The length of interval between successive childbirths  might influence the incidence of breast cancer, either by stimulating or by inhibiting the factors that are responsible for the initiation of breast cancer or its early development.This is a case-control study nested in a cohort of 47,479 Finnish grand-multiparous (GM) women born after 1934, and registered as having had at least five births before 2013. The 1354 women with breast cancer diagnosis were compared with controls (1:5) matched by parity and date of birth of the mother. Conditional logistic regression was used to estimate odds ratios of the risk of ductal and lobular breast cancer subtypes associated with each of the intervals between the 1st and 5th birth, stratified by age at diagnosis. Age at first and last birth before index date were used as covariates.Increased intervals between the 1st and 5th births were associated with an increased risk of lobular breast cancer. In contrast, regarding ductal cancer, premenopausal women with shorter length of interval (< 2 years) between the 1st and 2nd birth had greater risk and longer intervals (3+ years) were associated with reduced risk. Spacing between the 2nd and 5th birth did not influence the risk of ductal breast cancer.The findings of our study suggest that the effect of the length of birth interval on breast cancer depends on the age and histology. The protective effect of shorter birth intervals on lobular breast among postmenopausal women and the opposite effect on ductal cancer in premenopausal women may reflect distinct differentiation and functional roles of lobular and ductal cells, and possibly also different response to hormonal exposure. Age at first birth and the number of pregnancies are well-known risk factors of breast cancer –6, and eReproductive events and their timing can affect breast tissue differentiation through hormonal mechanisms –11. LeveStudies on pregnancy-related risk factors including birth intervals have mostly covered women with just a few or only one childbirth. There is an evident need for further studies on the importance of the 1st birth interval, and also later intervals on the etiology of specific subtypes of breast cancer extended to women with higher parity. Also, the consideration of age, stage and characteristics of the tumor at diagnosis is essential for clear understanding of the association between birth intervals and breast cancer risk. The present population-based study was especially aimed to clarify the role of each birth interval between the 1st and 5th birth as separate risk factors in ductal and lobular breast cancer subtypes among grand-multiparous (GM) women.This is a retrospective case-control study nested in a Finnish population-based cohort of GM women. The cohort, obtained from the Finnish National Population Register (NPR), consists of 47,479 Finnish women who were born after 1934, and registered as having had at least five births before January 1st, 2013. The NPR contains links between mothers and their children born after September 1953.The first breast-cancer cases (ICD-10 C50) diagnosed between the 5th childbirth and the 31st of December 2014 in GM women were included in the study. Altogether, 1354 such cases were identified in the Finnish Cancer Registry, in an automatic record linkage from NPR via unique personal identity codes assigned to each resident of Finland. The cancers recorded at the Finnish Cancer Registry have been notified by hospitals, pathological and hematological laboratories, physicians and dentists, and from death certificates .For each case, five controls were randomly selected among GM women cohort who were at the risk of breast cancer at the time of cancer onset of case and fulfilled the matching criteria. Matching was done by date of birth of mother and number of children and tolerance of ±6 months was allowed for the date of birth. Women who had emigrated or died before the index date were not eligible as controls.A conditional logistic regression model for matched case-control data was used for both univariate and multivariate analyses to examine the associations between study variables and breast cancer. The variables included in the model were each of the four birth intervals until the fifth birth, with age at first birth and age at last birth as covariates. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate the associations between the predictor variables and breast cancer.We categorized the lengths of the first four birth intervals into four categories: < 1 year, 1–1.99 years (reference category), 2–2.99 years and 3+ years. Longest interval category is 3+ years. Age at first birth is categorized into four categories: < 20 years (reference category), 20–24 years, 25–29 years and 30+ years. Because age at last birth might not be a fully independent risk factor but depends on the lengths of birth intervals, we performed the analyses in two models, with and without the age at last birth before index date. The findings of both models were virtually identical and we therefore presented only results from the model including age at last birth in the model, categorized into four categories: < 30 years (reference category), 30–34 years, 35–39 years and 40+ years. In addition, the logistic regression model was also adjusted for average interval between 5th and the last birth before index date. Potential interactions between the study variables were evaluated by adding the interaction terms in the logistic regression model.Since some previous studies on birth intervals and breast cancer risk have been based on average interval between first and last birth, we made an alternative analysis based on models where the four separate intervals between the 1st and 5th birth were replaced by their average. In this analysis, the average interval was categorized to < 2 years (reference category), 2–2.99 years and 3+ years.Ductal and lobular subtypes of breast cancer were analyzed separately and also stratified according to the spread of the disease at the time of diagnosis . Further stratification was carried out for age at diagnosis . Since there were only 32 cases of lobular breast cancer diagnosed at ages of < 50 years, no separate analysis was carried out for this group. All analyses were performed using R statistical software, version 3.2.3.Overall, 76% of women with ductal breast cancer subtype and 86% of women with lobular breast cancer subtype in our study were diagnosed at the age 50 years or above Table . The womTable While examining the difference between specific intervals it was observed that for ductal cancer at < 50 years the longer intervals were protective only between the 1st and 2nd and 2nd and 3rd intervals  vs. older (50+) ductal cancers. Shorter intervals were associated with decreased risk for lobular cancers, while shorter intervals  increased the risk of ductal cancer in premenopausal women. There was also indication of significantly higher risk for especially short intervals of less than one year for the premenopausal ductal cancers.Previous breast cancer incidence models show that increasing spacing between the 1st and 2nd child birth increases the overall breast cancer risk , 17, 22.On contrary to the findings by Russo , the risIn lobular breast cancer, the lowest ORs were virtually systematically observed in shortest birth intervals. Lobular breast cancer develops in the cells lining the lobules, which work as milk-producing elements. During many hundreds of past years, women in primitive life conditions without contraceptive aids conceived and gave birth several times, with short intervals between pregnancies. Consequently, they had to take care of their newborns through breastfeeding up until the next pregnancy; which was usually quite soon if life conditions were appropriate for ovulatory menstrual cycling. Thus, the lobular cells probably had to be active for milk formation in a regular rhythm, with an interval of just 1–2 years. The importance of this interval gets support from a study on Finnish mothers with ten or more childbirths which showed that the natural inter-pregnancy interval of 8.5 months plus the gestational period of 9 months’ results in the natural inter-birth interval of 17.5 months, which is in the middle of the interval length where we observed lowest ORs for lobular breast cancer .Breastfeeding is considered to have a protective effect against breast cancer risk by aiding the differentiation of mammary epithelium in its terminal phase , 31. TheWe also calculated the effect of average interval between 1st and 5th birth as the predictor of breast cancer risk and observed the significant association with lobular breast cancer only. The result is similar to the results of an earlier Finnish study based on partially same cohort as the present study but with somewhat different analysis method [Our study has some limitations. The information on breastfeeding history of the women was not available. It should also be noted that many of the key estimates involved in the discussion of postmenopausal ductal and lobular breast cancer subtypes in our study have wide confidence intervals; hence, the inferences based on such estimates are tentative at the best. Moreover, our study is based only on GM women cohort. Women capable to give birth to five or more children may be different from other women in terms of their physiology etc. Therefore, the findings concerning e.g. the effect of interval between the 1st and 2nd birth seen in our study may be different from those seen among women with only 2 children. To our knowledge, there are no studies among GM women in other populations. Moreover, the interval category < 1 year in our study has small numbers of observations. We still chose to present the findings from this category because a birth interval of less than 1 year clearly means that the pregnancy has been abnormal and according to our a priori theory may therefore carry an exceptional risk of breast cancer.The ages at first and last birth were not main study targets in this study but they were used for adjustment purposes. It is reassuring to see that we saw significantly increasing trends in risk of lobular breast cancer with increasing age at first birth and in risk of premenopausal ductal breast cancer with increasing age at last birth as expected based on earlier literature , 41.Our results indicate that two first pregnancies occurring with shorter intervals might increase the risk of ductal breast cancer among premenopausal women, whereas interval length may not be related to ductal breast cancer among postmenopausal grand multiparous women. For the lobular breast cancer, shorter intervals seem to be protective up to the fifth child. Our hypothesis was that the “natural birth interval” of 1–2 years would carry the lowest risk. This was not always the case, e.g., the risk of premenopausal ductal breast cancer was lower when the interval between the 1st and 2nd birth was longer. Results for the exceptionally short intervals of less than one year as a separate category in our analysis were inconsistent and had wide confidence intervals but gave a hint that it may be warranted to also look at this category in future studies. The mechanisms behind our observations of variation in risk of subcategories of breast cancer associated with birth intervals are still speculative. Further studies, including information on breastfeeding are needed to better understand these associations.


