The risk factors for breast cancer
Breast cancer is the most common type of cancer among women in Malaysia with an overall age-standardized incidence (ASR) of 46.2 per 100,000 population . The incidence of breast cancer differs among Malaysia states; it is the most common cancer among women in Penang, followed by Sabah . However, there is no previous study on risk factors associated done in Penang before. Determining the risk factors of breast cancer helps to identify women who may benefit most from screening or other preventive measures, also offers hopeful promise of modifying those factors, thus preventing breast cancer occurrence.
Many risk factors of breast cancer have been found and many of them have been recognized as established factors. Advancing age is one of the most important factors . Reproductive factors like timing of menarche and menopause, parity play a major role in breast cancer incidence [4, 5] . Also, lifestyle factors like alcohol consumption [6-9], high fat diet [10-14] and smoking [15-17] have been identified by many studies as risk factors for breast cancer. This study aimed to determine the relationship between the socio-demographic factors, family history, reproductive factors, the life-style factors and external factors with the occurrence of the breast cancer among the study population.
MATERIAL AND METHODS
A matched case-control study was conducted in Penang General Hospital, Penang Island, Malaysia between 20th November 2009 and 22th January 2010 using a standardized questionnaire that designed into two languages: English and Malay. Both cases and controls were matched by age group and ethnicity. Sample size was calculated according to that reported by CARIF-UM (Release New Malaysian Breast Cancer Genetic Study) which stated that 14% of breast cancer patients in Malaysia who have family history of breast cancer  and the relative risk for strong family history ranging from 2.5 to 4.5  , the minimum sample size was 149 patients per group.
Our study was approved by Clinical Research Centre and Medical Research Ethic Committee of Ministry of Health Malaysia. Considering the ethical issues, written consent was signed by each case and verbal agreement for interview participation was obtained from all control subjects. All the personal information collected was considered confidential.
The cases were recruited from a convenience sample of prevalent breast cancer women who attended the oncology clinic, day-care chemotherapy center, oncology ward, and the surgical ward during the period of conducting this research. Women with confirmed diagnosis of breast cancer histologically regardless of the stage and met the following criteria; above 20 years old, non-pregnancy, without any gynecological problems (e.g., artificial menopause by hysterectomy), hormonal and psychological problems, were called for interview. Only one patient refused to participate. Our controls were non-breast cancer women who attended the outpatient clinics and outpatient pharmacy during the same period. Women who are non-pregnant, matched by age group and ethnicity to the cases recruited, without any malignancies, gynological, hormonal and endocrine, and psychological problems are eligible to be our controls.
All data entry and analyses were conducted using SPSS version 15 Microsoft program. Descriptive statistics including mean and standard deviations (SD) for continuous variables, frequencies and percentages for categorical variables were used to describe the study population. Crude ORs with 95% CI were calculated using simple logistic regression models that examined the association between breast cancer status and risk factors. Significant independent variables with P values < 0.20 [20-23] in the univariate analysis were included in the multivariate forward conditional logistic regression model to simultaneously assess multiple risk factors for breast cancer then adjusted ORs were estimated with 95% CI.
In all, 300 women within two groups were interviewed; 150 women with breast cancer and 150 control women without breast cancer. The means ± SD age of cases and controls were 52.81 ± 11.13 years (range 23-83 years) and 52.40 ± 11.52 years (range 22-78 years), respectively. Statistically, there is no significant difference between cases and controls in term of age (P value= 0.75) and race frequency (P value= 1.00). Among each cases and controls group, 34.7 % were Malay, 50.7 % were Chinese, 14.0 % were Indian and 0.7 % were other races.
Socio-demographic Risk Factors
The results of socio-demographic risk factors obtained from univariate logistic regression analysis summarized in Table 1 showed that lower educational level and occupation were significantly related to breast cancer risk (P < 0.05). Compared to women with post-degree, illiterate women and primary educated women were at higher risk for breast cancer by (OR=6.0, 95%CI: 0.54 - 66.17) and (OR=5.5, 95%CI: 0.54 - 55.03), respectively. Also, the risk of getting breast cancer in unemployed women was higher by 2.31 times (95%CI = 1.44 - 3.70) than retired or employed women in either government or private sectors. However, marital status and monthly income level were not significantly related to breast cancer risks.
Family history of first degree relative with other types of cancer (nasopharyngeal, ovarian, Lung, bladder, stomach, or colon cancers) increased the risk significantly (P < 0.05) to get breast cancer by 5.44 (95%CI: 1.54-19.22). Also, having first degree relatives (mother, daughter, and sister) with breast cancer showed marginal significance (P = 0.057) (Table 2)
Reproductive Risk Factors
According to the reproductive factors (Table 3), women with late ages at menopauses (= 55 years old) (OR=2.8, 95%CI: 1.18 - 6.67), or history of menstrual irregularity (OR= 3.2, 95%CI: 1.00 - 10.08) or who had never breastfed (OR= 1.74, 95%CI=: 1.09 - 2.76) were more likely to have breast cancer. The protective effect of breastfeeding found to be a duration dependent; women who had breastfed for only few months had a higher risk by 1.51 ( 95%CI: 0.83 - 2.77) compared to breastfed women for a total of more than 1 year, and the risk increased in non-breastfed women to 2.08 (95%CI= 1.22 - 3.57). Nevertheless, no statistically significant association were observed between breast cancer and the age at menarche, number of children (parity), age at first full term pregnancy, number of abortions and menopausal status.
