The background parenchymal enhancement at breast magnetic resonance imaging use to predict breast cancer attracts many searchers to draw a possible relationship. However, the results of their relationships were conflicting. This meta-analysis was performed to assess breast cancer frequency associations with background parenchymal enhancement.A systematic literature search up to January 2020 was performed to detect studies recording associations between breast cancer frequency and background parenchymal enhancement. We found thirteen studies including 13,788 women at the start with 4046 breast cancer. We calculated the odds ratio (OR) and the 95% confidence intervals (CIs) between breast cancer frequency and background parenchymal enhancement by the dichotomous technique with a random or fixed-effect model.Women with minimal or mild background parenchymal enhancement at breast magnetic resonance imaging did not have any risk of breast cancer compared to control women . However, high background parenchymal enhancement at breast magnetic resonance imaging  and moderate  was associated with a significantly higher rate of breast cancer frequency compared to control women.Our meta-analysis showed that the women with high and moderate background parenchymal enhancement at breast magnetic resonance imaging have higher risks, up to 2.66 fold, of breast cancer. We suggest that women with high or moderate background parenchymal enhancement at breast magnetic resonance imaging to be scheduled for more frequent follow-up and screening for breast cancer to avoid any complications. The level of normal fibroglandular tissue that enhances the breast magnetic resonance imaging is recognized as background parenchymal enhancement , 2. BackThe American college of radiology breast imaging reporting, and data system, or breast imaging reporting, and data system lexicon categorized background parenchymal enhancement . Their cThe background parenchymal enhancement data is highly available due to the high number of prescribed breast magnetic resonance imaging for screening and diagnosing breast cancer. Breast magnetic resonance imaging is better to be scheduled at days 7–14 through the follicular phase of women's menstrual cycles since background parenchymal enhancement is more noticed in the luteal phase of the menstrual cycle , 6.Recently, high background parenchymal enhancement was considered as a marker of higher risk of breast cancer in women at high risk e.g. women using an adjuvant endocrine treatment –10. AlsoSo, background parenchymal enhancement can be used to improve the early discovery and inhibition of breast cancer . Though,The present study complied with the meta-analysis of studies in the epidemiology statement , which wThe study was a randomized controlled trial or retrospective study.The target population is women with and without breast cancer.The intervention program was based on assessments of background parenchymal enhancement.The study included women with and without breast cancer.Included studies were human studies in English language with the association between breast cancer frequency and background parenchymal enhancement in women with and without breast cancer. Excluded studies were commentary, review articles and studies with no measure of an association. Figure A protocol of search strategies was prepared according to the PICOS principle , and we A systematic search was performed in OVID, Embase, Cochrane Library, PubMed, and Google scholar till January 2020, using a blend of keywords “dynamic contrast-enhanced magnetic resonance imaging, magnetic resonance imaging, background parenchymal enhancement and breast cancer”. We gathered all studies detected in an EndNote file, we removed any duplication found and revised the title and abstracts to eliminate studies that did not show any association between breast cancer frequency and background parenchymal enhancement in breast magnetic resonance imaging, based on our inclusion and exclusion criteria. The remaining studies were examined for any possible association.Data were abridged into a stranded form . If one The main result concentrated on the breast cancer frequency association with background parenchymal enhancement. Background parenchymal enhancement outcomes were compared in women with and without breast cancer and the overall summary result were prepared to perform the statistical analysis.2 index was calculated; the I2 index is from 0 to 100%. When I2 was > 50%, we used the random-effect model and when it was < 50%, we used the fixed-effect model. I2 index of around 0%, 25%, 50%, and 75% respectively specify no, low, moderate, and high heterogeneity [p ≥ 0.05), and qualitatively, by visual examination of funnel plots of the logarithm of odds ratios versus their standard errors [We used the dichotomous technique with a random-effect model or fixed-effect to compute the odds ratio (OR) and 95% confidence interval (CI). The Iogeneity . A subgrd errors . All p-vA total of 2546 unique studies were detected, of which 13 studies fulfilled the inclusion criteria and were used in this meta-analysis study , 17–26.The 13 studies included 13,788 women at the baseline of the study; 4046 of them were breast cancer. All studies had different background parenchymal enhancement categories in women with breast cancer.Study size ranged from 32 to 4247 women at the baseline of the study. The number of breast cancer associated with background parenchymal enhancement ranged from 14 to 540. 9 studies reported data stratified women by minimal or mild background parenchymal enhancement ; 11 studies were with moderate background parenchymal enhancement; and 11 studies were with high background parenchymal enhancement in association with breast cancers frequency.8 studies observed higher breast cancer frequency associated with high background parenchymal enhancement and 8 studies with moderate background parenchymal enhancement. The magnitude of the increase of breast cancer frequency was significantly higher in high background parenchymal enhancement than that in moderate background parenchymal enhancement. The effect of background parenchymal enhancement on breast cancer frequency was detected in all populations studied.p = 004) than that in the normal women with high heterogeneity (I2 = 84%) as shown in Fig. p < 0.001) than that in the normal women with high heterogeneity (I2 = 78%) as shown in Fig. p = 0.66) with high heterogeneity (I2 = 96%) as shown in Fig. Women with high background parenchymal enhancement had significantly higher breast cancer frequency .Based on the visual inspection of the funnel plot as well as on quantitative measurement using the Egger regression test, there was no evidence of publication bias (In our meta-analysis study based on 13 studies including 13,788 women at the start with 4046 breast cancer. Women with moderate and high background parenchymal enhancement has up to 2.66-fold higher risk of breast cancer compared to normal women. This effect was detected in all populations , 17–26.Background parenchymal enhancement is chiefly affected by the estrogen hormone. Estrogen hormone affects many systems and organs, including the reproductive system, urinary system, cardiovascular system, bones, skin, hair, and brain. It is believed that background parenchymal enhancement is the radiologically visible form and image of the circulating estrogen hormone in the breast. Besides estrogen hormone, many other factors affect this dynamic enhancement process, such as the amount of contrast material, the patient's hemodynamic status, parameters of magnetic resonance imaging sequences, and vascular anatomy .So, background parenchymal enhancement might be a good tool for improving early discovery and inhibition of breast cancer; since its data is more accessible due to the high number of prescribed breast magnetic resonance imaging for breast cancer screening and diagnosis . A consiA cross-sectional study performed on women with normal risk showed a great association between higher levels of background parenchymal enhancement and breast cancer . This reNone of the selected studies reported an association between age, and ethnicity, and breast cancer frequency. Also, none of the studies answered whether higher background parenchymal enhancement is associated with all cancers or with a specific subtype of cancer. However, from the study results presented here, we recommend increasing the use background parenchymal enhancement for detection of the risk of breast cancer to oppose the possible negative outcome as early as possible.There may be selection bias in this study since so many of the studies found were excluded from the meta-analysis. However, the studies excluded did not satisfy the inclusion criteria of our meta-analysis.Minimal and mild were represented separately in some studies and together in some studies. So we presented them together here. Maybe if we studied each one alone we could have a significant effect of mild associated with breast cancer but the number of studies that showed them separately was small to conduct a meta-analysis.Our meta-analysis showed that the women with high and moderate background parenchymal enhancement at breast magnetic resonance imaging have an association with up to 2.66 fold risk of breast cancer compared to normal women. Background parenchymal enhancement can serve as a tool to improve fast discovery and inhibition of breast cancer. We suggest that women with high or moderate background parenchymal enhancement at breast magnetic resonance imaging to be scheduled for more frequent follow up and screening for breast cancer to avoid any complications.


