The aetiology of breast cancer is still poorly understood and known breast cancer risk factors explain only a small proportion of cases. Epidemiological studies conducted in different populations have identified a spectrum of well established and probable risk factors for breast cancer . These include age, socioeconomic status, reproductive events, breastfeeding, family history and lifestyle among others. However, most epidemiological breast cancer studies involve subjects living in North America and Western Europe, regions which represent only a fraction of the global population. Therefore there is a need to study breast cancer epidemiology in populations in less-well studied regions of the world, in order to gain a better understanding of breast cancer aetiology . It is noted that this is the first epidemiological study into breast cancer risk factors in the Cypriot population.
The main aim of this study was to assess the strength of associations between some recognized risk factors and breast cancer among Cypriot women. We should note that while the factors investigated here (other than BMI) were all self-reported, there is no reason to believe that any recall should be substantially differential, not least due to the standardised interview procedure by which information was collected from both groups of participants. A total of 1109 Cypriot women diagnosed with breast cancer between years 1999-2005 were recruited. It should be noted that the incidence of breast cancer in Cyprus is now around 400 cases per year. The cases in this study represents as many as 50% of the total number of cases diagnosed between 1999-2005. As many as 90% of all breast cancer cases in Cyprus are registered, receive treatment and are followed by the Bank of Cyprus Oncology Centre in Nicosia. This centralized point of access, ensures that the study participants, are to a large extent representative of all cases on the island, in terms of their socio-demographic characteristics. It should be noted that the recruitment of cases was based on the list of scheduled appointments during the study period and not on a random selection of all diagnosed cases.
The 1177 controls were recruited amongst women who participated in the National breast cancer screening programme with the use of mammography, to a large extent the same population that would give rise to the cases. Since no matching was employed, unavoidable (small) differences in the age distribution between the cases and the controls (mainly due to the under-representation of younger and older age-groups amongst the mammography screening users) were dealt with by adjusting for age in multivariable analyses. The Cypriot National screening programme for breast cancer in all women aged 50-69 was officially introduced in 2006, after being pilot tested at a small-scale in 2003. Recent data from the Cyprus Ministry of Health suggest that more than half of the women invited respond to the call. Even so this does not imply that the sample of controls are representative of the general female population on the island, in terms of the background socio-economic characteristics and levels of potential risk factors for breast cancer in the general population.
In terms of the basic demographic characteristics of the two groups, no major differences were detected in the levels of education or marital status. However, well established risk factors for breast cancer identified in other populations, such as family history of breast cancer, age at menarche and breastfeeding exhibited the strongest associations with breast cancer risk among Cypriot women [4, 5, 10]. Unlike Britain and other European countries, there are no formal occupation-based socio-economic classification systems in Cyprus. In the absence of such socio-economic indicators or information on family income, educational status was used as a proxy. Controlling for the possible confounding effect of educational status in multivariable models did not affect inferences about major risk factors of breast cancer.
Healthy volunteers who participate in epidemiological studies tend to have a higher educational level, compared to the rest of the population . In general, no major differences in the level of education between cases and controls were observed in this study. Nevertheless, it is possible that women who attend the screening programme are likely to be more educated, thus masking any such differences. Furthermore, a study of risk factors of breast cancer in Iran has shown that marital status may have an impact on the incidence of breast cancer in Iranian women. It was observed that women who never married were at higher risk for breast cancer . However, marital status by itself may not be a determining factor for modifying breast cancer risk. Since there is a strong interaction between marital status and parity, the increased breast cancer risk associated with single women may possibly be due to nulliparity.
Many studies have examined the association between body mass index (BMI) and breast cancer incidence. It was observed that in postmenopausal women, obesity (BMI > 30 kg/m2) was associated with about 50% increase in breast cancer risk when compared with lean women (BMI 20 kg/m2). This association was not observed in premenopausal women. In contrast, in some studies it was observed that during the premenopausal years, breast cancer risk was slightly lower in obese women . In our study, no information on menopause status at the time of diagnosis was available. By comparing BMI at the time of interview between cases and controls, no statistically significant differences were observed between the two groups. The relationship between BMI and breast cancer risk is complex and is better assessed in prospective studies where further anthropometric data are accurately collected at baseline and at regular intervals afterwards. In this context, no conclusive results regarding the association between BMI and breast cancer incidence in the Cypriot population can be drawn on the basis of this study.