In contrast to our knowledge about the number of cancers attributed to smoking, the number of cancers attributed to alcohol is poorly understood by the public. We estimate the increase in absolute risk of cancer (number of cases per 1000) attributed to moderate levels of alcohol, and compare these to the absolute risk of cancer attributed to low levels of smoking, creating a ‘cigarette-equivalent of population cancer harm’.Alcohol and tobacco attributable fractions were subtracted from lifetime general population risks of developing alcohol- and smoking-related cancers, to estimate the lifetime cancer risk in alcohol-abstaining non-smokers. This was multiplied by the relative risk of drinking ten units of alcohol or smoking ten cigarettes per week, and increasing levels of consumption.One bottle of wine per week is associated with an increased absolute lifetime cancer risk for non-smokers of 1.0% (men) and 1.4% (women). The overall absolute increase in cancer risk for one bottle of wine per week equals that of five (men) or ten cigarettes per week (women). Gender differences result from levels of moderate drinking leading to a 0.8% absolute risk of breast cancer in female non-smokers.One bottle of wine per week is associated with an increased absolute lifetime risk of alcohol-related cancers in women, driven by breast cancer, equivalent to the increased absolute cancer risk associated with ten cigarettes per week. These findings can help communicate that moderate levels of drinking are an important public health risk for women. The risks for men, equivalent to five cigarettes per week, are also of note.The online version of this article (10.1186/s12889-019-6576-9) contains supplementary material, which is available to authorized users. The health risks of smoking are indisputable and well understood by the public. Tobacco use accounts for 7 million deaths per year globally with an estimated two thirds of smokers expected to die from their habit , 2. SmokEach year approximately 3.3 million deaths occur due to the harmful use of alcohol, corresponding to 5.9% of all deaths globally . It is eAll known alcohol-related cancers have been shown to have a modest, but increased relative risk (RR) of incidence at moderate levels of drinking  , 14, 16.The aim of this study was to estimate the increase in absolute risk of developing cancer as a result of drinking moderate levels of alcohol in men and women, and compare this to the increase in absolute risk of developing cancer secondary to smoking. In essence, we aim to answer the question: ‘Purely in terms of cancer risk - how many cigarettes are there in a bottle of wine’?AA) (Alcohol Attributable Fraction for England 2013) [TA) (Tobacco-attributable cancer burden in the UK) [0) of cancer (Cancer Research UK (CRUK) 2010) [ANS), according to the expression: RANS = R0 – R0FAA – R0FTA, or alternatively: RANS = R0(1 – (FAA + FTA))  resulting from consumption of ten units of alcohol (one bottle of wine) or ten cigarettes per week we began by subtracting the sum of the Alcohol Attributable Fraction Fnd 2013)  for all  the UK)  for all K) 2010)  for the 3  for alAA  [TA  [AA by the frequency of alcohol-consumers who are never-smokers (53%), and the FTA by the frequency of smokers who do not consume alcohol (12%), for cancers in which both alcohol and tobacco are known risk factors  tract cancer , 26. Thesmokers) , and FTArinkers) , would o alcohol 2%, for c alcohol 2%, for cWe then multiplied the lifetime risk of cancer in never-smoking non-drinkers by the percentage increase in RR *100) of drinking ten (approximately one bottle of wine) and 30 (approximately three bottles of wine) units of alcohol per week (Alcohol Attributable Fraction for England 2008)  (Additio*100) of RR data for the consumption of ten units of alcohol per week was derived from studies which had adjusted for smoking in the case of upper aerodigestive tract cancers . RR dataIt is generally assumed smokers are dependent daily users, with tobacco consumption measured in cigarettes per day, despite an increasing prevalence of non-daily smokers in western countries . HoweverAA, FTA and the calculated RR of drinking ten units of alcohol, or smoking ten cigarettes per week, by a factor of 50% for cancers in which both alcohol and tobacco contribute , with the risk spread throughout the smoking-related cancers. The increase in absolute lifetime cancer risk for consuming ten cigarettes per week compared with ten units of alcohol for women however was comparable  as a result of breast cancer incidence being partly driven by alcohol .As alcohol consumption increases, differences in absolute lifetime risk of alcohol-related cancer between men and women become elevated. Drinking three bottles of wine per week , is associated with in absolute lifetime cancer risk to 1.9% for men and 3.6% for women, again due to a significant risk of breast cancer 2.4%)  for men ((1.0/2.1) × 10), and ten cigarettes (9.5) for women ((1.4/1.5) × 10). Drinking three bottles of wine a week, a representative consumption in hazardous drinkers, carries the same increase in absolute cancer risk of smoking roughly eight cigarettes per week for men, and 23 per week for women (approximately one packet) . Consumption of ten units of alcohol per week carried an equivalent increase in absolute cancer risk to four cigarettes per week for men (3.5), and ten cigarettes per week for women (9.8), as breast cancer risks did not require adjustment.We must first be absolutely clear that this study is not saying that drinking alcohol in moderation is in any way equivalent to smoking. Smoking kills up to two thirds of its users , and canUsing previously published resources reporting lifetime cancer risk, alcohol and tobacco attributable fractions and relative risk data for low to moderate levels of drinking and smoking, we have been able to estimate the approximate absolute lifetime risk of cancer in a non-smoking population, associated with moderate levels of alcohol consumption, and derive a cigarette equivalent in terms of harm. The ‘cigarette equivalent’ of a bottle of wine is five cigarettes for men and ten for women. The absolute risk of cancer increases with increasing alcohol consumption and the gender gap widens as a result of the association between alcohol and breast cancer. These figures occur on a background of a steady increase in alcohol consumption among women . The latWhile the association between hazardous drinking and breast cancer is well established , 14, a nRising levels of alcohol consumption over the past decade, are likely to be an important factor in the over 30% rise in breast cancer incidence in England  . Breast It is interesting to consider that the list of alcohol-related cancers selected by the WHO IARC may be conservative, as several other cancers have recently been identified as having a dose-risk relationship to alcohol including melanoma, cancer of the gallbladder, pancreas, lung and prostate , 45. FurThere are caveats with the methodology used in the study. Ideally all our risk estimates would have been calculated from systematic reviews and meta-analyses of alcohol consumption in non-smoking men and women, and cigarette consumption in teetotal men and women. While these data are available in a few individual studies, systematic review data are not available for subgroups of cancer type.AA and FTA to include non-smokers and non-drinkers only in alcohol-related and smoking-related cancers respectively and used adjusted RR data. We acknowledge however that the alcohol history of smokers is generally less accurate, and that a higher proportion of smokers may have previously been heavy drinkers. This factor may have led to a minor underestimate of the combined cancer risk. Furthermore FAA and alcohol-related RRs for cancer are derived largely from mortality, rather than morbidity data, and are therefore both likely to be underestimated, particularly in the case of breast cancer where the ratio of incidence to mortality is high  [We have therefore estimated the risks for each cancer type using the most recent and robust available data and by making a number of assumptions. The data on RRs for cancer are extremely heterogenous, and while the original studies controlled for the use of other substances, our methodology does not account for synergies between RRs of alcohol and tobacco. In order to remove some of the confounding influence where these two risk factors co-exist, we adjusted the Fable S7) . TherefoAA, FTA and RRs for consuming ten units alcohol per week or ten cigarettes per week by 50%. This reduced the ‘cigarette equivalent’ of one bottle of wine to four for men but remained ten for women.The best data available to us on the RR of cancer attributable to moderate levels of alcohol (ten units per week) were for consumption of less than 19 g per day, an average of 8.8 units per week if normally distributed. Similarly, our estimate of 30 units per week was derived from individuals drinking 20-39 g per day, i.e. 25.9 units per week  . These dThis study does not account for the duration an individual is exposed to a cancer-related risk factor. Cumulative exposure is directly related to the incidence of certain cancers, particularly tobacco smoking and lung cancer . FurtherIt is noteworthy that the attributable fractions and the absolute risk scores calculated here are dependent on both the prevalence of exposure to a risk factor within a population and the relative risk of that behaviour resulting in cancer. For smoking the prevalence is low , with aCritically our use of absolute ‘lifetime risk’ describes the average of the number of cancers experienced by a population, i.e. individuals with and without cancer, and is not an exact measure of an individual’s probability of getting cancer. In other words while this study estimates that drinking ten units of alcohol per week may cause a similar number of cancers in the population as smoking five to ten cigarettes per week, these two exposures may not carry the same cancer risk for any given individual. We have attempted to minimise this effect by using lifetime cancer risks from CRUK which have been calculated using the Sasieni method. This corrects incidence rates for the inclusion of more than one primary cancer occurring within the same individual, lowering the lifetime cancer risk .Furthermore this study does not take into account other smoking or alcohol-related outcomes such as respiratory, cardiovascular or liver disease in which case the conclusions would likely be quite different. Cancer deaths are a fraction of the total number of deaths associated with smoking and alcohol and this study is not a comparison of the overall mortality of smoking versus alcohol. Despite the caveats, our estimation of a ‘cigarette equivalent’ for alcohol provides a useful measure for communicating cancer risks that exploits successful historical messaging on smoking, reflects current epidemiological knowledge and includes an important aspect of gender differential.We have shown moderate levels of drinking (one bottle of wine per week) is associated with a significant increased absolute lifetime risk of alcohol-related cancers in women, driven largely by breast cancer. Drinking one bottle of wine per week is associated with an increase in absolute lifetime risk of cancer equivalent to smoking ten cigarettes a week for women, and five for men. These findings highlight moderate levels of drinking as an important public health issue for women and identify a need to promote national awareness, supported by the recent change in national drinking guidelines. This study offers the first attempt to use well established and well communicated links between cancer and tobacco as a mechanism to explain similar links between alcohol and cancer which have to date failed to reach most of the public.Additional file 1:Table S1. References for the percentage relative risk of drinking ten units of alcohol per week. Table S2. Calculation of lifetime risk of cancer in alcohol abstaining never smokers. Table S3. Frequency of smoking and alcohol consumption in the UK, Health Survey for England data combined years 2011–14 . Table S4. Calculation of absolute increase lifetime risk of cancer due to ten and 30 units of alcohol or ten and 30 cigarettes per week in non-smokers and non-drinkers respectively. Table S5. References and calculation of absolute increase lifetime risk of cancer due to ten and 30 cigarettes per week. Table S6. Calculation of absolute increase lifetime risk of cancer due to ten units of alcohol or ten cigarettes per week in non-smokers and non-drinkers respectively following a sensitivity analysis. Table S7. Incidence and mortality data for alcohol-related cancers (CRUK data). (DOCX 76 kb)Additional file 2:Contains a worked example of logarithmic transformation used to calculate RR of smoking 10 cigarettes per week. (DOCX 31 kb)