The objective of the study is the assessment of the nutrition as well as the eating habits and preferences of Polish women undergoing breast cancer treatment. The study included women undergoing breast cancer treatment aged over 50 years. Data were collected on 112 respondents, residents of a large city, for whom the average time elapsed since the completion of treatment was 5 years. Their eating habits and preferences were determined on the basis of the frequency of consumption of products with potentially beneficial and adverse effects on health, which made it possible to determine the pro-Healthy Diet Index-10 (pHDI-10) and non-Healthy Diet Index-14 (nHDI-14). The intensity of properties beneficially and adversely affecting health was assessed in three intervals: small, moderate, and large. On the basis of the BMI index persons with normal body proportions were identified as well as those above the norm. The effect of lifestyle and socioeconomic status on pHDI-10 and nHDI-14 was determined. More than half of the studied women had normal body weight and 39% were overweight. One in three women was characterised by a low level of physical activity. The participants of the study followed diets with a low intensity of unhealthy properties with a weak influence of protective properties of nutrition. A significant, adverse effect of the nutritional knowledge and health self-assessment on pro-Healthy Diet Index-10 and non-Healthy Diet Index-14 was demonstrated. Bad habits related to lifestyle  contributed to overconsumption of unhealthy products/dishes. The demonstrated dietary mistakes indicate that actions aiming to promote benefits of undertaking behaviour beneficial for health should also be carried out among women with breast cancer diagnosis after the completion of treatment.  The World Cancer Research Fund and the American Institute for Cancer Research (2007) emphasises that the incidence of malignant cancers increases with the social and economic development. In Poland the dynamics of increase in incidence and deaths caused by breast cancers is one of the highest in Europe. This is due to many limitations in screening tests and an insufficient oncology awareness among patients. Therefore, in Poland breast cancer ranks first in incidence of cancers in women. Most incidents of breast cancer (80%) occur after 50 years of age, whereas half of the cases are diagnosed between the age of 50 and 69 .Results of research indicate that both the level of women’s knowledge about breast cancer prevention and pro-health attitudes in this respect are insufficient in Poland . As breast cancer risk factors women most often list non-modifiable factors, e.g. genetic factors . A significant percentage of the respondents do not know that there are risk factors which every women can modify, such as an inappropriate diet, excessive body mass, excessive alcohol consumption. Also physical exercise is said to have an unquestionable effect on the possibility and rate of development of breast cancer . The situation necessitates intensification of prevention activities in order to decelerate and decrease the speed of incidence of breast cancer by modification or elimination of adverse risk factors.On the basis of many years of observation and research a large number of factors increasing breast cancer risk were identified. The data published by the International Agency for Research on Cancer (IARC) indicates that one quarter of breast cancer cases are linked to inappropriate diet, whereas pro-healthy lifestyle may contribute to lowering the risk of the disease by as much as 50%.The nutritional factors which modify the risk of breast cancer development are: consumption of monosaccharides, the amount and composition of fatty acids in the diet, consumption of fruit and vegetables, and the energetic value of the diet.Therefore, it seems that propagation of a healthy diet and spreading information on the prevention of cancers may significantly contribute to the lowering of their incidence. In Poland, in spite of many publications describing cancer risk factors, there are few analyses and studies available the results of which are based on standardised research tools and thus present the phenomenon in question. It seems that getting to know breast cancer risk factors may significantly increase women’s chances of avoiding the disease and, if the disease does occur, increase their chances of overcoming the disease, through appropriate modifications . It is therefore particularly important to develop appropriate attitudes which will make it possible to undertake all actions for the benefit of one’s own health and the health of others. A healthy person is a determinant of a country’s social and economic development.Objective of the studyThe objective of the study was the assessment of nutrition and eating habits and preferences of Polish women undergoing treatment for breast cancer.The study included 112 women undergoing breast cancer treatment (Amazons), gathered in the Poznań Amazons Association. The studied women had undergone radical surgery and/or chemotherapy, radiotherapy, hormonal therapy. An average time that elapsed between the completion of the treatment and the study exceeded five years. The respondents were women over 50 years of age 2 - underweight; the second included respondents with the BMI between 18.50 kg/m2 and 24.90 kg/m2 – normal weight; the third included participants with the BMI between 25.00 kg/m2 and 29.90 kg/m2 – overweight; and the fourth category included persons whose BMI was equal to or above 30 kg/m2 – obesity.The nutrition of the studied women was determined on the basis of the Body Mass Index. Four categories were adopted : the first included women whose BMI was lower than 18.50 kg/mIn the study the KomPan Questionnaire was applied which is used to assess the eating habits, frequency of eating in adults, and collect information on respondents’ beliefs on the role of food and nutrition . The questionnaire made it possible to make a summarised assessment of diet quality. In order to achieve this two indices were determined: 1) Pro-Healthy Diet Index (pHDI-10) determined on the basis of consumption of 10 groups of food with potentially positive effect on health: 1) wholemeal bread; 2) buckwheat, oatmeal, wholemeal pasta, other grains; 3) milk ; 4) fermented milk drinks; 5) cottage cheese ; 6) fish; 7) legume-based dishes; 8) fruit; 9) vegetables; 10) white meat-based dishes , 2) Non-Healthy Diet Index-14 – nHDI-14 determined on the basis of consumption of 14 groups of food with potentially adverse effect on health: 1) tinned meat; 2) energy drinks; 3) lard as a bread spread 4) fast foods; 5) wine, alcoholic beverages; 6) sweetened carbonated or still drinks; 7) white rice, white pasta; 8) red meat; 9) fried foods; 10) cheese; 11) butter; 12) sweets; 13) white bread and bakery products; 14) sausages. Then individual frequencies of consumption of certain groups of foods were assigned point value, which made it possible to assess the quality of diet in the scale from 0 to 100 points – the higher the value of the index, the higher the intensity of properties beneficial or adverse for health .The questionnaire also made it possible to assess the lifestyle of the studied women and their socioeconomic status. The lifestyle was determined on the basis of the assessment of behaviour related to eating habits, the level of physical activity, smoking and alcohol consumption. The socioeconomic status was described using the following variables: education, professional activity, place of residence, and self-assessment of the financial situation.In the analysis of the material basic statistical methods were used. For qualitative variables numbers in individual categories were compared, answers were added and fractions of the studied groups were determined. For qualitative variables basic descriptive statistics was used. The relationship between the compared grouping variables: Healthy Diet Index-10 and non-Healthy Diet Index-14 and variables describing socioeconomic status and lifestyle was assessed. For this Spearman’s or Pearson’s rank correlation coefficient was calculated.In order to check the effect of socioeconomic variables and lifestyle variables on the summary assessment of the diet multiple regression analysis was used. Variables which significantly differentiated the value of the discussed index (p<0.05) or tended to be significant (p<0.10) were qualified for the model.All calculations were performed using Statistica 10.0 software.All studied women lived in a large city (with a population of more than 100 thousand). The majority of them had secondary and university education  and with a weak influence of protective properties of nutrition .2=0.15 p<0.001). In the second model the following were placed: self-assessment of nutritional knowledge and health, the BMI, and smoking in the past (n=108). The variables included in the model determined 17% of the value of the non-Healthy Diet Index (r=0.42 R2=0.17 p<0.0015). It was demonstrated that the lower the self-assessment of nutritional knowledge and health and the higher the BMI and smoking in the past, the higher the value of non-Healthy Diet Index.Using a multiple regression analysis a group of biological, social and lifestyle factors influencing the summary assessment of the diet were identified. The following variables were analysed: the level of physical activity in leisure time and at work, smoking (now and in the past), self-assessment of health and nutritional knowledge, education, age, and the BMI. The variables which significantly differentiated the value of the discussed index (p<0.05) or tended to be significant (p<0.10) were qualified for the model. Two models were created: 1) for products/dishes positively affecting health, and 2) for products/dishes adversely affecting health. To this end the summary assessments of the frequency of consumption of individual groups of products/dishes were used: pro-Healthy Diet Index-10 and non-Healthy Diet Index-14. The following variables were introduced to the first model: education, self-assessment of nutritional knowledge and health (n=111). The higher the level of education and the self-assessment of nutritional knowledge and health, the higher the value of pro-Healthy Diet Index. The qualified variables determined 15% of the value of pro-Healthy Diet Index .The studied women treated for breast cancer were members of the Poznań Amazon Association. The majority of them were educated, working, aged over 50 years, and the average time since completion of their treatment was more than 5 years.Age is considered to be one of the main risk factors of breast cancer. The analysis of the collected material indicates that the average age of the studied women was 54 years. This is the age at which most breast cancers are diagnosed in Poland . The scientists have shown that hormonal changes occurring at menopause cause an increase in weight . Excessive weight at this time of life disturbs balance in steroid hormones and insulin management. Women with excessive weight are characterised by a significantly higher level of oestrogens compared to women with normal weight. Obesity may cause inflammation which in turn may lead to increased oestrogen production. Oestrogen has been recognised as one of factors contributing to the development of breast cancer .2 increases the risk of breast cancer by 17%.Being overweight is a complex factor with variable effect on the risk of breast cancer, depending on the age of subjects . For post-menopausal women obesity is a risk factor, whereas for younger women this factor is virtually insignificant . Chung et al., (2016) emphasises that overweight women above the age of 60 have a higher risk of the cancer risk. Our results are very alarming. More than 39% of women undergoing breast cancer treatment were overweight which was determined on the basis of body mass index. Protani et al., (2010) in their review of literature demonstrated on the basis of observation studies a higher risk of cancer relapse and death in overweight women and women whose weight increased after the diagnosis compared to women with normal weight. This is also confirmed by the studies of Kroenke et al., (2005), who noted that an increase in weight in women after breast cancer diagnosis was