Life Style and External Risk Factors
Breast cancer risk ratios were higher for women who had a history of benign breast disease (OR=2.8, 95%CI: 1.13 - 6.88) and who had never practiced low fat diet (white meat, white fish, skinless chicken and avoid deep fried food) (OR=1.81, 95%CI: 1.14 - 2.86). However, other lifestyle factors like; smoking, alcohol consumption, body mass index (BMI = 25 kg/m2) and external hormone use, like OCP and HRT were not significant statistically to be risks for breast cancer.
Among all factors included in the multivariable model (Table 5), occupation, breastfeeding and practicing low-fat diet play important protective roles against breast cancer; unemployed women (adjusted OR= 2.7, 95%CI: 1.59 - 4.61), never breastfed women (adjusted OR= 1.94, 95%CI: 1.15 - 3.27) and never practiced low-fat diet (adjusted OR = 1.97, 95%CI: 1.18 - 3.27) were found to be associated with breast cancer risk as statistically significant independent factors.
Other factors contributing to breast cancer risk were: family history of distant relatives with breast cancer (adjusted OR= 3.70, 95%CI: 1.48 -9.20) and first degree relatives with other cancers (adjusted OR= 5.27, 95%CI: 1.38 - 20.1). Also, women with histories of benign breast disease (adjusted OR= 3.14, 95%CI: 1.17 - 8.40) and menstrual cycle irregularity (adjusted OR= 4.94, 95% CI: 1.42 - 17.26) were more likely to have breast cancer. OCP use was significantly related to breast cancer risks; however, this was not related to the duration. While using OCP for < 1 year increased the risk by five times (95% CI = 0.99 - 29.36), using it for > 5 years increased the risk by only 3 times (95% CI: 1.02 - 9.00).
In a pooled analysis of 150 breast cancer cases and 150 non-breast cancer controls, associations between breast cancer and various demographic, reproductive, and lifestyle factors were examined. Both cases and controls were chosen intentionally from the same hospital during the same study period.
The risk of breast cancer has been reported to be associated with socio-demographic status [24-26]. Age is a very important risk factor; it was found that breast cancer incidence generally increases with age. The mean age at diagnosis for all breast cancer patients is 50.7 ± 11.0 years. The peak age reaches between 40 and 49 and thereafter the number of breast cancer patients decreases quite dramatically with only 4.0% above 70 years old (Figure 1). Also, only 2.0% of cases were diagnosed below the age of 30 which is consistent with Singletary findings .
According to the other socio-demographic factors studied, higher level of education has a protective effect (P< 0.001), which is consistent with other studies [27, 28]. However, this association becomes non-significant when other factors (e.g., family history, history of benign breast disease and menstrual irregularity) were taken into account using multivariate analysis. Also other study found that the risk of breast cancer is not significantly different among women with various education levels when the number of pregnancies and other factors were taken into account . In contrast, breast cancer risk is significantly higher among women with higher educational levels as revealed in other studies [29-33], while other found that the level of education has no association with breast cancer risk [34-36] .
Occupation status also plays an important role as a protection factor against breast cancer in both univariate and multivariate analysis (P < 0.001); this may be related to the education status. The risk of getting breast cancer in unemployed women is higher by more than two folds (Adjusted OR=2.71, 95% CI: 1.59 - 4.61) than employed women in either government or private sectors. However, another local study found that there is no association between occupation and breast cancer risk .
Family history is an important factor in our population; an adjusted OR of 3.7 (95%CI = 1.48 - 9.2) was found for women with a distant relative with breast cancer, which is within the OR range reported by previous literature [19, 37] and higher than that reported by others [3, 38]. However, having first degree-relatives with breast cancer is not significantly related to the breast cancer risk (P > 0.05). This may be explained partially because of the high frequency of controls (7 of 150 controls vs. 16 of 150 cases) that had first-degree relatives with breast cancer. Such a high number of family histories in controls may result in an underestimation of increased risk due to the family history.
Furthermore, history of first degree relatives with other cancer (gastric, pancreatic, colon, lung carcinoma.etc) is significantly more frequent in patients than in controls with the adjusted odd ratio of 5.27 (95% CI= 1.38 - 20.1). Recently, it has been discovered that clustering of first degree cases of breast, pancreas and stomach carcinomas in a family has been associated with mutations in the breast cancer susceptibility gene BRCA2 .