There was an inverse association of the serum ‘Magnesium’ profile or serum level of iron with the risk of BC, which disappeared after adjustment for the set of confounders accounted for: age, body mass index (BMI), socioeconomic status, overall physical activity, smoking status, age at menarche, number of full-term pregnancies, oral contraceptive use, hormone-replacement therapy use, family history of breast cancer, vitamin/mineral supplement use, the molecular subtype of breast cancer, and dietary patterns. No significant association was found between BC risk and the serum ‘Folate-Cobalamin-Vitamin D’ profile or serum folate, cobalamin or magnesium considered separately. These findings highlight that a higher-normal serum level of both iron and calcium, considered together as the serum profile, as well as a higher-normal serum level of calcium, considered separately, and a slightly below the normal range of serum vitamin D level may protect against breast cancer among postmenopausal women, independent of dietary patterns or the use of vitamin/mineral supplements. Therefore, the maintenance of the adequate status of vitamins and minerals and the regular monitoring of their blood markers should be included in breast cancer prevention.Breast cancer is the most prevalent cancer in females worldwide. Studies evaluating the blood vitamins and minerals status in the breast cancer etiology are limited, and the results are inconclusive. This study analyzed the association between serum vitamin-mineral profiles (V-MPs) and breast cancer (BC) risk with including dietary patterns (DPs) and the use of supplements. This case-control study involved 420 women aged 40–79 years from north-eastern Poland, including 190 newly diagnosed breast cancer cases. The fasting serum concentrations of vitamins  vitamin D) and minerals  were measured in 129 post-menopausal women, including 82 controls and 47 cases. Three V-MPs were derived with a Principal Component Analysis (PCA). A logistic regression analysis was performed to estimate the odds ratio (OR) and 95% confidence interval (95% CI) of the breast cancer risk associated with serum V-MPs and serum levels of single biomarkers. The risk of BC was lower by 88% (OR: 0.12; 95% Cl: 0.02–0.88;  Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer deaths among women worldwide . It is cBesides age, the multifactorial etiology of breast cancer also includes: Genetic, reproductive, and lifestyle factors . A direcIn regard to the water-soluble B-vitamins, folate, and vitamin B12 are important co-factors involved in one-carbon metabolism which plays a role in DNA synthesis, methylation, stability, and repair . There aIn regard to the minerals, calcium (Ca), magnesium (Mg), and iron (Fe) also appear to be involved in breast cancer etiology ,34. CalcB-group vitamins, vitamin D, calcium, magnesium, and iron play a role at various stages of cancer development; from an impact on cellular genetic material and gene expression to a role in DNA synthesis, methylation, and stability, and an influence on cell proliferation, differentiation, and apoptosis ,33,38,39The aims of the study were: (1) to assess the breast cancer risk for a higher versus lower level of serum folate, vitamin B12, vitamin D, iron, calcium, and magnesium; and (2) to evaluate the joint association of these biomarkers as serum vitamin-mineral profiles (V-MPs) with the risk of breast cancer in postmenopausal women from north-eastern Poland. In these observations, many potential confounders, including dietary patterns were taken into account. Dietary patterns (DPs) express the complexity of the diet and are currently considered the best approach to evaluating the diet as a matrix of various foods and therefore the main source of nutrients status . Thus, iThis study was approved by the Bioethics Committee of the Faculty of Medical Sciences, University of Warmia and Mazury in Olsztyn on 2 October 2013 (resolution no. 29/2013).The aim of the study, study stages, and sample collection procedures were explained to all subjects. All subjects gave their written informed consent to participate in the study, including for blood sample collection and to use clinical data for research.The present study was a part of a larger case-control study conducted in 2014–2017, concerning dietary patterns and breast cancer risk among 420 women from north-eastern Poland . Briefly®, Franklin Lakes, NJ, USA). Blood samples stood for 30 min at 22 °C, and then were centrifuged at 3000 rpm for 10 min at 22 °C, which allowed the separated serum obtained. The case-control status of the blood samples was blinded. All methods were fully automated and performed at the Laboratory of Biochemical Studies of Nutritional Status in the Department of Human Nutrition at the University of Warmia and Mazury in Olsztyn.Fasting venous blood samples were collected for 129 postmenopausal women, including 47 preoperative breast cancer cases and 82 controls. The procedure of the blood sample collection and the serum obtaining were described previously . In brie®, Basel, Switzerland) according to the manufacturer’s instructions. Serum concentrations of folate, cobalamin, and 25(OH) vitamin D were measured with electrochemiluminescence immunoassays (ECLIA) using an automated immune-analyzer Cobas e411 . The minimum detectable concentrations (MDC) were as follows: iron 5.00 μg/dL, calcium 0.8 mg/dL, magnesium 0.36 mg/dL, folate 0.640 ng/mL, cobalamin 100 pg/mL, and 25(OH) vitamin D 3.00 ng/mL.Iron, calcium, and magnesium concentrations were measured in serum samples using a Cobas Integra 400 plus auto-analyzer  with varimax rotation was used to identify (a posteriori approach) serum vitamin-mineral profiles (V-MPs). The values of serum vitamins and mineral concentrations were standardized and then included into the PCA. During identification of the number of serum V-MPs, the following criteria were considered: (i) the eigenvalues of the variable correlations >1.0, (ii) the plot of eigenvalues, and (iii) the total variance explained . Serum VThree serum V-MPs were identified . The ‘FoDietary data were collected for 420 peri and postmenopausal women, including 190 breast cancer cases and 230 controls . The freage;body mass index;socioeconomic status;overall physical activity;smoking status;age at menarche;number of full-term pregnancies;oral contraceptive use;hormone-replacement therapy use;family history of breast cancer;vitamin/mineral supplement use;molecular subtype of breast cancer;PCA-derived dietary patterns (in scores).Data regarding socioeconomic, lifestyle, reproductive, and medical factors were collected in an individual interview with each participant. The set of confounders included the factors given below, which can be involved in the breast cancer etiology : age;bodRespondents were asked about four single factors to describe their socioeconomic status (SES). The SES index was calculated as the sum of the values assigned to the response categories of each SES factor . The SESRespondents were asked to describe their physical activity at work and physical activity in leisure time by choosing one of three categories . Self-de2 test  or a Kruskal-Wallis test (continuous data) [2 test with Yates’ correction as necessary. Logistic regression analysis was used to estimate the odds ratio (OR) and 95% confidence interval (95% CI) of the breast cancer risk in associations with serum V-MPs and serum levels of single biomarkers. The references (OR = 1.00) were the control sample and the bottom tertile of each serum V-MPs or lower level of single biomarker concentration (<Me). Three models were created: model 1—unadjusted, model 2—adjusted for the aforementioned set of confounders, and model 3—fully-adjusted for the same confounders included in the model 2 and for DP scores. The level of significance of the OR was verified with Wald’s test [p values <0.05 were considered as statistically significant. All data were analyzed using STATISTICA software . The serum biomarker concentrations were expressed by the mean and standard deviation (SD). The continuous log values of biomarkers and Student’s t-test were used to compare them between cases and controls. The median (Me) of the biomarker concentrations was used to divide subjects into two categories . The categorical variables were presented in percentages. Differences in baseline case-control characteristics were verified with a Pearson Chius data) . The perd’s test . p valueThe baseline characteristics of the cancer-control sub-sample are shown in Breast cancer cases had a lower mean score of the ‘Folate-Cobalamin-Vitamin D’ profile (300.8 versus 349.3 points), and the ‘Iron-Calcium’ profile (127.0 versus 142.7 points) than controls. Compared to the controls, the number of breast cancer cases was lower in the upper tertile of the ‘Iron-Calcium’ profile (24.5 versus 39.5%), and the ‘Magnesium’ profile (18.4 versus 43.2%) than the bottom tertile .Compared to the controls, breast cancer cases had a lower mean serum concentration of most of the selected vitamins and minerals: 25(OH) vitamin D (21.9 versus 29.5 ng/mL), iron (97.8 versus 108.3 µg/dL), calcium (9.5 versus 9.6 mg/dL), and magnesium (2.0 versus 2.1 mg/dL), excluding folate and cobalamin. Compared to the controls, fewer cases of breast cancer had elevated levels of serum concentration of 25(OH) vitamin D ≥24.6 ng/mL (34.0 versus 60.5%), iron ≥103.0 µg/dL (38.0 versus 58.0%), and calcium ≥9.6 mg/dL  and 88%  and 79% . This association disappeared after the adjustment for dietary patterns (fully-adjusted model 3). The serum ‘Folate-Cobalamin-Vitamin D’ profile was not significantly associated with the risk of breast cancer  and 72%  compared to the lower level  and 68%  compared to the lower level. In the higher level of the serum iron concentration (≥103.0 μg/dL), the risk of breast cancer was lower by 56%  compared to the lower level. This association disappeared after the adjustment. There were no significant associations of the serum level of folate, cobalamin, and magnesium considered separately with the risk of breast cancer (In the higher level of the serum vitamin D concentration (≥24.6 ng/mL), the risk of breast cancer was lower by 67%  within the normal laboratory range (from 8.5 to 10.5 mg/dL)  was assoCalcium metabolism is closely related to the vitamin D status . SimilarAlthough high adherence to the serum ‘Magnesium’ profile decreased the risk of breast cancer, this association disappeared in the fully-adjusted model. There is a lack of epidemiological or clinical studies regarding the association between serum magnesium level and breast cancer risk. The molecular mechanism of the magnesium role in breast cancer etiology can be explained by a recent experimental study which suggested that the over-expression of oncogenic protein tyrosine phosphatase PRL-2 can promote oncogenesis by modulating intracellular magnesium levels through binding with the magnesium transporter . The avaIdentification of the serum ‘Iron-Calcium’ profile supports the positive correlation between calcium and iron shown by Joo et al.  in a stuLikewise, in some other studies, including the recent meta-analysis of four studies, no significant associations between the serum level of folate ,57 or viA major strength of this study is the novel approach in the breast cancer risk assessment by considering together blood concentrations of several vitamins and minerals as overall vitamin-mineral profiles. This is the first study to include the combined effects of serum levels of folate, vitamin B12, vitamin D, calcium, iron, and magnesium on breast cancer risk. The strengths of the current study include the serum biomarker measurements, which are better reflected in the circulation nutrient status than other measures of exposure  and are not influenced by a recall bias . Blood lThere are several study limitations. First, it was a relatively small sub-sample size. The cancer sub-sample size was limited by the number of breast cancer patients of the oncological surgery department in one hospital. Moreover, only newly diagnosed breast cancer cases, not benign or remission, qualified. However, the sample size (129) was greater than the minimum sample size (at least 42 of the controls and 42 of the cases) when calculated using the WHO sample size calculator considering 80% test power and 5% significance level . The secThe present findings indicate the need to include the monitoring of vitamin and mineral status, particularly calcium and vitamin D, as endogenous markers in both conventional screening of breast cancer and in the treatment protocol. Further prospective studies with longitudinal measurements of serum biomarkers levels as well as randomized clinical trials are needed to establish cut-offs of the levels of vitamins and minerals which help to protect against breast cancer. In a further explanation of the role of nutrients in breast cancer etiology, genetic mutation carriers which have a genetic predisposition to develop highly aggressive cancers should be taken into account . A betteIn summary, the study revealed that a higher-normal serum level of both iron and calcium, considered together as the serum profile, as well as a higher-normal serum level of calcium, considered separately, and a slightly below the normal range of serum vitamin D level may protect against breast cancer among postmenopausal women, independent of dietary patterns or the use of vitamin/mineral supplements. In the prevention of breast cancer, special attention should be paid to maintaining adequate blood levels of vitamins and minerals and to preventing deficiencies. Thus, the regular monitoring of blood levels of their biomarkers should be included in a breast cancer reducing strategy.