linked to a higher percentage of disease relapse and death in these women. Chan et al., (2014) determined the relative risk of developing breast cancer. On the basis of literature review they analysed the body mass index of more than 200 thousand women with breast cancer. The authors found that an increase in the BMI by 5 kg/mThe results of many studies indicate that often women diagnosed with breast cancer try to change their lifestyles in order to improve their health and prevent relapses . In the current study this was manifested in a small percentage of women who smoke (39% gave up smoking after being diagnosed) and drink alcohol. Factors which have positive effect on health include also physical exercise appropriate for age and physical efficiency which is the foundation of the Food pyramid . However, although the awareness in this respect has grown in Poland, low level of physical activity was noted in 35% of the studied women. Specialists indicate that appropriate physical activity adjusted to specific needs and capabilities of an individual prevents overweight and obesity and is conducive to maintaining normal body weight . If one of the factors modifying breast cancer development is overweight and obesity, it seems that physical activity, defined as the regulator of energy balance and an effective way of preventing accumulation of fat reserves, should play a significant part in the lives of all studied women . What is more, the studied women positively assessed their nutritional knowledge. However, the summary assessment of the frequency of consumption of foods positively and adversely affecting health showed that the studied women had a diet with a low intensity of unhealthy properties with a weak effect of protective properties of nutrition. This result shows that the studied women are aware of which products/components of diet negatively affect health, therefore they eliminate them from their menus. On the other hand however, the respondents have insufficient knowledge about products/components of diet which positively affect health.The results of research show a directly proportional relationship between the consumption of products with a high glycemic index and breast cancer development . This applies especially women at post-menopausal age . Moreover, specialists indicate type 2 diabetes as the disease which is often diagnosed in women treated for breast cancers. Hence the results obtained in the studied group are alarming. One in five studied women consumed sweets at least once a day, and 76% of the respondents had them every week.Only less than half of the studied Amazons declared eating fibre-rich products, such as buckwheat, oatmeal, wholegrain pasta in every average week. One in three women declared eating wholemeal bread at least once a day. However, the results of research show a protective action of food fibre in cancers. Women whose diet is rich in food fibre have a lower risk of developing breast cancer compared to respondents whose diets provide little fibre. This is also confirmed by the results of the Nurses’ Health Study and the results of the Diet and Health Study carried out by the National Institutes of Health-AARP .There is a lot of evidence that biologically active food components, found among others in fruit and vegetables, play an important part in prevention of various diseases, including cancers . In the current study more than half of the women undergoing breast cancer treatment did not consume fruit and vegetables at least once a day. And the beneficial role of plant products depends on the consumed amount. It is recommended to provide at least four portions of fruit and vegetables a day . It should be added that two from 112 studied women did not consume fruit and vegetables at least once a day.The results indicate that in every average week more than 60% of the studied women had red meat and nearly one in two women undergoing breast cancer treatment used butter as bread spread. The results of epidemiological studies confirm increased risk of breast cancer development in women who frequently, e.g. daily, consume red meat and prefer saturated fatty acids in their diets . On the other hand, the protective effect of fatty sea fish in the development of breast cancers has been noted, which in the studied group were consumed by one in two respondents . Therefore, also in this respect, the diet of the studied women undergoing breast cancer treatment requires modification.It seems that there is convincing evidence that the diet of the studied women undergoing breast cancer treatment should be changed, in particular in terms of foods with preventive effect. It is recommended to increase the consumption of food fibre, fruit and vegetables, fatty sea fish providing n-3 polyunsaturated fatty acids and limit the consumption of simple carbohydrates. It is also necessary to introduce physical activity of at least moderate intensity to a daily schedule of every woman participating in the study. A significant effect of nutritional knowledge and health self-assessment of the studied women on both Healthy Diet Index-10 and non-Healthy Diet Index-14 was demonstrated. On the other hand, the awareness resulting from general education is manifested significantly only in case of choice of products positively affecting health. Bad lifestyle habits  contributed to overconsumption of products/dishes with negative health effect.The results of our analyses show the directions of actions for persons and institutions in charge of disseminating information about the prevention of malignant cancers both in the society and among persons affected by the disease, to ensure that the effects of research are used to lower the risk of breast cancer. On the basis of the results it seems that the studied women had a low level of knowledge about health benefits of appropriate diet and physical activity. Therefore, educating this group of people is important as apart from its therapeutic advantages, it may contribute to an improvement in life quality of the studied women.1. The nutrition of the studied women differed from the recommendations for a healthy diet. The studied women had a diet with a low intensity of unhealthy properties and a weak effect of protective nutrition properties.2. A significant adverse effect of nutritional knowledge and self-assessment of health on pro-Healthy Diet Index-10 and non-Healthy Diet Index-14 was demonstrated.3. The awareness resulting from general education manifests itself significantly only in case of the choice of products beneficially affecting health. Bad habits related to lifestyle  contributed to overconsumption of unhealthy products/dishes.4. The demonstrated dietary mistakes indicate that actions aiming to promote benefits of undertaking behaviour beneficial for health should also be carried out among women with breast cancer diagnosis after the completion of treatment.Research of the Department of Anthropology and Biometry, University School of Physical Education in Poznań.


Recent large-scale genetic studies, particularly genome-wide association studies (GWAS), have emphasised the importance of common genetic variation in endometrial cancer susceptibility. Although each of these variants only confer modest effects on endometrial cancer risk, together they are likely to explain a substantial amount of the familial relative risk of the disease. Therefore, methods to combine genetic risk variants, such as polygenic risk scores (PRS) have gained traction as an attractive method for individualised risk prediction and management. Here, we discuss the benefits of a PRS for endometrial cancer and considerations required for clinical implementation. However, assessing genetic variants’ combined effect by polygenic risk score (PRS) has gained traction as a means to stratify patients into high- and low-risk strata. Theoretical PRS calculations by Bafligil et al., using 24 curated endometrial cancer genetic risk variants, predicted a 3.16-fold difference in endometrial cancer risk between women in the top 1% of the PRS distribution compared with the mean PRS.5 are exciting and support further research into the development of a PRS for endometrial cancer. Studies to assess risk stratification of women in independent cohorts are currently underway. This work will refine the number of variants to include in PRS calculations for improved accuracy. Additionally, the integration of an endometrial cancer PRS with other known endometrial cancer risk factors (e.g. obesity) should further improve risk stratification accuracy.The results from Bafligil et al.7 However, outcome is significantly worse for women with late stage disease .7 Unlike many cancers, the incidence and mortality rates of endometrial cancer are increasing, probably due to the rising rates of obesity, sedentary lifestyles and the ageing population. These increases are projected to continue over the next decade, providing impetus for the development of early detection and disease prevention.8The overall survival for endometrial cancer is similar to that observed for breast cancer .9 This would also provide opportunities for targeted interventions for high-risk women such as progestin  treatment and/or bariatric surgery, which have demonstrated remarkable success at endometrial cancer risk reduction.10 However, while the use of a PRS would provide access to personalised risk information to a wider group of women, careful consideration for implementation of the PRS into population-based screening will be required and large-scale studies necessary to assess its clinical impact.An endometrial cancer PRS could potentially provide personalised risk information for a considerable proportion of women. Population-based risk management strategies could identify women at high risk of developing endometrial cancer for screening and allow for less monitoring for women with a low PRS.6 This is an area requiring focus, given non-endometrioid subtypes of endometrial cancer are associated with poorer patient outcomes; these patients would greatly benefit from the early detection and preventative opportunities a PRS could provide. Secondly, all endometrial cancer genetic risk variants identified to date were discovered using European corhorts.6 Thus, PRS constructed using these variants may not provide suitable risk stratification in women of other ethnicities, reinforcing the need for future endometrial cancer GWAS to be performed in diverse population sets.The progress of PRS for endometrial cancer should be considered in the light of two major limitations. Firstly, GWAS for endometrial cancer to date have been unselected for subtype and consequently, the results from these studies are largely driven by the more common endometrioid endometrial cancer cases. Indeed, there are currently no genetic risk variants reliably associated with any non-endometrioid endometrial cancer subtype.9 Assessment of the improved predictive value of these integrated risk models will be imperative in the development of risk stratification and screening programmes for endometrial cancer.9 “Is it possible to develop a personalised score that reflects a woman’s individual risk of developing endometrial cancer” emerged as the most important endometrial cancer research priority in a recently completed James Lind Alliance Priority Setting Partnership.11 Its endorsement by patients, the public and healthcare professionals supports the urgent need for a robust, clinically tractable endometrial cancer risk prediction model to improve outcomes from this disease.Despite these limitations, the potential benefits offered by a PRS to provide personalised risk assessment for endometrial cancer are exciting. While opportunities for population-based screening are evident, integration of a PRS could also be used in the familial cancer setting, to predict which women from Lynch Syndrome families are most likely to develop endometrial cancer and would benefit from prevention interventions. Larger GWAS meta-analyses planned by the ECAC will not only identify new genetic risk regions for endometrial cancer but also refine risk estimates associated with known regions, thus improving prediction accuracy of constructed PRS. It is likely that maximal benefit of an endometrial cancer PRS will be in combination with lifestyle and clinical measures.