Breastfeeding is an important protective factor among our population; women who had never breastfed their baby have a 1.74 (95%CI: 1.09 - 2.76) higher risk of getting breast cancer and the adjusted odd ratio is 1.94 (ever versus never, 95%CI = 1.15 - 3.27) in the multivariate analysis. Our finding is in agreement with these studies [40-48], however, others failed to find any association [31, 36, 49-52].
Moreover, the duration of breastfeeding has also an important effect; found that the longer the lactation period, the least the risk of breast cancer. This inverse relationship between the duration of breastfeeding and the risk of breast cancer have been suggested by other studies [46, 53-60], however, other revealed that this is mainly confined to women diagnosed before the age of 40 with a weak trend for older patients .
History of irregular menstrual cycle (Polymenorrhea, Oligomenorrhea, or Amenorrhea) had an increased risk; the OR range (3.17- 4.94) and this supports the Turkish study  which found that menstrual irregularity increased the risk by 1.61 (95% CI 1.05-2.49). Others [55, 63, 64] did not find any significant relation between menstrual irregularity and breast cancer risk. However, it has been reported that menstrual irregularity decreased the risk 
This study detected a significant association between oral contraceptive use and breast cancer, consistent with other local studies [27, 36, 66] and other international studies [46, 67]. Whereas we could not find any relationship between the duration of OCP used and the risk of breast cancer, so our study does not support the growing body of evidence that long-term use of oral contraceptives, especially during certain parts of reproductive life, is associated with a modest increase in breast cancer risk [46, 68]. However, most studies found no or weak association of OCP use with the risk of breast cancer [34, 69-71]. The association between OCP use and breast cancer is also related to the duration, dosage, type of OCP and the age of first use .
Previous history of benign breast disease is highly significant in the present study (P < 0.05). The adjusted OR was 3.14 (95%CI= 1.17 - 8.40). Similar finding in Wang et al., (1992) study with adjusted OR: 2.40 (95%CI= 1.40 - 4.00). Whereas, there was no significant association between previous histories of benign breast disease and breast cancer risk in the other local studies [27, 36]
Practicing low-fat diet (take only white meat, white fish, and skinless chicken and avoid deep fried food) exhibited an inverse association with the risk of breast cancer, which is significant in both univariate and multivariate analysis (crude OR 1.81, 95%CI= 1.14 - 2.86) and (adjusted OR: 1.96, 95%CI=1.18 - 3.27) respectively for women who had never practicing low fat diet. Red and fried meat consumption and fatty foods were suggested as important risk factors for breast cancer [11, 73]. For each additional 100 g (3.5 oz) daily of meat consumption the risk of breast cancer increased risk by 56% in a French case-control study . Another cohort study  reported a significant relative risk (RR) of 1.7 for women who reported eating the skin on poultry. Null high consumptions of fatty forms, namely fried fish and chicken with skin were associated with an increase of breast cancer risk . Other case-control studies reported a protective effect of poultry and fish against the development of breast cancer . Also, there was no evidence for a positive association between total dietary fat intake and risk of breast cancer and no reduction in the risk even among women whose energy intake from fat was less than 20 percent of the total energy intake . Some case-control studies and cohort studies have shown weak and inconsistent associations between high intake of dietary fat and poultry with the occurrence of breast cancer [14, 78].
Other well-established factors that have been studied; smoking cigarettes, alcohol intake, regular use of HRT, pre and post-menopausal body mass index (BMI), marital status and the level of monthly income , age at menarche, age at first full-term pregnancy, number of abortions, menopausal status and parity were found not to be significant in this study (P > 0.05).
Strength and Limitation
To our own knowledge, the present study is the first case-control study of breast cancer to investigate the risk factor in Penang Island, Malaysia. Both cases and control were matched by age group and ethnicity which add some strength to our study. This research studied almost all the socio-demographic, reproductive, lifestyle and external risk factors, so the confounding effects of all of these factors had been taken into consideration when getting our result by multivariate analysis. Furthermore, the questionnaire was designed into two languages (English and Malay), hence most of the three main ethnic groups in Penang (Chinese, Malay, and Indian) are fluent in either or both of them.
As other case-control studies, our work has some limitations. The question regarding menstrual history (age at menarche, age at menopause) of the respondent are likely to be affected by recall bias. There was a chance of error in recall especially for age at menarche that had been many decades earlier and this may have affected the results. We tried to minimize this bias through assisting the memory of subjects.
Some of the Chinese cases were excluded due to the language barrier (they cannot speak Malay or English), that may cause some selection bias. Finally, generalizability of our findings may be precluded by our population features; they have high mean ages, low educational level and belong to a mid socioeconomic class, also by the difference in the ethnicity distribution among different Malaysia states.
In summarily, family history with breast cancer or other cancer, history of benign breast disease, menstrual irregularity, and oral contraceptive used were found to be significantly associated with increased breast cancer risk, whereas breastfeeding, occupation and practicing low fat diet have protective effects against breast cancer. Late age at menopause and education level are significant risk factor only in the univaraite analysis.
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