P=0.03; AG + AA compared with GG: OR = 1.64, 95% CI = 1.08–2.51, P=0.02; AG compared with GG + AA: OR = 1.61, 95% CI = 1.04–2.48, P=0.03; OR = 1.64, 95% CI = 1.09–2.45, P=0.02), while HIF-2 rs17039192 had no influence on breast cancer. Considered the comparison of sample size and potential heterogeneity of previous case–control studies, we concluded that HIF-1 rs11549467 has a marginal effect on BC risk. Further well-designed studies with larger sample size were required.Hypoxia-inducible factors (HIFs) play a crucial role in cancer progression. Several epidemiological studies have demonstrated that HIFs polymorphisms can influence the susceptibility of multiple cancers. However, the relationship of HIFs polymorphisms (rs11549467 and rs17039192) and breast cancer (BC) risk was still unknown. Thus, we performed a case-control study based on 560 BC patients and 583 healthy controls to explore the association between them. Our results indicated a boardline connection between HIF-1 rs11549467 and BC risk (AG compared with GG: OR = 1.61, 95% CI = 1.05–2.49,  Cancer Statistics, 2018, a total of 266, 120 new breast cancer (BC) cases and 40,920 BC-related deaths were expected to happen in American women in 2018 [From the evidence supplied by  in 2018 . As is w in 2018 .It has been a common finding that intratumoral hypoxia indicates poorer prognosis, higher metastasis risk, and lower sensibility to radiotherapy and chemotherapy for cancer patients . HypoxiaTo date, several epidemiological studies have demonstrated the influence of HIFs polymorphisms on multiple cancers susceptibility, such as lung, breast, pancreatic, gastric etc.  Thereintn=560) were enrolled in the Department of Oncology, The Second Affiliated Hospital, Xi’an Jiaotong University, from January 2013 to October 2014. All BC patients were newly diagnosed using pathology and detailed immunohistochemical analysis, as was described previously [n=583) were matched to cases based on age (±5 years). All participants were Han Chinese women and supplied a written informed consent to provide us detailed data about self-administration. The present study was approved by the Institutional Review Board of Xi’an Jiaotong University .Breast cancer cases  to extract genomic DNA from whole blood samples, according to the manufacturer’s instructions. DNA concentration was confirmed by the DU530 UV/VIS spectrophotometer . For candidate SNPs in HIFs, we used data from HapMap database of Chinese population and finally elected two SNPs  included in our study. SNP genotyping was conducted with Sequenom MassARRAY RS1000 according to the standard protocol recommended by the manufacturer. The corresponding primers used for each SNP in our study are listed in P value less than 0.05. Five different genetic models were used to evaluate the association between SNPs and breast cancer risk : the allele model (a compared with A); the co-dominant model ; the recessive model (aa compared with AA + Aa); the dominant model (AA compared with Aa + aa); and the overdominant model (AA + aa compared with Aa). We employed SPSS software to access odds ratios (ORs) and 95% confidence intervals (CIs).Fisher’s exact test was used to exam the Hardy–Weinberg equilibrium (HWE) among controls for each polymorphism. Two-sided Pearson’s chi-square tests were adopted to evaluate the differences in allelic frequencies for each SNP between patients and controls, and it was considered statistically significant if the P=0.716). However, the body mass index (BMI) of control groups was significantly higher than BMI of patient groups ; thus, all results were adjusted to BMI.The present study contained 560 BC patients and 583 healthy controls, the characteristics of which were described in our previous studies , the detP=0.1183 and 0.74 for rs11549467 and rs17039192, respectively) presented statistically significance between breast cancer patients and control subjects. Statistical analysis showed that rs11549467 had an increased influence on breast cancer risk in the codominant, dominant, overdominant, and allele model , while rs17039192 was not associated with breast cancer (We genotyped the two SNPs (rs11549467 and rs17039192) in 1143 included subjects , and the genotyping success rates of the two SNPs were 100%. The genotype distribution of control groups accorded with HWE (t cancer .P>0.05). In subgroup analyses, no significant association was found with the risk of breast cancer among Asians and in the hospital-based studies .Since boardline connection was found between HIF-1 rs11549467 and BC risk, we conducted a meta-analysis based on five articles including 898 BC cases and 751 healthy controls . Pooled HIFs play a critical role in facilitating cells to adapt to hypoxia. Existing evidences proved that HIFs took part in many pivotal aspects of cancer progression. In this case–control study, we aimed to investigate the association between HIFs polymorphisms and breast cancer risk among Northwest Chinese women. The results indicated a boardline connection between HIF-1 rs11549467 and BC risk, while HIF-2 rs17039192 had no influence on breast cancer.HIF-1 rs11549467 is a missense mutation polymorphism leading to an amino acid of alanine substituted by threonine. This amino acid change may significantly enhance the transcription activity of HIF-1A and effect on the downstream target genes expression ,21. The Rs17039192 is a functional polymorphism in HIF-2α, which was encoded by the human EPAS1  gene . PreviouBreast cancer is a multiple-factorial disease with complicated etiopathogenesis, genetic factors only occupy a part of these. Focusing oncology research on genetic factors, 70 SNPs were identified as BC-related by large-scale replication studies and genome wide association studies. As a focus area of oncological research into genetic factors, 70 SNPs were identified as BC-related mutation by large-scale replication studies and genome wide association . SNPs maThe present study has some potential limitations. First, all the included subjects came from the same hospital name Xi’an Jiaotong University, thus selection bias may exist inevitably in the present study. Second, we failed to consider other significant risk factories such as lifestyle, living environment, and family history because of lack of data. Third, all analyses in our study were based on the genotype distribution of the two SNPs, functional studies revealed the molecular mechanism were absent.In conclusion, our results suggest that HIF-1 rs11549467 has a marginal effect on BC risk, while no association was found between HIF-2 rs17039192 and BC risk.


Breast cancer is a global health problem being the most common cancer of women in both developed and under-developed countries. Public and individual awareness can play a vital role in the prevention, early diagnosis and treatment of breast cancer. However evidence is sparse on awareness and practice of breast cancer screening methods used among women of reproductive age in Ethiopia. The present study was designed to determine factors associated with breast cancer screening awareness and practices of women in Addis Ababa.A facility based cross-sectional study was conducted among women who came for maternal and child health care services to selected public health centers. The participants were interviewed using a structured questionnaire. Following data collection, data entry and analysis was done using Epi-Info version 7and SPSS Version 21 respectively. Cross tabulation of each independent variable with the dependent variable with their 95% confidence interval was done and those variables associated at binary logistic regression with a significance level of 0.2 were entered into multiple logistic regression.About half (53%) of women have heard about breast cancer and 35.5% of women are aware of at least one breast cancer screening method. Among those who are informed about breast cancer screening, 97% indicated that screening improves the chance of survival. Among the common screening methods; self-breast examination, clinical-breast examination and mammographic examination were practiced by 24.3%, 7.6% and 3.8% of respondents, respectively. Women who had high level of income were about 3 times more likely to be aware about breast cancer screening methods, , while women who attended secondary and tertiary school were 2 and 4 times more likely to practice breast cancer screening methods  and  respectively.This study has showed that self-reported breast cancer screening coverage is low. About two-thirds of women had no information about breast cancer screening methods. Breast cancer (BC) is a proliferation of malignant cells that arises in the breast tissue and the term represents a range of diseases from non-invasive to metastatic carcinoma . It is tEvidence shows poor awareness of breast cancer symptoms, prevention mechanisms, risk factors and treatment options have usually been associated with patient delay in seeking help, making treatment less effective and minimal survival rate –11. ScreScreening is a relatively available resource for early detection though awareness about breast cancer screening is very low  and globThere were only a limited number of studies undertaken on the awareness and practices of breast cancer screening methods among women of reproductive age in Ethiopia , 15. The2; with an estimated density of 5535.8 people per square kilometer. Based on the2007census of the Central Statistical Agency of Ethiopia, the total population estimate of Addis Ababa for the year 2015 was 3.55 million and the proportion of males and females was 49 and 51%, respectively. The number of females in the reproductive age group constitutes 35.5% of the total population. There were 84 public health centers in Addis Ababa city administration . Those who had no family history of breast illness were 66% less likely to be aware about breast cancer screening compared to those who had family history of breast illnesses, ] and  respectively. And those women who lack awareness of breast cancer were 99% less likely to practice breast cancer screening methods as compared to those who had good awareness of breast cancer  but was less compared to a study from Nigeria. This could be due to the socio-demographic differences between the two study areas. What was striking in this study was that 14.5% of women (knew) mammography as a method for breast cancer screening and which was higher than the study done in Ethiopia and Nigeria , 20, thiOur study showed that factors like family history of breast cancer and income is associated with the awareness of women about breast cancer, in which family history of breast illness perhaps gave them a chance to have an information and increases health seeking behavior. When a family has better income it will also increase access to education and information. These findings were contrary to study conducted in Northern Ethiopia , but conSBE, CBE and mammographic examinations were practiced by 24.3, 7.6 and 3.8%, respectively. This is lower than the study done in Nigeria. And this could be due to the differences in socio-economic factors between the study areas. And the main reason mentioned for not having clinical breast examination (CBE) was not having symptoms 86.4% which was similar to the study done in Benin Nigeria .Majority of the participants in this study (86.4%) mentioned absence of symptoms as the main reason for not undergoing CBE and this is similar to the study of north Ethiopia . The simThis study showed only (3.8%) had mammographic examination slightly higher than the study of North Ethiopia; while the main reasons for non-practice of mammographic examination were not having symptoms, lack of attention to BC, and its expense 75.6, 11.9 and 6.5% respectively. While in the study of north Ethiopia the main reasons given by the women for not having mammographic examination were, doubt about its importance 33.8%, lack of awareness about it is 31.9% and unavailability of the service 14.0% . And thiA limitation of the study is the cross-sectional nature of the data made it impossible to reach at the causal relationship between the different independent and outcome variables. Lack of literatures from developing countries hinders further discussion and comparison.This study highlights the need to address the awareness and practice of breast cancer screening among women. Differences in awareness related outcomes analyzed according to socio-demographic and other factors noted in the results suggest potential target groups for future. These suggest that local and national activity might work in collaboration to address a wide range of challenges identified in this study.