Background: Data on burden and changing trends of breast cancer are of value for policymaking. We aimed to determine the pattern of breast cancer incidence, mortality, and disability-adjusted life-years (DALYs), as well as temporal trends, from 1990 to 2017.Methods: We collected detailed information on breast cancer between 1990 and 2017 using the results of the Global Burden of Disease study. The number of incident cases, deaths, and DALYs attributable to breast cancer are reported as well as age-standardized rates. Estimated annual percentage changes (EAPCs) in age-standardized rates were calculated to quantify the temporal trends. Moreover, the attributable burden to breast cancer risk factors was also estimated.Results: There were 1,960,682 incident cases and 611,625 deaths of breast cancer globally in 2017, contributing to 17,708,600 DALYs. The age-standardized incidence rates (ASIRs) increased between 1990 and 2017, while the age-standardized mortality rates and DALY rates decreased. The corresponding EAPCs were 0.41, −0.62, and −0.56, respectively. These trends were heterogeneous across regions and countries. The increase in the ASIRs was more prominent in countries with a low sociodemographic index. The percentages of breast cancer deaths due to alcohol use and tobacco were decreasing, while deaths due to high body mass index and high fasting plasma glucose were increasing.Conclusion: Breast cancer remained a major public health concern globally. The trends of incidence, mortality, and DALYs were heterogeneous across regions and countries, suggesting that the allocation of appropriate health care resources for breast cancer should be considered at the national scale and even at the subnational scale. In women, breast cancer is the most frequently diagnosed cancer and the leading cause of cancer-associated death worldwide . Early bDespite the rapid development of diagnostic and therapeutic methods for breast cancer, different regions and individual countries develop at different speeds, leading to the substantial diversity of disease burden . NonhereThe prognosis of breast cancer patients is correlated with age at diagnosis, stage at diagnosis, pathological findings, treatments accepted, and regular follow-up . In termSummarizing and comparing breast cancer metrics and trends considering different aspects are important for decision making regarding health policies, screening protocols, and lifestyle guidelines, which might affect the outcomes of breast cancer patients and everybody's pattern of life.The Global Burden of Disease (GBD) study provides annual estimated incidence, mortality, disability-adjusted life-years (DALYs) data made by age and sex, and temporal trends of breast cancer among different regions and countries. We collected GBD data concerning breast cancer from 1990 to 2017 and estimated the disease burden of breast cancer at the global, regional, and national levels. In addition, we presented the contributions of different risk factors to mortality due to breast cancer.http://ghdx.healthdata.org/gbd-results-tool) , years of life lost (YLLs) and DALYs, and the age-standardized data of breast cancer from 1990 to 2017 from the Global Health Data Exchange query tool (ts-tool) . SDI, scts-tool) –13.We used the annual incident cases, deaths, YLDs, YLLs, and DALYs to estimate the burden of breast cancer. The Cause of Death Ensemble model was applied to estimate mortality based on the available data and covariates from the vital registration system and sample, and cancer registry incidence data . In addiThe age-standardized rates, including age-standardized incident rates (ASIRs), age-standardized mortality rates (ASMRs), age-standardized DALY rates, and estimated annual percentage change (EAPC), were used to quantify the breast cancer burden trends . It is nThe GBD study proposed an attributable burden formula to quantify the burden of diseases and impairments attributable to 84 behavioral, environmental and occupational, and metabolic risk factors , 18. FouP < 0.05 were considered statistically significant. Moreover, the uncertainty intervals (UIs) were calculated to quantify the effects of uncertainty on cause-specific estimation mortality, mainly brought by specifications of the cause-specific model, varied availability of data, and diversity of sample size. The 95% UIs were calculated with the 2.5th and 97.5th percentiles and all the estimates were reported next to each point estimate  and 611,625 deaths  globally in 2017, contributing to 17,708,600 DALYs  . Breast The highest absolute number of breast cancer incident cases was estimated in East Asia, with 386,508 cases  in 2017, while high-income North America contributed the highest ASIR of 49.54 per 100,000 (95% UI: 47.62–51.52) . Breast Most deaths occurred in South Asia in 2017 , and the highest increase in breast cancer deaths was also in South Asia, with a 208.26% increase (95% UI: 120.90–269.39%). The highest ASMR was detected in Western Sub-Saharan Africa in 2017  . The ASMSouth Asia, East Asia, and Western Europe were the areas with the highest DALYs due to breast cancer in 2017, while Western Sub-Saharan Africa and Oceania had the highest age-standardized DALY rates . Except The unsupervised hierarchical cluster analysis classified the countries and territories into four clusters . Twenty-r = 0.31, p = 0.001) when the SDI was limited below 0.68. In contrast, for SDI above 0.68, countries with higher SDI experienced more rapid decreases in the ASIR of breast cancer from 1990 to 2017  and the EAPC of age-standardized DALYs rates and the SDI  when the SDI was above 0.60. However, the correlation disappeared for SDI below 0.60 (low 0.60 . A signilow 0.60 .The contributions of different risk factors to breast cancer deaths are demonstrated in This study presents the recent burden and trends of incidence, mortality, and DALYs associated with breast cancer at the global, regional, and national levels based on the GBD 2017 results. Our analysis revealed that breast cancer remained a major public health concern globally, and the trends of incidence, mortality, and DALYs were heterogeneous across regions and countries. Age-standardized rates in 1990 and SDI in 2017 were both associated with EAPC. Moreover, the changes of the attributable burden to different breast cancer risk factors between 1990 and 2017 also varied.In general, our analysis found that both the breast cancer incidence and number of cases increased from 1990 to 2017. However, the temporal trends of breast cancer incidence varied by region and country mainly based on socioeconomic status. For example, in high SDI countries, such as the USA, Canada, and Australia, the ASIR began to fall after 2000 partly owing to declines in the use of postmenopausal hormonal treatments after the findings linked postmenopausal hormone use to increased breast cancer risk, as first reported in the USA , 27. NevConsistent with the increase in incident cases, we also noted an increase in breast cancer deaths at the global level. The ASMR of breast cancer have been significantly decreasing in high and high-middle SDI regions, such as Western Europe, high-income North America, and Australasia. The decline in ASMR might be attributable to recent improvements in therapeutic approaches, including surgical technology, radiation therapy, and systemic treatment. An increasing number of novel drugs, including cyclin-dependent kinase 4/6 inhibitors, poly ADP-ribose polymerase inhibitors, and programmed death-ligand 1 inhibitors, have been shown to improve outcomes and have been recently approved for breast cancer treatment in the past few years . HoweverInterestingly, our study revealed that in higher SDI countries, the age-standardized DALY rates have decreased but the proportions of the burden associated with YLDs have increased. The increase in YLDs in high-income countries is consistent with the overdiagnosis and overtreatment of some breast cancers . MoreoveFurthermore, we found that the EAPC of ASIR, ASMR, or age-standardized DALY rates between 1990 and 2017 was significantly negatively associated with the baseline rates in 1990. This result might be partly explained by the fact that increased baseline rates are correlated with low amounts of significant rate variations. The other reason is that countries with low age-standardized rates are more likely to consider breast cancer as a low priority in disease prevention and treatment programs compared with other public health issues.Alcohol use is an important risk factor contributing to the incidence and mortality of many kinds of cancer, including breast cancer . A stronOur results are in line with previous publications that analyzed other data sources –41. For Our analysis estimated the disease burden and trends of breast cancer at the global, regional, and national levels in many aspects, including the number of incident cases, deaths, DALYs, age-standardized rates, EAPCs, factors associated with EAPCs, and attributable burden to breast cancer risk factors. However, several limitations should also be noted when interpreting our results. First, although several modeling methods were applied to analyze the GBD data, the low quality of data sources in several countries may have affected the produced estimates. For example, underreporting breast cancer on death certificates and underestimating breast cancer due to a lack of medical information may cause some fluctuations in the incidence and mortality rates. Second, breast cancer is now classified into several molecular subtypes according to the expression of hormone receptors and HER2 . Their eIn conclusion, breast cancer remains a major public health burden worldwide. In the past 30 years, the incident cases of breast cancer, as well as death cases and DALYs, have increased globally. As prevalent cases are early breast cancer identified during early screening rounds and routine breast screening is becoming more popular in less developed regions, the incidence is expected to increase temporarily in the near term. On the other hand, the breast cancer burden trends vary among countries based on socioeconomic status. Breast cancer mortality and DALY rates are decreasing in developed countries while still increasing in developing countries mainly due to differences in accessibility to novel drugs and the application of clinical guidelines. The information provided in this study should help to illustrate the global disease burden and trends of breast cancer and guide the allocation of appropriate health care resources for breast cancer prevention, screening, and treatment.http://ghdx.healthdata.org/gbd-results-tool.Publicly available datasets were analyzed in this study. This data can be found here: PJ, YG, G-HD, and Z-MS designed the project. PJ and YG equally contributed to perform the data analyses and to write the manuscript. M-LJ acquired the original data and developed the methodology. XH contributed to conceptualizing the study and edited the manuscript. G-HD and Z-MS equally supervised the overall work. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Increased knowledge of breast cancer risk factors has meant that we are currently exploring risk-based screening, i.e. determining screening strategies based on women’s varying levels of risk. This also enables risk management through primary prevention strategies, e.g. a lifestyle programme or risk-reducing medication. However, future implementation of risk-based screening and prevention will warrant significant changes in current practice and policy. The present study explores women’s perceptions of the implementation and organisation of risk-based breast cancer screening and prevention to optimise acceptability and uptake.A total of 143 women eligible for breast cancer screening in the Netherlands, the United Kingdom, and Sweden participated in focus group discussions. The focus group discussions were transcribed verbatim and the qualitative data was analysed using thematic analysis.Women from all three countries generally agreed on the overall proceedings, e.g. a risk assessment after which the risk estimate is communicated via letter (for below average and average risk) or consultation (for moderate and high risk). However, discrepancies in information needs, preferred risk communication format and risk counselling professional were identified between countries. Additionally, a need to educate healthcare professionals on all aspects of the risk-based screening and prevention programme was established.Women’s insights identified the need for country-specific standardised protocols regarding the assessment and communication of risk, and the provision of heterogeneous screening and prevention recommendations, monitoring the principle of solidarity in healthcare policy. After mammographic screening was shown to effectively reduce breast cancer mortality, most European countries initiated one-size-fits-all population-based screening programmes based on women’s attained age . Over thPotential implementation of risk-based breast cancer screening and prevention will require extensive changes in current practice . The proIt has been established that breast cancer risk assessment is feasible in a screening setting and that women are generally interested in knowing their risk , 10. HowFocus group discussions (FGDs) using a semi-structured interview guide exploring women’s perceptions regarding the organisation of risk-based breast cancer screening and prevention in the Netherlands (NL), the United Kingdom (UK), and Sweden (SE).Women were selected from the participant databases of three large prospective cohort studies collecting breast cancer risk information in NL, UK, and SE, i.e. the PRISMA , PROCAS (Predicting the Risk of Cancer at Screening) , and KARParticipants who consented to being approached for follow-up studies were randomly sampled and sent a comprehensive information leaflet. British participants were randomly sampled within their risk category, aiming to invite an equal number of women per category. Women with a previous