spend money on their health and better medical care access. Greater awareness among educated women about mammography screening tests 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 a woman is educated, the later she marries, the later the age of pregnancy, the shorter the period of breastfeeding, and the lower parity is characteristic 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 33.
Consanguinity is becoming a very strong factor for cancers and other genetic diseases in many countries 34,35. Our study showed that daughters of unrelated parents had a decreased breast ca risk, whereas the risk increased 2.5-fold for those with first-degree related parents. A similar finding was reported in the United Arab of Emirates (UAE) in which having unrelated parents halved the risk (RR=0.5, 95%CI: 0.27- 0.93) 35. A study among Israeli Arabs of Palestinian origin showed an increase in diabetes and duodenal ulcers 34. Consanguineous practices in populations might affect the gene frequency in these populations, which could have a major effect on the carrier rate of such genes. Therefore, in countries with high consanguinity, the incidence of diseases and syndromes should be monitored with caution.
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 a family history of breast ca 36. In our study, women with a family history of breast cancer had a fourfold increased risk of 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 a family history of breast cancer was significantly more prevalent in breast cancer patients 37. The risk of breast ca ranged from 1.5 to 3.6 in a pooled analysis depending on the relative in question, with the highest risk reported among women who had a mother or a sister with breast ca 38. Furthermore, women living in the Gaza Strip and who had a positive family history of breast ca showed an increased risk of breast ca (OR=2.7, 95%CI: 1.04-7.20). Similar results were reported among Algerian women, where the odds for breast cancer were four times higher among those with a family history of the disease (95% CI: 2.22-7.77) 39. These two factors, i.e. consanguinity and family history of breast cancer, may 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 14-16. Also, parity and age of marriage are among the most common 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 15.
In several studies, older age at menarche was inversely associated with breast ca risk. The high-risk groups were females with menarche before the age of 11 years 4 . Around 117 studies showed that the breast ca risk increased by a factor of 1.050 for every year less at menarche 15, and a delay of two years at menarche led to a 10% reduction in breast ca worldwide 40. In our study, older age at menarche was shown to be associated with an increased risk of breast ca. The risk increased three-fold with menarche at the age of 13 or more. In the north of the West Bank, the estimated risk was 6.5 which also showed an increase the risk for breast ca 24 . The protective result of menarche at an older age was explained by the lower cumulative number of ovulatory cycles, which is negatively associated with the risk, younger age at menarche, and older age at menopause, means a female would have more cycles and an increased risk 41,42 .
According to the Palestinian Central Bureau of Statistics (2016), the mean age of first marriage was 19.8 years in the southern region of Palestine 43. Consequently, many women may have their first pregnancy and first delivery at a young age (below 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 for breast ca. We could not see any difference according to whether a woman had her first child before the age of 18 years or after. In contrast, a study in the north 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 24. Another study in the Gaza Strip showed that women who had their first pregnancy after the age of 35 years had an 11-fold increase in breast cancer risk 2.
Our results revealed no significant association between full-term pregnancies and the risk of breast ca. However, the 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 for not only one type but for all subtypes of breast ca in pre- and post-menopausal women. The reduction in the risk ranged from 18% to 60% 44. In the north of Palestine, a 50% decrease in risk was reported among women with four full-term pregnancies or more 24.
One of the well-established protective factors against breast ca is breastfeeding. In our results, almost all women who had children had engaged in breastfeeding, but the protective effect in our analysis was not in the breastfeeding itself but in its duration. Previous studies found that breastfeeding itself was protective. A Saudi study reported that never having breastfed doubled the risk (OR=1.89, 95%CI: 1.19-2.94) 45. 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) 46. Breastfeeding is assumed to protect against breast ca through hormonal mechanisms that include postponing the resumption of ovulatory menstrual cycles after pregnancy, reducing estrogen levels in the breast, and having fully differentiated breast tissue that is less susceptible to hormones 47.
The results of studies about the duration of breastfeeding have been 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% 48. Similar results were reported in an American study for different age and ethnic groups 49. 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 versus those who had never breastfed, with a decrease in risk of 25-30% for an additional three years of breastfeeding. Among Palestinian women in the north, the risk for those who had never breastfed was doubled compared with those who had lactated for four years or more 24 . No association was found between breastfeeding duration and the risk of breast ca in either developed or developing countries 48.
Regarding the use of hormonal contraceptive pills (OCP) and their association with breast ca, our study showed that previous oral OCP use for more than two months significantly doubled the risk of breast ca (AOR=2.22), but failed to show any link to the duration of using OCP. Similar results were revealed among Jordanian females 50,51. Regular use of OCPs in Jordanian women was shown to be associated with an increased risk of breast cancer (OR = 2.25, 95% CI 1.34-2.79; p = 0.002), although the duration of use was not associated with an increased risk of breast cancer (p > 0.05) 51. However, many studies found a slight increase in the risk 52. Other studies reported that the increased risk was only for the 10 years that followed the last OCP use 31. Other studies have found a decreased risk among women, but at least 10 years after the last use of OCPs 53. A study in Iran showed that long term OCP use (>/=10 years) (OR = 3.17, 95% CI: 1.27-7.95, P = 0.01) increased the risk of breast ca 54. On the contrary, some studies showed that OCP played a protective role against breast ca. A study in the Central African Republic showed a decrease in the risk for breast ca (0.62) 55. 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 56.
Hormone replacement therapy (HRT) was very strongly associated with the 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) 45,50. 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 non-HRT users. As the duration of use increased, so did the adjusted hazard ratio (HR) (adjusted HR for 2 to <5 years was 1.33 and was 1.72 for ≥ 5 years) 8. In our study, 77% of women used HRT for less than 5 years (mean 3 years, standard deviation 2.61 years) with no significant difference between the study cases and control group. An increased risk among HRT users was shown in most studies. Martino et al. showed a 30% increase in risk of breast ca in past users compared with 60% in current users, revealing a dose-response relationship with duration of use 57. Nevertheless, it was reported that HRT therapy using estrogen alone had a reduced breast ca risk in young women but increased the risk in older women 58. In our study, women could not tell us which type of HRT they used and the exact duration of its use.
Some limitations must be taken into consideration to explain the findings of this study. Firstly, the study was carried out on patients living in the south of Palestine. Thus, known risk factors may be different in the general population. Secondly, there could be information (recall) bias from the self-reporting of information of some variables such as the age of menarche, age of menopause, breastfeeding practices, and abortion experiences. Also, women were not able to report which type of OCP and HRT they used and the duration of its use. Thirdly, the use of women who came for screening of breast ca as the control group introduced some selection bias in the study. Nevertheless, the results and limitations of the study contribute to the ongoing research in the field of breast ca among Palestinian women. Also, this study was conducted in an Arab developing country where lifestyle changes can provide other important information about breast ca risk factors.