Inflammation is an important candidate mechanism underlying cancer and cancer treatment-related cognitive impairment. We investigated levels of blood cell–based inflammatory markers in breast cancer survivors on average 20 years after chemotherapy and explored the relation between these markers and global cognitive performance.One hundred sixty-six breast cancer survivors who received post-surgical radiotherapy and six cycles of adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy on average 20 years before enrollment were compared with 1344 cancer-free women from a population-based sample (50–80 years old). Breast cancer survivors were excluded if they used adjuvant hormonal therapy or if they developed relapse, metastasis, or second primary malignancies. Systemic inflammation status was assessed by the granulocyte-to-lymphocyte ratio (GLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII). Cognitive performance was assessed using an extensive neuropsychological test battery from which the general cognitive factor was derived to evaluate global cognitive performance. We examined the association between cancer, the general cognitive factor, and inflammatory markers using linear regression models.P for interaction for GLR = 0.038, PLR = 0.003, and SII = 0.033).Breast cancer survivors had a lower general cognitive factor than non-exposed participants from the comparator group  −0.35 to −0.06). Inflammatory markers were higher in cancer survivors compared with non-exposed participants (mean difference for log(GLR) = 0.31; 95% CI 0.24 to 0.37, log(PLR) = 0.14; 95% CI 0.09 to 0.19, log(SII) = 0.31; 95% CI 0.24 to 0.39). The association between higher levels of inflammatory markers and lower general cognitive factor was statistically significant in cancer survivors but not among non-exposed participants. We found a group-by-inflammatory marker interaction; cancer survivors showed additional lower general cognitive factor per standard deviation increase in inflammatory markers (This is the first study to show that (1) cancer survivors have increased levels of inflammation on average 20 years after treatment and (2) these inflammatory levels are associated with lower cognitive performance. Although this association needs verification by a prospective study to determine causality, our findings can stimulate research on the role of inflammation in long-term cognitive problems and possibilities to diminish such problems. Patients with cancer frequently report cognitive problems that can affect their quality of life and daily functioning substantially. Studies have shown that patients with non-central nervous system (non-CNS) cancer can experience cognitive problems during and after completion of treatment including chemotherapy, and a subgroup of patients had cognitive problems up to 20 years after treatment , 2.The cancer survivor population is aging and growing because of increased life expectancy and more specifically because of advances in cancer treatment and improved screening. In turn, this results in an increasing number of cancer survivors coping with cognitive problems. The driving forces underlying these cognitive problems have not been sufficiently clarified, impeding the approach and process of developing effective interventions. Cognitive problems in patients with cancer could be induced by cancer itself, cancer-related treatment, or shared risk factors for the development of both cancer and cognitive problems , 4. DiseIn recent years, inflammation in particular has been suggested as an important and potentially intervenable mechanism in the pathogenesis of cognitive problems in patients with cancer. Higher levels of inflammatory factors such as cytokines are observed in patients with cancer prior to start of any treatment , during Most studies examined the inflammation status by investigating cytokines using different cytokine panels , 6, 8–19In this study, we investigated global cognitive performance, levels of blood cell–based inflammatory markers, and their relation in breast cancer survivors who had received post-surgical radiotherapy and six cycles of adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy on average more than 20 years previously. We furthermore examined whether inflammation and cognitive performance were differentially associated between breast cancer survivors and cancer-free women from a population-based sample.In this study, we selected women who had survived breast cancer and had received adjuvant CMF chemotherapy. We compared them with women from the general population, who were cancer-free and had never received chemotherapy.Women with a history of unilateral, invasive breast cancer were identified on the basis of registries of the Netherlands Cancer Institute in Amsterdam and the Daniel den Hoed Cancer Clinic of the Erasmus Medical Center in Rotterdam as described previously . BrieflyBreast cancer survivors were eligible if they were 50–80 years old at the time of inclusion in 2008, if invasive breast cancer was their first and only malignancy, if they had not developed relapse or distant metastasis, if they had sufficient command of the Dutch language, and if they did not have any contraindications for magnetic resonance imaging (MRI). In addition, ever use of hormonal therapy was applied as an exclusion criterion. Because adjuvant hormonal therapy was not part of the standard treatment for patients with breast cancer in the Netherlands until the mid-1990s, only a few women received this treatment. To enhance homogeneity within the group of breast cancer survivors, we included hormone treatment-naïve cancer survivors only.n = 5) and incomplete data of neuropsychological tests . This sample comprised the non-exposed participants used in our previous cognitive study [n = 39) and incomplete data of neuropsychological tests (n = 191), resulting in 1344 non-exposed participants  started in 2006 and was the first cohort in which an extensive set of neuropsychological tests was implemented at baseline. For this reason, RS-III was chosen as the reference subcohort, which was composed of 3392 participants (65% out of invitees). From these participants, women 50–80 years old without a history of cancer or dementia were eligible as non-exposed participants  directly after the blood sample was drawn. Hematologic measurements included absolute granulocyte, lymphocyte, and platelet counts in 109 per liter.All participants had fasting blood samples taken during the research center visit. Full blood count measurements were performed by using a COULTERWe used the granulocyte count as proxy for the neutrophil count because we did not have this measurement available in our sample. Because most of the granulocytes are represented by neutrophils, we believe this did not affect our results , 27. ForThe GLR and PLR were calculated as the ratio of granulocyte count to lymphocyte count and as the ratio of platelet count to lymphocyte count, respectively . The SIICognitive performance was evaluated between November 2009 and June 2010 for breast cancer survivors and between February 2006 and December 2008 for non-exposed participants on the same day the blood sample was drawn. Cognitive performance was assessed by a neuropsychological battery in the research center of the Rotterdam Study. Six tests were administered: the Mini–Mental State Examination, Letter-Digit Substitution Test (LDST), Word Fluency Test (WFT), Stroop Test , Purdue Pegboard Test (PPB) , and 15-Word Learning Test (15-WLT) . Global cognitive performance was assessed via the general cognitive factor, which was generated by using principal component analysis of the following tests: LDST , WFT (number of words), Stroop interference , PPB test , and 15-WLT  .We assessed education level  and smoking status  by interview. Body mass index (BMI) (in kilograms per square meter) was computed from measurements of height and weight. Diabetes mellitus was defined as use of antidiabetic medication, a fasting serum glucose level of at least 7.1 mmol/L, or a random serum glucose level of at least 11.1 mmol/L . HistoryLinear regression models were used to investigate mean differences in the general cognitive factor and inflammatory markers between breast cancer survivors and non-exposed participants. Inflammatory markers were log-transformed because of their skewed distribution. We constructed two nested models: model I was adjusted for age (continuous) and education (four categories), and model II was additionally adjusted for smoking status (three categories), BMI (continuous), diabetes mellitus (yes/no), history of stroke (yes/no), history of myocardial infarction (yes/no), and CES-D sum-score (continuous). To investigate whether levels of the general cognitive factor were explained by different inflammatory markers, we adjusted additionally for each inflammatory marker separately.The association between the general cognitive factor and inflammatory markers was investigated for breast cancer survivors and non-exposed participants using linear regression models. To study whether this association was stronger in breast cancer survivors than in non-exposed participants, we computed interaction terms between history of cancer/cancer treatment and each inflammatory marker. We explored effect modification by stratifying for mean BMI.Since mean age was higher in the breast cancer survivors compared with the non-exposed participants Table , we repeP value of less than 0.05 was considered statistically significant.Multiple imputation was used for missing data on covariates  with five imputed datasets, based on history of cancer/cancer treatment, inflammatory markers, general cognitive factor, and other covariates . Rubin’s method was used for pooled regression coefficients (β) and 95% confidence intervals (CIs) . All anaCharacteristics of breast cancer survivors and non-exposed participants are presented in Table Breast cancer survivors had higher median levels of GLR, PLR, and SII than non-exposed participants. History of breast cancer/cancer treatment was associated with higher inflammatory markers, also after adjustment for age, education, smoking, BMI, diabetes mellitus, history of stroke, history of myocardial infarction, and CES-D sum-score (mean difference for log(GLR) = 0.31, 95% CI 0.24 to 0.37, log(PLR) = 0.14, 95% CI 0.09 to 0.19, log(SII) = 0.31, 95% CI 0.24 to 0.39; Table Breast cancer survivors had a lower general cognitive factor than non-exposed participants (mean difference = −0.21, 95% CI −0.35 to −0.06, corresponding with an effect of 3.6 years of age given a decline in general cognitive factor of 0.59 points per 10 years; Table A lower general cognitive factor was associated with higher inflammatory markers in breast cancer survivors Table . In non-P for interaction between cancer and standardized log-transformed GLR = 0.038, PLR = 0.003, and SII = 0.033; Fig. The interaction term between inflammatory markers and history of cancer/cancer treatment was significant for each inflammatory marker, indicating that the association between higher inflammation levels and lower general cognitive factor was more pronounced in breast cancer survivors than in non-exposed participants (2 compared with those with a higher BMI (Table The association between higher inflammatory markers and lower general cognitive factor differed more between breast cancer survivors and non-exposed participants with a higher BMI than in those with a lower BMI. However, stratified analyses for BMI showed that the effect of one–standard deviation increase in inflammatory marker on general cognitive factor was higher among breast cancer survivors with a BMI below 27.3 kg/mMI Table .Table 4AThis study is the first report investigating the association between blood cell–based inflammatory markers and cognitive performance in breast cancer survivors with an average time since cessation of chemotherapy of more than 20 years. Breast cancer survivors had lower global cognitive performance and higher inflammatory markers