breast cancer diagnosis were excluded. The Dutch FGDs took place from September – November 2016, the British in February 2017, and the Swedish in April 2017.The FGDs followed the same semi-structured interview guide in all three countries, which was based on previous research , 14 and The data were thematically analysed per country, independently by pairs of two researchers  using an inductive approach. Six stages were adhered to during data analysis, i.e. familiarisation with the data, coding, developing themes, reviewing themes, defining and naming themes, and final analysis . ConsensWe invited 1650 women of whom 143 participated (8.7% response rate) in 20 FGDs. Nine FGDs were conducted in NL , five in SE (38 participants), and six in UK (51 participants), with group sizes ranging from 5 to 10 participants. Table Women from all three countries were willing to complete a questionnaire, and provide a blood/saliva sample and access to their mammogram to collect breast cancer risk factor information. Most Dutch women would not like an automated risk result after completing a web-based questionnaire. Some Swedish women argued that a web-based questionnaire may limit accessibility. British women emphasised the importance of offering every woman the same risk assessment, after discovering at the FGDs that some women had been asked to provide a saliva sample (for determination of single nucleotide polymorphisms (SNPs)). Women whose risk estimate did not include data on SNPs were doubtful about the accuracy and felt they had not received the complete picture. These procedural differences were dictated by financial restraints, with insufficient research budget available to facilitate the analysis of genetic variation for all PROCAS participants. Since national policy would dictate standardised breast cancer risk assessment, this inconsistency would not occur with potential future implementation.Most Dutch women favoured a voluntary risk assessment aged 40, enabling women at above average risk to start screening at around 40, with current Dutch screening policy starting at 50. For (below) average risk women they advised an additional mammogram at age 45 to bridge the ten-year interval before screening continuation at 50 to decrease potential anxiety. Most Swedish women concurred that a risk assessment should take place when women turn 40, because they argued that changing your lifestyle becomes easier from that age onwards. British and Dutch women suggested integrating the risk assessment into the cervical screening programme.Dutch and Swedish women generally agreed that below average and average risk results can be relayed in a letter. Above average risk feedback should be done through a consultation, either via telephone or face-to-face, tailoring the modality to personal preferences indicated at time of consent. Swedish women also suggested group meetings to provide additional information about risk and screening/preventative options. They also recommended the use of modern technology such as video chat. Women from both countries mentioned the GP or a specialised nurse for relaying risk feedback. Dutch women also suggested radiographers employed by the screening centre. Women from both countries also emphasised that they wanted risk feedback from a medical professional with expert knowledge in the field.Swedish women indicated that they would like to have their risk expressed in a proportion. Additionally, Dutch and Swedish women would like to see their risk represented both in a percentage and visually. Dutch women indicated a preference for recording the risk appointment and both Swedish and Dutch women would like to receive the information in writing to take home. Swedish women stressed that professional support would be required to cope with an above average to high risk result. Women from both countries would like a website or mobile phone application with reliable information about breast cancer risk, screening and prevention. Dutch women also emphasised that professionals need to be adequately informed to prevent the provision of conflicting information about risk and/or preventative options.All women, regardless of risk, were satisfied with the format in which their risk was presented to them, i.e. in relative and absolute risks, stating both the chances of getting and not getting breast cancer. Women who were classified as below average to average risk were satisfied receiving their risk in an information letter. Women at moderate to high risk indicated that they appreciated the option of a telephone or face-to-face consultation, although they felt it was sometimes hard to take in all the information due to its emotionally charged nature. They would therefore have appreciated a written report of the consultation.Some women who were classified as moderate to high risk indicated that the original letter inviting them to get their risk assessed should have expressed more urgency. These women felt that they did not anticipate the consequences of the risk assessment and thought too lightly of it. Another concern for women at moderate to high risk was the knowledge of their GPs. The majority of British FGD participants indicated that their GP was insufficiently informed about tamoxifen/raloxifene and their usage as preventative medication. Consequently, a majority of GPs refused to prescribe the risk-reducing medication, referring women back to the research team. GPs were more willing to continue a prescription, once it had been issued by the local family history consultants under a shared care agreement, which has now become standard practice. Due to this set back, most British women were not in favour of receiving risk feedback and screening and prevention advice from GPs in the future. Instead they recommended the development of special women’s clinics operated by specialised nurses, radiographers, radiologists, and gynaecologists, integrating breast and cervical cancer screening. Additionally, British women signalled a need for pathways and protocols to standardise interaction between primary and secondary care providers to avoid individual variation.British and Dutch women expressed concern that risk-based screening and prevention may not be equally accessible to all women. The costs of additional mammography in Britain were only covered by the country's National Health Service (NHS) for high-risk women who were under 60 years old. The costs of preventative medication were also not covered. Some Dutch and British women also mentioned potential costs associated with diet and lifestyle changes. They feared that the principle of solidarity in healthcare finance and delivery will be hindered. Therefore, the British and Dutch women called for policy changes to ensure equal access.An overview of women’s information needs is provided by Table This study presents the first exploration of Dutch, Swedish, and British women’s perceptions of the potential future implementation and organisation of risk-based breast cancer screening and prevention. There was general agreement between women from the three countries on the overall proceedings, e.g. a risk assessment  potentially during a cervical screening appointment around the age of 40, after which the risk is communicated via letter or consultation depending on level of risk. However, by comparing hypothetical and actual risk scenarios and focusing on possible culture-specific perceptions, we were able to identify pertinent topics that will need to be addressed before future implementation. It transpires that perceived preferences regarding the organisation of risk-based breast cancer screening and prevention based on hypothetical scenarios (Dutch and Swedish women) do not necessarily correspond to needs and preferences in practice (British women). Dutch and Swedish women’s expressed intent based on their theoretical risk is not always in line with the behaviour of the British women who had received their actual breast cancer risk estimate.Women from all three countries concurred that a first risk assessment should take place around the age of 40. Although the Swedish screening programme starts screening women at this age, this would mean a policy change for the British and Dutch breast cancer screening programmes that currently start at age 50. Moreover, before women can be categorised into meaningful risk groups, advancements in breast cancer risk prediction are required. Although existing breast cancer risk prediction models, e.g. Tyrer-Cuzick and BOADICEA, perform well on a population level, they lack discriminative accuracy when applied to individual women . By addiAdequate understanding of this novel screening and prevention programme is crucial for informed decision-making. First, women need to comprehend the advantages and disadvantages of participating, which some British women felt insufficiently aware of, calling for a more balanced overview in the information leaflets. However, a recent study evaluating the psychological impact of risk communication with PROCAS participants showed no major harms with low anxiety and cancer worry scores after risk communication . After pSwedish and Dutch women emphasised a role for modern technology in the provision of information, suggesting video chat for risk feedback and counselling, and a telephone application and/or website for up-to-date information on breast cancer, screening, and prevention. This is in accordance with current practice aiming to maximise the quality and efficiency of care by utilising technology in healthcare delivery , 23. HowA notable difference in the preferred level of information provision was seen between Dutch and British women. Dutch women wanted comprehensive knowledge of, for example, the measurement properties of the risk prediction model, and the effectiveness of risk-reducing medication and lifestyle changes. These information needs were, however, based on a hypothetical concept of risk-based screening and prevention. British women, who received actual risk feedback and corresponding screening and prevention advice, were satisfied with the relatively basic level of information they were provided with. This may reflect the lower education level of the UK participants. However, the Swedish women who, like the Dutch women, explored their information needs in a hypothetical context, adhered more closely to British women’s information needs. The Swedish women were, on average, highly educated, however, in Swedish society it is relatively uncommon to talk about health risks. This unfamiliarity with the topic may have hindered Swedish participants to brainstorm freely and generate information needs. In general, research shows that the general population struggles to understand information about risk . InformaBritish women identified a great need to educate professionals, GPs in particular, on all aspects of the risk-based screening and prevention programme to ensure consistent information provision. Although this study showed that the preferred professional to provide risk feedback and counselling differs per country and depends on existing care pathways, it is probable that a gap in knowledge will exist . This haBritish, Dutch, and Swedish women’s perceptions of the organisation of risk-based breast cancer screening and prevention generally appear in line with those of healthcare professionals. This is a good starting point, however, for future implementation these perceptions will need to be integrated into countries’ existing healthcare policies, taking into account current regulations and available resources. Additionally, the current screening pathway will need to remain available for women who do not want to know their breast cancer risk. Furthermore, the mass assessment and storage of sensitive (genetic) risk information will require the development of new moratoria to regulate accessibility and usage . MeanwhiTo our knowledge, this is the first study to qualitatively explore women’s perceptions of the future implementation and organisation of risk-based breast cancer screening and prevention. Moreover, the participation of a substantial number of women from three different European countries enables international comparisons and insights into ways to optimise women’s informed decision-making and uptake. However, although the present study provides relevant insights, it is not always clear whether differences in perceptions are due to cultural aspects or the ‘hypothetical’ versus ‘actual’ nature of the risk scenarios. We therefore have to be careful when specifically attributing differences in women’s perceptions to cultural variety.Furthermore, we have identified the perceptions of a relatively homogeneous and selective sample of women. Focus group attendees had previously participated in both screening and scientific research on risk-based breast cancer screening and prevention, i.e. the KARMA, PRISMA, or PROCAS study. Additionally, we had limited to no response from women with a low socioeconomic status or British women at (below) average risk. Our focus group discussions served as a first exploration of women’s perceptions of the organisation of risk-based breast cancer screening and prevention; a topic that has not been widely studied. With our qualitative study we gained a rich, contextualised understanding of a topic through intensive study of particular cases . Our in-Integration of risk-based breast cancer screening and prevention is dependent on a country’s existing healthcare policy and care pathways. Women’s insights revealed that country-specific standardised protocols for the assessment and communication of breast cancer risk, and the provision of heterogeneous screening and prevention recommendations need to be developed. Additional training needs to be made available for participating healthcare professionals. The principle of solidarity in healthcare policy needs to be monitored, taking into account women who do not want to know their breast cancer risk.Additional file 1. Semi structured interview guide used for focus group discussions in all three countries.