Family history of breast cancer is one of the most well established, widely accepted risk factors for this disease. Having one first-degree relative with breast cancer approximately doubles a woman's risk for developing breast cancer. The risk is elevated significantly by increasing the number of affected relatives [19, 20]. Our findings are in accordance with other published studies and suggest that a positive family history of breast cancer is one of the most significant risk factors for this disease in Cyprus. In fact, if women with positive family history of cancer are more likely to attend mammography clinics for screening, the observed association may actually be an underestimation.
Breast cancer risk is associated with several reproductive factors. It is well established that breast cancer risk increases with early age at menarche [21–23]. This association is consistent with the hypothesis that breast cancer risk is related to the extent of breast mitotic activity. This activity is driven by estrogen and progesterone exposure during the luteal phase of the menstrual cycle , which determines the probability of tumorigenic somatic events . Therefore, an early age at menarche increases the period during which the breast is mitotically active and subsequently increases breast cancer risk. Similarly to previous investigators, we observed that an early age at menarche is associated with an elevated risk of breast cancer in our population.
The effect of breastfeeding on breast cancer risk has been controversial indicating either no association, or a weak protective effect against breast cancer . Studies in countries with a long duration of breastfeeding have reported substantial protective effects, whereas a number of studies in Western populations failed to detect an association, possibly due to the low prevalence of prolonged breastfeeding . A meta-analysis of breastfeeding and breast cancer risk, by the Collaborative Group on Hormonal Factors in Breast Cancer, showed that increasing duration of breastfeeding confers a protective effect on breast cancer risk, over and above that already known to be afforded by parity itself . Breastfeeding is hypothesized to reduce the risk of breast cancer primarily through two mechanisms, differentiation of breast tissue  and reduction of the lifetime number of ovulatory cycles . The results of our study suggest an inverse association between breastfeeding and breast cancer risk, even though a dose-response relationship with self-reported duration of breastfeeding was not observed, possibly a result of misclassification. This finding is consistent with the results of the large collaborative study showing breastfeeding to be protective for breast cancer . Breastfeeding is one of the few potentially modifiable factors that can reduce breast cancer risk. Further investigations are warranted in order to understand the underlying mechanisms of the protective effect of breastfeeding and how protection might be conferred. Once these are determined, interventions, which would mimic breastfeeding, could be developed for the benefit of women who have never breastfed .
Surprisingly, we observed an inverse association between hormone replacement therapy (HRT) and breast cancer risk. Results from randomized controlled trials and from observational studies have shown that use of HRT increases breast cancer risk. Furthermore, the effect of HRT on breast cancer risk depends also on the different combinations of HRT as well as on the duration of usage [30–34]. Overall, studies have concluded that oestrogen-progestagen combinations increase the risk of breast cancer, and that the risk was elevated, in women who were treated for at least 5 years [32, 34]. The above results should be interpreted with caution due to the difficulties experienced by Cypriot women in recalling information regarding type and exact duration of HRT use. However, there is no reason to believe that such recall was differential among cases and controls. Unlike other studies [34, 35], the vast majority of women in our sample reported never having used HRT while only a small percentage of women in our sample reported use for periods longer than 5 years (e.g. 7.8% among healthy controls). Furthermore, while in prospective studies one would expect to find an association between HRT use and breast cancer risk, in our retrospective study it is not surprising to observe an inverse association. It is very likely though that cases, once diagnosed with breast cancer, were not prescribed with HRT which would explain the reverse association seen in our study.
Only a weak association was observed between lifestyle risk factors such as exercise and smoking. It should be noted though that these parameters refer to current status only, as no information for past habits, duration or intensity of smoking were available. As a result, any association is hard to interpret due to problems with directionality of effect e.g. associations with exercise may be more likely to reflect that women diagnosed with breast cancer are less likely to currently exercise, rather than a causal relationship between lack of exercise and breast cancer.