compared with women without a history of cancer. The tendency for lower global cognitive performance with higher inflammatory markers was more pronounced in breast cancer survivors, suggesting a potential role for inflammation in the pathophysiology of cognitive problems in cancer survivors. This effect was not modified by BMI. More insight in mechanisms underlying cognitive problems could help identifying those women who are at an increased risk of cognitive problems and developing prevention strategies.We previously reported on differences in cognitive performance between breast cancer survivors and non-exposed participants . In thisInterestingly, levels of inflammatory markers were higher in breast cancer survivors, compared with non-exposed participants, on average 20 years after cancer treatment. Inflammation plays a critical role in tumorigenesis, tumor progression, and cancer metastasis , 37. ResThe found association of blood cell–based inflammatory markers and cognitive performance in breast cancer survivors is in line with previous observations before, during, and shortly after therapy , 17, 18.Owing to our study design, we cannot determine whether the association between inflammation and impaired cognitive performance is causal. However, also a causal association could not illuminate the exact underlying mechanisms by which inflammation leads to brain changes and subsequent cognitive problems. Peripheral pro-inflammatory cytokines are able to cross the blood–brain barrier, which may initiate the release of local cytokines . Local cOur study has several strengths. First, we have a large sample size of breast cancer survivors who have been treated on average more than 20 years ago, enabling us to investigate long-term effects. Moreover, we used non-exposed participants from a population-based cohort study, who underwent the same examinations as the breast cancer survivors. This design provided standardized ascertainments of outcome and covariates. All participants received a neuropsychological test battery, enabling us to investigate global cognitive function by the general cognitive factor. Lastly, we were able to investigate inflammation status using blood cell–based inflammatory markers, which are low-cost and easy to use in the clinic.Study limitations include the design by which we cannot disentangle the effects of cancer and cancer treatment on cognition and levels of inflammatory markers. Some studies show that patients treated with chemotherapy have higher inflammatory markers during and after treatment compared with chemotherapy-naïve patients . HoweverWe found that breast cancer survivors who had been treated with chemotherapy on average more than 20 years ago have higher blood cell–based inflammatory markers compared with women without a history of cancer. Higher levels of inflammatory markers tended to be associated with poorer cognitive performance in both cancer survivors and cancer-free women, and expression was stronger in breast cancer survivors. This finding suggests that inflammation could have a role in the pathogenesis of long-term cognitive impairment in cancer survivors. Further prospective studies are important to determine the causality of the association and to investigate the effects of lowering inflammation on the development of cognitive problems in cancer patients and survivors, for instance, by exercise or anti-inflammatory drugs.


Breast cancer is associated with overweight and obesity after menopause. However, clothing size as a proxy of adiposity in predicting postmenopausal breast cancer is not widely studied. We aimed to explore the relationships between postmenopausal breast cancer risk with adipose indicators (including clothing sizes) and weight change over adulthood.Prospective cohort study.England, Wales and Scotland.17 781 postmenopausal women from the UK Women’s Cohort Study.Incident cases of malignant breast cancers  9 code 174 and ICD 10 code C50).From 282 277 person-years follow-up, there were 946 incident breast cancer cases with an incidence rate of 3.35 per 1000 women. Body mass index , blouse size , waist circumference  and skirt size  had positive associations with postmenopausal breast cancer after adjustment for potential confounders. Increased weight over adulthood  was also associated with increased risk for postmenopausal breast cancer.Blouse and skirt sizes can be used as adipose indicators in predicting postmenopausal breast cancer. Maintaining healthy body weight over adulthood is an effective measure in the prevention of postmenopausal breast cancer. This study may be the first to report the use of both blouse and skirt sizes as measures of body size.The large study sample with long follow-up duration and linkage of participants’ ID with the National Statistics National Health Service central register provides accurate information on breast cancer diagnosis.All adipose indicators, blouse and skirt sizes, were self-reported.We were unable to evaluate in more detail the effect of weight gain at different ages.Breast tumour characteristics were not available, and we could not explore whether our findings may differ by breast cancer subtypes.Breast cancer is the most common cancer among women worldwide, accounting for 25% of new cases.To date, many adipose indicators namely weight, body mass index (BMI), waist circumference, waist to hip ratio are used in research and health education programmes. BMI is an established indicator for general obesity, while central obesity is commonly measured using waist circumference. Among postmenopausal women, higher BMI and larger waist circumference during adulthood, and weight gain over adulthood are associated with increased breast cancer risk.Clothing sizes are objective, easy to recall and less likely to be misreported. From a public health perspective, clothing sizes may be useful when anthropometric measurements are not available or challenging in their measurements due to extreme obesity. Skirt or trouser sizeThe recruitment of participants and characteristics of the UKWCS have been described in detail previously.A total of 174 local research ethics committees were contacted and permission to carry out the baseline UKWCS study was obtained.The participants were not involved in the development of the research question and outcome measures. They were also not involved in the design and conduct of the study. The results are not disseminated to the participants apart from the UKWCS website.All women were flagged for death and cancer registration on the office of National Statistics National Health Service central register. Causes of death and cancer diagnosis were coded in the International Classification of Diseases (ICD) 9 and 10. All malignant breast cancers (ICD 9 code 174 and ICD 10 code C50) registered after the participants returned their questionnaires were taken as incident cases. Prevalent cancers identified from the questionnaires and incident cases identified within 1 year from the date of questionnaire returned were excluded to rule out reverse causation since undiagnosed breast cancer may influence weight.Anthropometric measures such as weight, height, waist and hip circumference at enrolment; and weight at age 20 years were self-recorded. BMI was categorised into groups of underweight, normal weight, overweight and obese according to the WHO criteria.Socioeconomic characteristics, dietary pattern , lifestyle , reproductive history, information on past health experience, sibling and parental health were reported at baseline.The follow-up (person-years) for each participant was counted from the beginning of the study until the date of breast cancer diagnosis or the censor date (1 April 2014), whichever occurred first. The median follow-up was 16.9 years. The relationships between adipose indicators and weight change; and postmenopausal breast cancer were explored using Cox’s proportional hazards regression. HRs with 95% CI were reported. Linear trends, using the exposure categories as a continuous variable were also presented. Potential confounders such as age, highest education levels achieved, time spent walking (hours/day), family history of breast cancer, oral contraceptive (OC) use, HRT use, parity, age at first birth, age of menarche and dietary pattern  were included in the fully adjusted models. In addition, BMI at 20 years was also adjusted for all adipose indicators, except BMI at 20 years. All statistical analyses were conducted using Stata V.14.After excluding the prevalent cases at baseline and incident cases developed within 1 year of questionnaire returned, 17 715 postmenopausal women were included in this analysis. From 282 277 person-years follow-up, there were 946 incident breast cancer cases with an incidence rate of 3.35 per 1000 women.2 and 21.5 (2.9) kg/m2, respectively (The mean (SD) age of the postmenopausal participants at enrolment was 58.8 (7.5) years. The majority were white (99.1%), about one-fifth had tertiary qualifications, 10% were smokers, 11% self-reported being on a vegetarian diet, 3% reported a family history of breast cancer, about 41% had ever taken HRT, 52% ever used OC and 17% were nulliparous. The mean (SD) BMI at enrolment and at 20 years of age were 24.9 (4.3) kg/mectively . The corectively .10.1136/bmjopen-2018-022599.supp1Supplementary file 1Incidence rates (per 1000 women) for postmenopausal breast cancer increased by BMI categories at enrolment, BMI categories at 20 years old and weight change (from 20 years old to enrolment age) . Obese wAfter adjustment for potential confounders, adipose indicators at enrolment namely BMI, waist circumference and clothing sizes (blouse and skirt sizes) were associated with increased risk for postmenopausal breast cancer . PostmenBMI and blouse size , as well as waist circumference and skirt size , had positive association with postmenopausal breast cancer. There was an increase of 3% in HR for every unit increase in BMI and 6% in HR for every 5 cm increase in waist circumference after adjustment for confounders. There was an additional 1% increase in HRs for both BMI and waist circumference after additionally adjusted for BMI at 20 years for both BMI and waist circumference. For every 2-unit increase in blouse and skirt sizes (as UK clothes size increased by 2 units), the HRs for blouse and skirt sizes were 1.08 (95% CI: 1.01 to 1.14) and 1.12 (95% CI: 1.06 to 1.19), respectively. The HRs increased to 1.10 (95% CI: 1.03 to 1.18) and 1.14 (95% CI: 1.06 to 1.22) for blouse and skirt sizes, respectively, after additional adjustment for BMI at 20 years of age.Weight change over adulthood was associated with increased risk for postmenopausal breast cancer . For every 1 kg weight change, there was a corresponding 2% risk increase after adjusting for confounders. Similar results were observed when weight change was additionally adjusted for BMI at 20 years . There wOur results suggested that clothing size such as blouse and skirt sizes can be used as adipose indicators in predicting postmenopausal breast cancer. Trouser and skirt sizes have been reported to predict cancer risks independent of BMI,Skirt size and waist circumference were highly correlated and performed equally well in predicting postmenopausal breast cancer risk. Our findings provide additional evidence of using skirt size as a proxy for central obesity in predicting postmenopausal breast cancer. On the other hand, there was no previous report on blouse size associated with increased risk of postmenopausal breast cancer. Blouse size could serve as an indicator for general obesity as it has a strong correlation with BMI. Blouse size also performed as well as BMI in predicting breast cancer among postmenopausal women. A previous study conducted in the UK reported that among 362 respondents, only 3% reported a clothing size different from their clothing labels.Overweight and obese women at enrolment had up to 32% increased risk of postmenopausal breast cancer. The association between overweight/obesity with