A proportion of breast cancer cases are attributable to combined modifiable risk factors. The World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) has recently updated the recommendations for cancer prevention and a standard scoring system has been published. The aim of this study was to evaluate the association between compliance with the 2018 WCRF/AICR cancer prevention recommendations (Third Expert Report) and the risk of breast cancer in the SUN (“Seguimiento Universidad de Navarra”) prospective cohort. Spanish female university graduates, initially free of breast cancer, were included . An 8-item score to measure compliance to the recommendations was built: body fat, physical activity, consumption of wholegrains/vegetables/fruit/beans, “fast foods”, red/processed meat consumption, sugar-sweetened drinks consumption, alcohol intake, and breastfeeding. A stratified analysis was conducted according to menopausal status. A non-significant inverse association was observed for overall breast cancer. The inverse association became statistically significant for post-menopausal breast cancer after multivariable adjustment . The results suggested that the possible inverse association with breast cancer was attributable to the combined effects of the different nutritional and lifestyle components. Breast cancer is the second most commonly diagnosed tumor around the world, representing 11.6% of the total cancer cases . There wBoth modifiable and nonmodifiable risk factors may increase the risk of breast cancer . Up to 2In 2007, the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) released recommendations related to diet, physical activity, and body fat for cancer prevention . Since tIn order to overcome the existing limitations for direct comparability across studies, a guide for research applications has been developed following the updated Third Expert Report for cancer prevention of the WCRF and AICR ,13. As fThe SUN Project is a multi-purpose prospective cohort study where all participants are university graduates. The design and methods of this cohort are described in more detail elsewhere . BrieflyUp to December 2019, 22,894 participants were recruited and 14,063 of them were female. To allow a minimal follow-up of 2 years, in the present analysis, we only included those participants who were recruited before March 2017. We excluded 1225 participants with no follow-up information (retention 91.4%). Additionally, women with prevalent breast cancer at baseline (n = 108), with energy intakes outside of predefined limits  [This study was conducted according to the Declaration of Helsinki guidelines. Ethical Approval for this study was provided by the Institutional Review Board of the University of Navarra . All participants included in this study were fully informed about the study objectives and they voluntarily gave informed consent according to the methods approved by our Institutional Review Board.The baseline questionnaire gathered information about medical history, lifestyle, sociodemographic factors, and anthropometric measurements. Physical activity was ascertained at baseline through a validated 17-item questionnaire . In addiThe proposed 2018 WCRF/AICR Score included 8 items : (1) havFor the recommendation on “fast food”, we included ultra-processed foods as the total amount of the food items meeting the ultra-processed food category of the NOVA system . ProcessThe score of each recommendation was added to obtain the total score. Therefore, the total scores ranged from 0 to 7 points (from 0 to 8 points when breastfeeding was included), with higher values indicating higher compliance with the cancer prevention recommendations. The score was further categorized according to previously defined cut-off points : minimalIncident breast cancer was the primary end point and was considered when a new diagnosis of breast cancer occurred during the follow-up and women were free of breast cancer at the beginning of the study. The new diagnosis of breast cancer was initially self-reported by the participant. Women with a self-reported diagnosis of breast cancer were asked to provide a medical record for confirmation purposes. These documents were evaluated by a trained oncologist who was blinded to exposures of participants and adjudicated the confirmed cases. Moreover, for cases, we also included deaths due to breast cancer reported to the research team by the subject’s next of kin, work associates, and postal authorities or those deaths due to breast cancer identified through the National Death Index, which provides information of the vital status of people living in Spain . The breBesides the variables used to build the 2018 WCRF/AICR Score, the baseline questionnaire gathered information on age, years at university, smoke habits, family history of breast cancer, age of menopause (collected in the baseline questionnaire and updated in the 16-year and 18-year follow-up questionnaire), age of menarche, age of first pregnancy, previous or current use of hormone-replacement therapy, use of oral contraceptives, and medication use.Means and standard deviations were used to summarize the quantitative baseline characteristics of participants and percentages for categorical variables.To assess the relationship between the 2018 WRCF/AICR recommendations and the risk of breast cancer, we fitted Cox regression models. We estimated Hazard ratios (HR) and their 95% confidence intervals (CI). The score was analyzed as a continuous variable (one-unit increment) and as a categorical variable according to the previously defined cut-off points . For all analyses, we fitted two multivariable models with successive degrees of adjustment for potential confounders and considered overall breast cancer incidence  and, then, we did separated analyses according to menopausal status. Selection of confounding variables was based on directed acyclic graphs and information from previous studies. Model 1 was adjusted for age as the underlying time variable and age (in decades) and recruitment period (3 categories) as stratification variables. Model 2 was also adjusted for total energy intake , years at university, smoking status (never smoker/former smoker/current smoker), family history of breast cancer , menopause (yes/no), age at menarche (≤11/12–13/14/≥ 15 years), age at first pregnancy , use of hormone replacement therapy (yes/no), and oral contraceptive use (yes/no). Analysis for overall breast cancer was additionally adjusted for age at menopause. For post-menopausal women, in addition to age of menopause, model 2 was also adjusted for time since recruitment. Participants with breast cancer, both confirmed and probable cases, were followed up until the date of breast cancer diagnosis, and those without breast cancer until the date of death or last contact. In order to assess the incidence of pre- or post-menopausal breast cancer as an outcome, we split the time at risk of our participants into the time during which they were pre-menopausal and the time during which they were post-menopausal. For women with missing information on age at menopause, we defined post-menopausal status according to the 75th percentile of age at menopause in the study population (52 years of age) [p < 0.05. Statistical analyses were run using the statistical program Stata v.15 .Moreover, we estimated the individual association of each component of the 2018 WCRF/AICR score with confirmed breast cancer risk, after adjustment for all other components of the score and the aforementioned potential confounders. All statistical tests were two-sided and statistical significance was set at A total of 10,930 women were included in the analysis, with a median follow-up of 12.1 years. During 123,297 women’s year of follow-up, we identified 119 confirmed incident cases of breast cancer. When we assessed adherence to the recommendations as a continuous variable, women with higher compliance showed a non-significant lower risk of breast cancer, after adjusting for potential confounders . No signThe mutually adjusted HRs for the individual components of the 2018 WRCF/AICR score and confirmed breast cancer are shown in In the present large prospective study, an inverse association was observed between a higher adherence to the 2018 WCRF/AICR recommendations and incidence of post-menopausal breast cancer. None of the individual components of the score were significantly associated with the risk of breast cancer.There is growing evidence on the co-occurrence of risk behaviors and their association with chronic diseases such as cancer ,27. ThusThe few studies whichhave evaluated the association between the updated recommendations and breast cancer are consistent with our results. Turati F et al.  conducteWith respect to menopausal status, there is more inconsistency. In a previous case-control study conducted by Turati F et al. , the assThe magnitude of the associations described in our study were toned down when the breastfeeding item was additionally included in the score. Our questionnaire collected any type of breastfeeding and the score recommendation is only referred to the exclusive breastfeeding. Also, the questionnaire only included four possible answers and the cut-off point for the highest category was >3 months. So, this previous result may have been affected by the possible non-differential misclassification produced by the impossibility of distinguishing how much of all breastfeeding time was exclusive and the actual duration of exclusive breastfeeding. Similarly, when probable breast cancers were analysed, the estimated associations were weakened. Again, some degree of misclassification could have happened in these results since unconfirmed diagnoses could include benign breast conditions.Regarding the specific associations for each individual component, we did not find any association with any of the individual components. Previous evidence about the components related to diet have suggested the importance of overall diet quality as compared to individual food components in breast cancer . Our finOur study has potential limitations. First of all, the SUN Project is largely formed by young people, which could explain the reduced number of incident cases of breast cancer. This could have led to suboptimal statistical power and unstable estimates for some comparisons. However, the age-adjusted standardized incidence was calculated and it was found to be similar to the one described for the Spanish population . Second,Regarding the strengths of our study, we have to point out the prospective nature of the SUN Project, which reduces the possibility of reverse causation bias, the long follow-up of the sample, and the high retention rate. To our knowledge, this is the first prospective study evaluating the association between the 2018 WRCF/AICR recommendations and invasive breast cancer risk. Our results suggest the importance of the approach done in this study, allowing the evaluation of combined possible modifiable risk factors, based on a standardized scoring system to solve the problem found in previous studies on the comparability of the results.In conclusion, in this cohort, a protective association was observed between higher compliance of the 2018 WRCF/AICR recommendations and the risk of post-menopausal breast cancer for overall cases. In addition, our results suggested an inverse association of these recommendations with the occurrence of breast cancer, which might be produced by the combined synergistic effects of the diverse individual components. The findings of this study support the advice to comply with WRCF/AICR recommendations to prevent breast cancer among post-menopausal women.