postmenopausal breast cancer remained after further adjustment for BMI at 20 years. Women who gained the most weight since the age of 20 years old, had almost 30% increased risk of postmenopausal breast cancer after adjustment for potential confounders and BMI at 20 years. Similar findings have been reported by other researchers.et alDifferent periods of weight gain  were consistently associated with increased breast cancer risk.Consistent with previous literatureAccording to the latest report (2017) from the World Cancer Research Fund International/American Institute for Cancer Research, being overweight or obese during young adulthood decreases the risk of postmenopausal breast cancer.There are a few limitations which need to be considered while interpreting the results. All adipose indicators, blouse and skirt sizes were self-reported. Some overweight or obese women may be more likely to under-report their weight compared with normal-weight participants. On the other hand, blouse and skirt sizes offer an objective standard as a proxy to report overweight/obesity which are potentially less liable for misreporting. We were unable to evaluate in more detail the effect of weight gain at different ages, other than that of weight at age 20 years and weight at enrolment. Breast tumour characteristics were not available, and we could not explore whether our findings may differ by breast cancer subtypes. On the other hand, we believe we are the first to report that both blouse and skirt sizes predict postmenopausal breast cancer risk equally as well as other more invasive measures of body size. In addition, our study sample is large with long follow-up duration. The linkage of participants’ ID with the National Statistics National Health Service central register provides accurate information on breast cancer diagnosis.Overweight/obesity (BMI and blouse size), central obesity (waist circumference and skirt size) and weight change during adulthood are associated with increased risk of postmenopausal breast cancer. Clothing size such as skirt and blouse sizes can be used as a proxy for adipose indicators in predicting postmenopausal breast cancer. Clothing sizes offer an objective standard as a proxy to report overweight/obesity which are useful in the public health setting. Maintaining healthy body weight over adulthood is an effective measure in the prevention of postmenopausal breast cancer.


The long time from exposure to potentially harmful chemicals until breast cancer occurrence poses challenges for designing etiologic studies and for implementing successful prevention programs. Growing evidence from animal and human studies indicates that distinct time periods of heightened susceptibility to endocrine disruptors exist throughout the life course. The influence of environmental chemicals on breast cancer risk may be greater during several windows of susceptibility (WOS) in a woman’s life, including prenatal development, puberty, pregnancy, and the menopausal transition. These time windows are considered as specific periods of susceptibility for breast cancer because significant structural and functional changes occur in the mammary gland, as well as alterations in the mammary micro-environment and hormone signaling that may influence risk. Breast cancer research focused on these breast cancer WOS will accelerate understanding of disease etiology and prevention.Despite the plausible heightened mechanistic influences of environmental chemicals on breast cancer risk during time periods of change in the mammary gland’s structure and function, most human studies of environmental chemicals are not focused on specific WOS. This article reviews studies conducted over the past few decades that have specifically addressed the effect of environmental chemicals and metals on breast cancer risk during at least one of these WOS. In addition to summarizing the broader evidence-base specific to WOS, we include discussion of the NIH-funded Breast Cancer and the Environment Research Program (BCERP) which included population-based and basic science research focused on specific WOS to evaluate associations between breast cancer risk and particular classes of endocrine-disrupting chemicals—including polycyclic aromatic hydrocarbons, perfluorinated compounds, polybrominated diphenyl ethers, and phenols—and metals. We outline ways in which ongoing transdisciplinary BCERP projects incorporate animal research and human epidemiologic studies in close partnership with community organizations and communication scientists to identify research priorities and effectively translate evidence-based findings to the public and policy makers.An integrative model of breast cancer research is needed to determine the impact and mechanisms of action of endocrine disruptors at different WOS. By focusing on environmental chemical exposure during specific WOS, scientists and their community partners may identify when prevention efforts are likely to be most effective. Despite the considerable personal and societal burden from breast cancer, primary prevention efforts encounter challenges. Unlike other cancers that are linked to a predominant risk factor . FoBreast cancer etiology appears to be driven in part by perturbations to breast tissue as well as alterations of the mammary gland micro-environment during critical windows. Here we briefly summarize breast tissue changes occurring during each WOS, review evidence that addresses environmental carcinogenesis during each WOS, and outline the motivation for ongoing research on the chemicals and metals targeted in BCERP.The prenatal period is a particularly vulnerable WOS because breast tissue begins to develop in the embryonic stage when epidermal cells in concert with embryonic mesenchyme become breast buds –18. FastPregnancy and birth cohorts reveal possible associations between environmental chemicals during the prenatal period and breast cancer. The Child Health and Development Studies (CHDS) found high levels of maternal exposure to dichlorodiphenyltrichloroethane (DDT) during pregnancy increased the daughters’ later breast cancer risk to age 52 nearly fourfold compared to daughters of women with low levels of exposure Table  25]. Al. Al25]. Another class of chemical exposures of concern during the prenatal WOS is polycyclic aromatic hydrocarbons (PAH). PAH are produced as a result of combustion of hydrocarbons. Some of the common sources of PAH exposure include consuming grilled meats and certain other food items , inhalinLike DDT and other organochlorines, PAH are lipophilic and stored in fat tissue including breast tissue . Most PAdelayed median puberty endpoints by 5–11 months when comparing extreme categories of exposure  and per- and polyfluoralkyl substances (PFAS) on breast development and breast density. PFAS are used in many commercial products because of their non-stick, stain-resistant, and waterproof characteristics. Sources of human exposure include production facilities, firefighting training, consumer products, diet, and drinking water. Dietary sources include seafood  and foodPregnancy is another period of rapid breast tissue and micro-environmental changes during which susceptibility to environmental exposures may increase the risk of breast cancer . During In mice, there is a greater than 100-fold increase in the number of mammary epithelial cells during pregnancy demonstrating the rapid changes that occur in mammary tissue. Despite the rapid proliferation, a full-term pregnancy renders the mammary epithelium resistant to tumorigenesis subsequent to the pregnancy. This is observed in studies of exposure to carcinogens , 97–99 aEpidemiologic evidence directly linking environmental exposures during pregnancy and breast cancer risk arises from the previously mentioned prospective CHDS which measured PCB and DDT soon after pregnancy and confirmed breast cancer diagnoses with medical records. Relative risk estimates for breast cancer comparing upper to lower quartiles of 16 individual PCB congeners ranged from 0.2 to 6.3; a composite score of exposure was associated with an odds ratio of 2.8 (95% CI 1.1–7.1)  showed that the increased incidence of breast cancer with use of exogenous estrogen and progesterone –127 was PBDE are a class of over 200 organohalogenated compounds widely used as flame retardants and may modulate steroidogenesis including expression of aromatase –136. BPAMetalloestrogens are metals that activate the ER, leading to estrogen-like changes. Metalloestrogens are prevalent environmental contaminants with multiple routes of human exposure. They often accumulate in tissues and organs . MBCERP members are examining whether exposure to PBDEs, BPA, or selected metals during the menopausal transition is associated with breast cancer risk in humans, and evaluating potential mechanisms to explain these associations in rodent models.The long time between exposures during the early WOS  and breast cancer occurrence has multiple implications for breast cancer research. First, because many environmental exposures are stored long-term in adipose tissue, even compounds now banned, such as DDT and PBDE, may continue to be relevant for breast cancer risk. Bioaccumulation of lipophilic chemicals and their long-term storage also means studies incorporating biomarkers in breast tissue need to consider both the effects on adipose tissue as well as epithelial and stromal tissues.Second, because it may be decades after the relevant windows of exposure before breast cancer is diagnosed, the examination and validation of intermediate biomarkers of response, apparent closer to the timing of exposure and before diagnosis, are imperative, particularly in prospective human studies. BCERP first started as a cohort study of the environmental exposures that may accelerate puberty. The main outcome of the cohort study was based on Tanner Stages . As BCEROne intermediate outcome is mammographic breast density (MBD), defined as the fraction of connective and glandular tissue to adipose tissue on a mammogram –181. MBDLittle is known of the drivers of breast tissue changes across adolescence, early adulthood, and the menopausal transition and thus the contributors to breast density. Most of what is known about normal breast tissue characteristics is from mammography data in women over 40 years of age. In women under 40 years, two alternative imaging methods have been used to assess breast composition including three studies of magnetic resonance imaging (MRI) in women aged 15–30 years –190 and Given the changes in mammary tissue architecture and hormone signaling during the prenatal, pubertal, pregnancy, and menopausal transition windows, these critical time periods may reflect windows of heightened risk. Thus, measuring the impact of environmental chemical and metal exposures during these WOS is essential to understand their roles in breast cancer risk; these issues have not been addressed by the majority of epidemiologic studies to date.Experimental studies in cell lines and animals are providing causative mechanistic links between environmental exposures and altered mammary carcinogenesis, particularly during key WOS. Increasingly, epidemiologic studies are able to link the human exposure of chemicals and metals during relevant WOS through the use of intermediate breast outcomes including specific breast tissue characteristics and breast density in adolescence and adulthood to address the challenge of long latency time posed in cancer research.For many of the studies described here, community engagement strengthens the research design as well as the dissemination and implementation of study findings. To address knowledge gaps and accelerate translation of environmental breast cancer research findings related to WOS, BCERP integrates basic and population researchers with communication scientists and representatives of community-based organizations Fig. . CommuniAlthough the median age when women are diagnosed with breast cancer is 62 years , primary