ESR1), rs16886165 (MAP3K1), rs2214681 (CNTNAP2), rs4237855 (VDR), rs9594579 (RANKL), rs8183919 (PTGIS), rs2981582 (FGFR2), and rs1799950 (BRCA1) with sporadic breast cancer. These results provide useful insight into the genetic susceptibility to sporadic breast cancer in the Uruguayan population and support the use of genetic risk scores for individualized screening and prevention.Among Latin American women, breast cancer incidences vary across populations. Uruguay and Argentina have the highest rates in South America, which are mainly attributed to strong, genetic European contributions. Most genetic variants associated with breast cancer were described in European populations. However, the vast majority of genetic contributors to breast cancer risk remain unknown. Here, we report the results of a candidate gene association study of sporadic breast cancer in 176 cases and 183 controls in the Uruguayan population. We analyzed 141 variants from 98 loci that have been associated with overall breast cancer risk in European populations. We found weak evidence for the association of risk variants rs294174 ( BRCA1, BRCA2, PALB2, ATM, and CHEK2) have been identified in 30 to 40% of patients with a family history of breast cancer, but only in 5% of sporadic breast cancer cases. A large proportion of heritability still needs to be explained by low-penetrance variants and, therefore, a major effort has been underway to identify single-nucleotide polymorphism (SNPs) associated with breast cancer risk. These SNPs are not very informative by themselves, but together may account for almost half of the familial relative risk (FRR) [Breast cancer is the most common cancer among women in populations of European descent, representing 25% of all cancers . As in ask (FRR) .Latin American countries show great disparities in incidence and mortality rates across the continent. Uruguay, Argentina, and southern Brazil have incidence rates as high as southern Europeans , while Bolivia has an incidence rate of 13 cases per 100,000 women per year . This trBRCA1 and BRCA2. Founder mutations that have been described in Chile, Brazil, Colombia, Uruguay, and Argentina can be explained by the complex demographic history of Latin American populations. The admixture and demographic dynamics promoted the drift to higher frequencies of rare variants [BRCA1 than in BRCA2, as observed in European countries, except from Uruguay, Costa Rica, Puerto Rico, and Cuba, with higher numbers of BRCA2 mutations [In Latin America, genetic analyses have been focused on variants . Almost utations . The attempt to understand the genetic contribution to breast cancer in Latin America was centered in familial, hereditary, and early onset breast cancer, sometimes without making a distinction between patients regarding familial history or age at diagnosis . Just a In Uruguay, European ancestral proportions from autosomal markers show no substantial association with breast cancer, but a weak association of European mitochondrial haplogroup H with breast cancer risk was found in a previous study . This reHowever, given the strong European genetic contribution, the small population size, and quasi-null immigration since the 1950s, it is likely that the same candidate gene variants found amongst breast cancer cases in Europe could be increasing disease risk in Uruguay as well.In this study, we analyzed a set of 144 candidate gene SNPs, previously associated with sporadic breast cancer in European patients, in the Uruguayan population. Common susceptibility loci are reported in genes whose rare variants explain a major fraction of hereditary breast cancer risk, which may, together, explain an appreciable fraction of the genetic variation in sporadic breast cancer.A case control study was carried out in public hospitals and private clinics across Uruguay between 2010 and 2012. Women were eligible if they were over 45 years old and had been diagnosed with sporadic breast cancer in the previous year. Controls were women of the same ages with normal mammograms and no familial history of breast or ovarian cancer, randomly selected from the same health centers as the patients. Participation involved completing an interviewer administered risk factor questionnaire and giving a blood sample. All patients provided written informed consent for participation in all aspects of the study. The details of the 416 women sampled, the recruitment strategy, participation, and data collection methods have been described previously . The pre® DNA Kit  and stored at −20°C until analysis. SNP genotyping was undertaken by LGC-KBioscience Ltd. , who use their own form of competitive allele specific PCR system (KASParTM), and also at the University of Chicago using Sequenom Mass Array technology  [Genomic DNA was extracted from peripheral blood leukocytes using a FlexiGeneCA, USA) . DNA extA panel of 141 SNPs in 98 candidate genes was genotyped in a sample of 176 patients and 183 controls, 13 patient samples, and 28 control samples failed during the process. The panel included 133 SNPs described by the Collaborative Oncological Gene-Environment Study (COGS) for breast cancer and 8 highly polymorphic SNPs from the HapMap project populations. SNPs with minor allele frequencies below 1% or genotyping rates lower than 90% were excluded. Samples with less than 90% genotyping rates were also excluded from further analysis. After filtering, 118 SNPs, 172 cases, and 160 controls remained for analysis . A set of 160 ancestry informative markers (AIMs) were genotyped along the autosomes and the X chromosome. The individual ancestral contribution from European, Native American, and African populations was estimated using STRUCTURE software, as described previously .Deviation from Hardy–Weinberg equilibrium (HWE) was ascertained for each SNP in cases and controls. The allelic association test was applied to individual SNPs, and multiple logistic regression adjusting for age, body mass index (BMI), and individual ancestry  effects p < 0.05) between patients and controls in age, education, or SES, they were discarded. This approach is similar to the one used by Tsao and Ling [A randomized analysis (RDM) was implemented to account for confounder differences between cases and controls in a more efficient way. Therefore, a sub-sampling method without replacement was applied to create a set of sub-samples matched by each one of three variables ). A set of 1000 random sub-samples, each consisting of 100 cases and 108 controls, was generated. To check the homogeneity of each sub-sample, a chi-square test or t test was performed. If the sub-samples showed significant differences  and corresponding 95% CIs were estimated.We performed a logistic regression analysis to examine the association of individual SNPs and haplotypes with breast cancer risk in each subsample, adjusted for BMI, ancestry, and age. The results were summarized by the frequency of significant p-values (significance level 0.05). If the number of significant BRCA1, BRCA2, ESR1, and VDR genes in the Uruguayan population, a set of SNPs was chosen with a worldwide representation. SNPs selected for the analysis were in linkage disequilibrium in European populations; rs8176193, rs16942, and rs8176092 for BRCA1, rs206081, rs11571787, and rs4942505 for BRCA2, rs1514347 and rs6912184 for ESR1, and rs7975232, rs1544410, rs2239182, and rs2239179 for VDR. Data from the 1000 Genomes database was used to calculate haplotype frequencies in Africans (GWD–Gambians from the West Division and YRI–Yoruba from Nigeria), Asians (CHB–Chinese from Beijing and CHS–Chinese from the South), Europeans , and Latin Americans .To improve the association analysis, haplotype frequencies were calculated for the genes with two or more SNPs in significant linkage disequilibrium (LD). However, to understand the genetic structure of Population structure was analyzed in the Uruguayan sample using the candidate gene panel of SNPs to explore these particular genomic regions. Principal component analysis (PCA) was performed using R software . PopulatAfter quality control, data was available for 118 SNPs in 172 cases and 160 controls. All of the variants genotyped were found to be under HWE in controls after FDR correction .CNTNAP2 and VDR genes with the disease is supported by the randomized analysis. The logistic regression results for the eight SNPs associated with breast cancer are listed in BRCA1, are risk variants with moderate effects ranging from 38–88% enhanced risk. BRCA1 rs1799950 minor allele (G) showed a protective effect of ~50% decreased risk for the carriers of this variant. All, but rs1799950 of ESR1 rs2941740 had a genotyping rate lower than 90%, it was excluded from the traditional analysis. Nevertheless, it stands out with the highest percentage of significant sub-samples in the randomized analysis (86% as a single SNP and up to 91% within haplotypes) and is, therefore, worthy of mention. Since BRCA2 SNPs not showing an association with breast cancer using the traditional approach, this gene appears associated in the haplotype analysis  with breast cancer only for the protective haplotype, which includes the major allele from rs2981582. This SNP was previously found as significantly associated with the disease, its minor allele increasing risk. BRCA1, BRCA2, ESR1, and VDR genes in the Uruguayan population, a set of SNPs was chosen with a worldwide representation. The frequency of the Uruguayan haplotypes was compared with that of parental populations, i.e., African, European, and Asian populations (as a surrogate for Native Americans), and other admixed Latin American populations (BRCA2 frequencies) [To understand the genetic structure of ulations . These huencies) .VDR haplotypes (rs7975232|rs1544410|rs2239182|rs2239179). Some differences are remarkable. For example, the VDR ACCC haplotype frequencies in Uruguay and Colombia are close to each other, but are higher than those in European populations.The PCA helps to understand the general genetic structure of the samples. When the Uruguayan samples are compared against the European, African, or Asian populations, they show a clear European pattern. However, the controls are more homogeneous, while the patients comprise a more heterogeneous group .BRCA1/2 mutations [Breast cancer is a common cancer in Latin American countries. Previous studies in Latin American populations focused mainly on hereditary breast cancer and utations . This stutations . The resTo the best of our knowledge, this is the first study to explore these candidate genes in sporadic breast cancer patients in South America. Studies conducted in other Latin American countries either examined hereditary breast cancer or did not take into account family history at the time of selecting the patients. The few sporadic breast cancer studies available analyzed a small number of SNPs that are different from those included in the present study . The admixture structure in Latin American populations represents an important factor to be considered in breast cancer studies. In the past decades, admixture mapping was developed as a powerful method of gene mapping . This meBRCA1 and BRCA2 have been the primary targets in Latin American studies, and one of their main achievements is the detection of new variants only present in those populations. Our experimental design did not allow us to identify new variants in the Uruguayan population. The BRCA1 or BRCA2 haplotype architecture is not different from that present in Europeans or other Latin Americans. However, the BRCA1 rs1799950 G variant described as benign in hereditary breast cancer, was protective in our study, in agreement with other sporadic breast cancer studies in European populations [In familial breast cancer, ulations . In factESR1, FGFR2, VDR, CNTNAP2, and BRCA2 have a weak association with sporadic breast cancer in the Uruguayan population. The reduced sample size and the bias detected for SES decreased statistical power and confounded the traditional analysis. Nevertheless, the randomized approach suggests that genetic risk factors for sporadic breast cancer in Uruguay are similar to those in other populations of European ancestry [BRCA2 seems to be a good candidate gene to explore in the future given the information available from previous studies in hereditary breast cancer in Uruguay. In these previous studies more mutations were described in BRCA2 than in BRCA1 with some of them being population-specific mutations [BRCA2 mutations are slightly more common between older women with sporadic breast cancer [FGFR2 (rs2981582) and MAP3K1 (rs16886165), with BRCA2 mutant carriers, has been described [FGFR2, rs16886165 in MAP3K1 and rs3803662 in TOX3 are associated with breast cancer in populations of European ancestry [The sub-sampling approach provided a different approximation to the analysis of the variants. Using this method, a random set of sub-samples was created by a variable selection procedure. The method reveals that ancestry . Moreoveutations ,44. A plutations , and BRCt cancer . Moreoveescribed , but it ancestry , and theancestry , the assancestry ,51. EvenESR1 rs2941740 in the haplotype analysis and the haplotype rs2941740_G|rs1999805_T|rs827423_C showed a strong support. In a recent study, the authors identified the 6q25 region, where ESR1 is located, as associated with breast cancer in U.S. Latinas, Mexican, and Colombian patients. The rs2941740 is one of the 48 SNPs showing robust evidence of association in GWAS. The 6q25 region was also previously described as associated with breast cancer and Native American ancestry in U.S. Latinas. In this region, breast cancer risk decreases with higher Native American genetic contribution, which suggests that a particular genomic structure related with breast cancer risk may exist [ESR1 gene, which encodes the estrogen receptor α, is an important candidate gene in the 6q25 region and risk allele carriers show abnormal gene expression [The subsampling method allowed us to reintroduce ay exist . Most ofpression . The mecpression . Howeverpression . Recently, we described the influence of epigenetic ancestry in sporadic breast cancer. DNA genome demethylation was positively correlated with African ancestry in breast cancer patients, but not in control individuals. The data suggests that the usual DNA hypomethylation in breast cancer patients is reinforced by the genome structure due to population-specific contributions . ComplexEven though we found a weak association between European ancestry and breast cancer in Uruguay , there aBRCA1, BRCA2, ESR1, VDR, and FGFR2 was found; however, these associations did not persist after FDR correction. Given the small sample size, particularly the number of patients collected, even though it was representative of the Uruguayan population, was not enough to detect the expected differences. The a posteriori power estimation, considering an effect size of 0.26 (the highest from the iCOGs publication) and a confidence level of 95%, is lower than 70% [In this study, a weak association with well-known candidate genes than 70% . We had FGFR2, ESR1, VDR, or BRCA2 could be associated with breast cancer in Uruguay and other admixed Latin American populations.Given the current interest in identifying risk factors for complex diseases in populations other than Europeans, it is informative to analyze candidate genes in Latin American populations with a high contribution from European parental populations. Our findings suggest that known candidate genes like


Compared to Ile/Ile (A/A) genotype, frequency of Ile/Val (A/G) genotype was significantly higher among cases than in control group and observed to increase the breast cancer risk . The frequency of Val (G) allele was significantly higher in cases as compared to controls . Compared to Ile (A) allele, significant increase in the risk of breast cancer was observed with Val (G) allele . We observed significant association between HER2 Ile655Val polymorphism and breast cancer risk under the dominant  and codominant  model. In our study, BCL-2 (-938C > A) and BAX (-248G > A) polymorphism were not found to be associated with breast cancer risk. This present study for the first time shows significant association of HER2 Ile655Val polymorphism with risk of breast cancer in Indian population. Therefore, we suggest that each population need to evaluate its own genetic profile for breast cancer risk that may be helpful for better understanding the racial and geographic differences reported for breast cancer incidence and mortality.Breast cancer is the most common carcinoma in women worldwide. The present case-control study was aimed to examine the association of BCL-2 (-938C> A), BAX (-248G > A), and HER2 (I655V i.e. A > G) polymorphisms with breast cancer risk in Indian population. This study enrolled 117 breast cancer cases and 104 controls. BCL-2 (-938C > A), BAX (-248G > A), and HER2 Ile655Val polymorphisms were screened by PCR-RFLP method. There was no significance difference in the allelic and genotype frequency of the BCL-2 (-938C > A) and BAX (-248G > A) polymorphisms between cases and controls. In relation to HER2 Ile655Val polymorphism, the statistical analysis of observed genotypic frequencies showed significant association ( Breast cancer is the leading cause of cancer-related deaths and it is the most common type of cancer among women worldwide . In IndiHuman epidermal growth factor receptor 2 (HER2/neu/EGFR2/ERBB2/c-erbB-2) protooncogene encodes a 185 kDa transmembrane glycoprotein , 12 whicN = Z2P(1 − P)/d2 ). The written informed consent was collected from all participating subjects/individuals. The relevant clinical history of all the cases of the study was collected and clinical history was used for the selection of appropriate cases as per exclusion/inclusion criteria of the study. The mean age of cases was 48.69 years and median age was 48 years. Cases had age range between 18 and 73 years and age group of 45 to 60 years had a peak prevalence rate.In the current case-control retrospective study, a total of 117 cases of primary breast cancer were included, which fulfilled the relevant selection criteria, and a total 104 nonmalignant lesions cases of the breast tissue were taken as control after obtaining the ethical clearance from Institute Ethics Committee . Inclusion criteria were that the required tissue sample was retrieved from the paraffin blocks prepared from primary breast tumor site only cases, which were diagnosed as infiltrating ductal carcinoma, not otherwise specified . Exclusion criteria were patients with history of recurrence of breast tumor (only cases of primary breast carcinoma were included in the study), history of prior radiation exposure to the site (prior radiotherapy) and history of neoadjuvant chemotherapy. The sample size was estimated by using the following formula: µl reaction mixture containing 1 µl genomic DNA, 10X PCR buffer 2.5 µl, 2.5 µl dNTP, 0.5 µl of each primer, and 1 µl Taq DNA polymerase. For BCL-2, PCR conditions include initial denaturation at 96°C for 5 min followed by 35 cycles at 96°C–for 45 seconds, at 56°C for 45 seconds, and at 72°C for 30 s and a final extension step at 72°C for 10 minutes. For BAX, PCR conditions include initial denaturation at 95°C for 5 min followed by 35 cycles at 95°C–48 seconds, at 54°C for 45 seconds, and at 72°C for 40 s and a final extension step at 72°C for 8 minutes. For HER2, PCR conditions include initial denaturation at 94°C for 5 min followed by 35 cycles at 94°C–30 s, at 62°C–45 seconds, and at 72°C for 30 s and a final extension step at 72°C for 7 minutes.Genomic DNA was isolated from paraffin embedded tumor tissue blocks by phenol-chloroform method. Genotyping of the SNPs BCL-2-938C>A, BAX-248G>A, and HER2  was performed by using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. PCR reactions were performed in a 25 μl of each PCR product was digested with different restriction enzymes as shown in After PCR reaction, 10 p > 0.05). Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were determined to assess the strength of association of BCL-2 (-938C>A) and BAX (-248G>A) and HER2 Ile655Val polymorphism with breast cancer risk. Statistical significance was set at p < 0.05.Chi-square test was applied for comparing genotype and allele frequencies for statistical significance between breast cancer patients and controls. Observed and expected genotype frequencies of BCL-2, BAX, and HER2 gene polymorphism in controls showed no deviation from Hardy-Weinberg equilibrium. Chi-square test showed that there was no significant deviation from Hardy-Weinberg equilibrium for BCL-2, BAX, and HER2 SNP genotypes (p-0.980). Similarly, there was no significant difference in allele frequencies between cases and control (p-0.937). Also, we did not find any significant association between BCL-2(-938C>A) polymorphism and breast cancer risk under recessive, dominant, and codominant models.The genotype and allele frequencies of BCL-2 (-938C>A) polymorphism in cases and control are summarized in p-0.956). Similarly, no significant difference was observed in allele frequencies between cases and control (p-0.747). Also, there was no significant relationship between BAX (-248G>A) polymorphism and risk of breast cancer under recessive, dominant and codominant models.The frequencies of GG, AG, and AA genotypes in cases and controls were 79.48%, 17.09%, and 3.41%, and 77.88%, 18.26%, and 3.84%, respectively . The stap-0.001) and codominant  model, whereas no significant relationship was found under the recessive model .The genotype and allele frequencies of HER2 Ile655Val polymorphism in cases and control are summarized in In this present study, we reported no significant association of the BCL-2 (−938C>A), BAX (−248G>A), and HER2 Ile655Val polymorphism with tumor grade .Apoptosis is highly programmed cell death and has a significant role in functionality and development of multicellular organism. Damaged and redundant cells are eliminated by activation of apoptosis through various physiological or pathological death signals for maintaining homeostasis . ApoptosBCL-2 protein plays significant function in the regulation of apoptosis and cell cycle delay. BCL-2 overexpression is found to be associated with different types of cancers such as prostate cancer, chronic lymphocytic leukemia, non-small cell lung cancer, breast cancer, esophageal cancer, lung cancer, and endometrial cancer –25. DysrBAX is a proapoptotic protein which controls apoptosis through regulation of mitochondrial outer membrane permeabilization . In nume-0.04) on 20 eligible reports of 10,642 cases and 11,259 controls. Xie et al. [SNP at codon 655 of the HER2 gene shows isoleucine (ATC) to valine (GTC) substitution (I655V) in the transmembrane domain-coding region and was found to be associated with breast cancer risk . HER2 bee et al.  also repe et al.  and Slove et al. .In the Brazilian population, HER2 Ile655Val polymorphism was suggested as a candidate marker for breast cancer susceptibility, although negatively associated with breast cancer susceptibility . SimilarOur finding was inconsistent with the previous studies which did not find any association of Her2 Ile655Val gene polymorphisms with the breast cancer risk in Turkish –51, KoreThere were some limitations in the present study. Firstly, the sample size was small. Indian population is thought to be most diverse due to different sociocultural traditions. A single larger study with diverse sample size may help us in better understanding the association of the genetic variation of these genes with breast cancer risk. Secondly, the gene-environment and gene-gene interactions have not been taken into account. Combination of gene-environment interactions and gene polymorphisms should be taken into consideration to better understand the genetic background of breast cancer. Further studies on larger sample size are needed to confirm our findings.In conclusion, the present case-control study concludes that BCL-2 (-938C>A) and BAX (-248G>A) polymorphism were not significantly associated with breast cancer risk. This current study for the first time revealed significant association of HER2 Ile655Val polymorphism with high risk of breast cancer in Indian population. These genetic risk factors identification can be useful in predicting the occurrence of breast cancer and defining high risk individuals. Hence, we suggest that each population need to evaluate its own genetic profile for breast cancer risk that may be helpful for better understanding the racial and geographic differences reported for breast cancer incidence and mortality.