This systematic review and meta-analysis was performed to determine the protective effect of omega-3 fatty acids in fish consumption against breast cancer in Asian patients. The authors conducted a meta-analysis of published research articles on protective effect of omega-3 fatty acids in fish consumption against breast cancer in Asian patients published between January 2000 and July 2018 in online database of PubMed, ProQuest and EBSCO. Pooled odds ratios (OR) were calculated by using fixed and random-effect models. Publication bias was visually evaluated by using funnel plots and statistically assessed in Egger’s and Begg’s tests. Data were processed by Review Manager 5.3 (RevMan 5.3) and Stata version 14.2 (Stata Corporation). This study reviewed 913 articles. There were 11 studies which conducted systematic review then continued by meta-analysis of relevant data with total number of samples were 130,365 patients. The results showed there was protective effect of omega-3 fatty acids in fish consumption against breast cancer in Asian patients . There was not any study with significant publication bias included.This analysis confirmed the protective effect of omega-3 fatty acids in fish consumption against breast cancer in Asian patients. Breast cancer is a major health concern in the world as it is one of the most common malignancies found worldwide. Although Asian countries has lower incidence rate than Europe and United States, the death rate of breast cancer in Asia is considerable . This kind of neoplasm has multifactorial etiology. The breast cancer risk factors are divided into nonmodifiable and modifiable risk factors . In the past few decades, epidemiological studies have suggested that healthy diet and lifestyle are essential to prevent breast cancer . One of the dietary factors associated with breast cancer risk is low intake of fish .The low intake of fish is associated with higher breast cancer risk. Some studies have suggested that omega-3 fatty acids in fish consumption is beneficial for breast cancer prevention and survivorship. Fish fatty acid is commonly referred to longer chain omega-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) . However, due to wide geographical variation, the demography of breast cancer patients in developing countries differs from those in developed countries. The changes in dietary pattern and lifestyle due to globalization and economic improvement, as well as the availability of breast cancer screening programme might affect the breast cancer risk of the people. A study by Zheng et al., (2013) firstly found that fish consumption is associated with lower risk of breast cancer. High intake of fatty fish is significantly associated with lower breast cancer risk . However, some subsequent studies of fish consumption and breast cancer led to contradictory conclusions . So, in fact, the research findings seem to be inconsistent. The different results possibly happened due to different dietary pattern of fish in Asian population and Western population, whom the latter has lower intake, which may impact the significance of the results.Through measurement of breast cancer risk, it can be classified whether a person has a safe risk to breast cancer, being adequate for breast cancer prevention or harmful to the occurrence of breast cancer . Therefore, this study aims to determine the protective effect of omega-3 fatty acids in fish consumption against breast cancer in Asian patients through meta-analysis study, so that the conclusion drawn from studies on omega-3 fatty acids in fish consumption and breast cancer association will have stronger strength of recommendation.Study design and research sampleThis study was a quantitative research with meta-analysis study design. The meta-analysis of the study followed PRISMA Statement to prefer reporting items . Meta-analysis was performed to examine protective effect of omega-3 fatty acids in fish consumption against breast cancer in Asian patients. The research samples were published research articles published between January 2000 and July 2018 in online database of PubMed, ProQuest and EBSCO. Operational definitionsThe variables of this study included omega-3 fatty acids in fish consumption as independent variable and breast cancer as dependent variable.Research procedure This research was conducted through data collection to identify published research articles on protective effect of omega-3 fatty acids in fish consumption against breast cancer in Asian patients in online database of PubMed, ProQuest and EBSCO . Identification process of 913 articles was held by identifying the title of the articles, continued by reviewing the abstract, and then the full-text of the articles. An article must be excluded if: (a) unrelevant to subject outcome, (b) the methods was not case control and cohort study (c) the information provided in the results was insufficient for data extraction.Data collection techniqueThe data collection was performed by online searching. The online searching was limited to English language articles. The article type was limited to journal articles. The research subject was limited to research with human subject. The time of publication was limited from January 2000 to July 2018. The abstract of articles with potentially relevant title were reviewed, while the articles with irrelevant title were excluded. Furthermore, articles that have potentially relevant abstract were continue to be reviewed in full-text, while the articles with irrelevant abstract were excluded. The inclusion criteria of this study sample was research on protective effect of omega-3 fatty acids in fish consumption against breast cancer in Asian patients with case control or cohort study methods. Exclusion criteria were (1) the article was not available in full-text and (2) the inclusion criteria were not satisfyingly fulfilled or the information provided in the article was insufficient for data extraction. The following data were obtained from each article: first name of authors and year of publication, region, type of study, number of sample, pre or postmenopause status of the sample, fish consumption and dietary assessment.Two independent investigators carefully extracted information from all studies that fulfilled the inclusion criteria in accordance with a standardized protocol. Disagreements were resolved by three other investigators. Quality assessment was conducted by using Newcastle–Ottawa Quality Assessment Scale (NOS). The papers with a total score of 0-3, 4-6, and 7-9 points were classified as the poor, moderate, and high quality .Data analysis2>50% because these tests presented minimal statistical power on cases with few studies and small sample sizes. A random effect model was used when significant heterogeneity was observed; otherwise, a fixed effect model was used. Publication bias was visually evaluated by using funnel plots and statistically assessed through Egger’s and Begg’s tests. Meta-analysis was carried out in Stata version 14.2 (Stata Corporation). A two-tailed P-value of <0.05 was considered as statistically significant.The analysis was performed to obtain the value of log odds ratio as the combined odds ratio value from the research. Results were pooled using odds ratio with corresponding 95% confidence intervals (CIs). Significant heterogeneity was indicated by IThe selection of articles was conducted to obtain 11 studies with total samples of 130,365 patients related to protective effect of omega-3 fatty acids in fish consumption against breast cancer in Asian patients .2= 45%) showed a variation of homogeneous research on the occurrence of breast cancer. Funnel plots to identify publication bias among studies protective effect of omega-3 fatty acids in fish consumption against breast cancer in Asian patients was shown in In This analysis confirmed the protective effect of omega-3 fatty acids in fish consumption against breast cancer in Asian patients . Dietary fish had been studied in a variation of homogeneous research or no heterogeneity among studies on the occurrence of breast cancer. High consumption of fish has been associated with lower breast cancer risk . On the other hand, some studies had led to contrary results which fish intake had no correlation to lower risk of breast cancer . In other population, such as European, fish intake had been positively associated with lower breast cancer risk (OR=1.11) as well as in Western countries (OR=1.08) and US (OR=1.05) . In Norway, no association found between 5.54 g to 96.77g/ day of fish consumption and breast cancer development . The contradictory results of our study to the latter study, possibly due to the different habit of fish consumption in Asian people as the subjects of our study. It has been known that fish intake of Asian population is considerably higher than Western population . Therefore, fish intake in Western populations might be too low to affect breast cancer risk as well as to give an expected protective effect.Previous study with meta-analysis which combined 26 international studies involving 883,585 female participants, including 20,000 breast cancer patients, found that omega-3 fatty acids intake from fish provided 14% reduction of breast cancer risk . Another study by Yang et al., (2014), has found that by increasing the ratio of omega-3 and omega 6 intake, lower risk of breast cancer can be obtained. The study also suggested higher ratio of omega-3 and omega 6 intake as deterrent factor of breast cancer.Fish is well known as an important source of protein worldwide. Commonly found fish has omega-3 as its content. Omega-3 has been known as fat content of common fish . Fish fatty acids usually referred to the longer chain of omega-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) . EPA and DHA are expected to prevent breast cancer by decreasing epidermal growth factor receptor and human epidermal growth factor-2 signaling which reduce proliferation. Ki-67 decrease had also been observed in benign and malignant mammary neoplasm after EPA and DHA supplementation in most preclinical models . In addition, factor-κB nuclear translocation and signaling also reduced through the agonist effects of EPA and DHA on peroxisome proliferator-activated receptor gamma and through interaction with the G protein receptor GPR120, which are expected to decrease inhibitors of apoptosis as well as cytokines, adhesion molecules, and metalloproteases . There were several limitations in this meta-analysis review. First, three studies seemed potentially eligible to be included in this meta-analysis but the full-texts were not accessible. Second, nine studies seemed potentially eligible to be included in this meta-analysis but they had insufficient data and unrelevant risk factors for calculation. This issue may raise the possibility of selection bias. Third, data validation not available for dietary questionaires in several studies. Fourth, the number of cases sample in one study was relatively small as it can reduce the statistical strength .This analysis confirmed the protective effect of omega-3 fatty acids in fish consumption against breast cancer in Asian patients. Based on fish consumption, Asian population has more significant protection from breast cancer than Western population. The results of this study recommend the need to maintain dietary fish intake. Dietary fish could possibly effective for breast cancer prevention. This study also suggests the need for education and counseling about eating habits and the importance of consuming foods with high fish content. The example of fish which commonly found and contain omega-3 fats are salmon, mackerel, herring, lake trout, bluefin tuna, sturgeon, sablefish, anchovy, albacore tuna, whitefish, arctic char, sardines, bluefish, mullet, halibut, striped bass, mahi mahi, pollock, rockfish, rainbow trout, shark, catfish, carp, cod, flounder, grouper, haddock, ocean perch, red snapper, swordfish, pike, sole, tilapia, etc. The authors declare no conﬂict of interest.