Vitamins involved in one-carbon metabolism are hypothesized to influence breast cancer (BC) risk. However, epidemiologic studies that examined associations between B vitamin intake and BC risk have provided inconsistent results. We prospectively examined, in the Italian ORDET cohort, whether B vitamin consumption was associated with risk of BC and BC subtypes.After a mean follow-up of 16.5 years, 391 BCs were diagnosed among 10,786 cohort women. B vitamin intakes were estimated from food frequency questionnaires. Cox proportional hazard models adjusted for energy intake and confounders, estimated hazard ratios (HR) with 95% confidence intervals (CIs) for BC according to intake.RRs were 0.61  for thiamine; 0.48  for riboflavin; 0.59  for vitamin B6, and 0.65  for folate. As regards risk of BC subtypes, high riboflavin and folate were significantly associated with lower risk of estrogen receptor positive (ER+) and progesterone receptor positive (PR+) cancers, and high thiamine was associated with lower risk of ER-PR- cancers. High riboflavin was associated with lower risk of both HER2+ and HER2- cancers, high folate with lower risk of HER2- disease, and high thiamine with HER2+ disease.These findings support protective effects of thiamine and one-carbon metabolism vitamins  against BC in general; while folate may also protect against ER+PR+ and HER2- disease; and thiamine against ER-PR-, and HER2+ disease. One-carbon metabolism is a network of biochemical pathways that provides methyl groups for a variety of essential biomolecules and biological processes. Disruption of one-carbon metabolism can interfere with DNA replication, DNA repair, and regulation of gene expression through methylation, each of which could promote carcinogenesis. The B vitamin folate/folic acid is a major dietary source of methyl groups, whereas riboflavin (vitamin B2) and vitamin B6 are essential cofactors for enzymes involved in one-carbon metabolism that may influence methyl group bioavailability. Thus it is reasonable that dietary intake of B vitamins may influence the development and progression of cancer, and dietary changes in the intake of these nutrients may modify the risk of cancer –4.While many epidemiological studies have investigated the effect of dietary folate intake on breast cancer risk, relatively few studies have evaluated the influence of intake of other B vitamins on risk. Finding on folate have been inconsistent . Two 201Breast cancer is now classified into subtypes based in theory on gene expression profiles but determined in clinical practice by the expression of estrogen receptor (ER), progesterone receptor (PR), overexpression of human epidermal growth factor receptor 2 (HER2) and the Ki67 proliferation index .These subtypes differ in prognosis and factors that influence their occurrence ,19. OnlyORmones and Diet in the Etiology of Breast Tumours) study.The aim of the present study was to investigate the hypothesis that breast cancer subtypes defined by ER, PR and HER2 status  have differing etiologic pathways differentially influenced by intake of nutrients involved in one-carbon metabolism. We investigated women enrolled in the Italian ORDET . The study complies with the Helsinki Declaration, and participants gave written informed consent to use clinical data for research.At recruitment, information on lifestyle, menstrual history and reproductive history was collected; height, weight, and waist and hip circumferences were measured; and blood and urine samples were collected. The women also completed a self-administered semi-quantitative food frequency questionnaire (FFQ) .The ORDET database was linked to the local Varese Cancer Registry, which is considered a high quality registry with less than 3% of cancers identified only through death certificates , to asceThe FFQ only became available 30 months after starting recruitment. Women recruited at the beginning (n = 1500) did not complete the FFQ and were excluded from the present analysis. We also excluded women found to have a cancer diagnosis before recruitment, or who were lost to early follow-up, leaving 9093 women potentially eligible women. We subsequently excluded women for whom variables used as covariates in the statistical model were missing, and those for whom the ratio of total energy intake (determined from the FFQ) to basal metabolic rate (determined by the Harris-Benedict equation) was in tDietary habits over the preceding year were assessed using a validated semi-quantitative FFQ, as described in detail elsewhere . VolunteHazard ratios (HRs) with 95% confidence intervals (CIs) of developing breast cancer in relation to intakes of thiamine (B1), riboflavin (B2), niacin (B3), vitamin B6, and folate (B9) were estimated by multivariable Cox proportional hazard modelling with age as primary time variable. Vitamin intakes were categorized into quartiles based on the distribution of intake in the whole cohort, with the lowest quartile as reference. HRs were also calculated for 1 standard deviation increments in vitamin intake as a continuous variable.We ran a minimally adjusted model, with energy intake as covariate, and a fully-adjusted model with the following additional covariates: height (m), waist-to-hip ratio, age at menarche (years), menopausal status , oral contraception use (yes or no), parity , years of education, family history of breast cancer (yes or no), and alcohol intake (g/day). Tests for linear trend were calculated by assigning an ordinal number to each quartile.The proportional hazards assumption for B vitamins and all other covariates in relation to breast cancer risk was tested using the Grambsch and Therneau method . In all In additional analyses, we tested whether effects of vitamin intake differed with alcohol intake, menopausal status, and BMI. To do this we performed stratified analyses using product terms  that were multiplied by vitamin intake as a continuous variable. These models were adjusted with the same covariates as in the fully-adjusted model, with appropriate exclusions . The significance of interactions was assessed using a likelihood ratio test that compared the model that included the product term and the model that did not include it.We investigated associations between vitamin intake and breast cancer in general, and also breast cancer subtypes defined by ER status , PR status , combined ER and PR status  and HER2 status .The heterogeneity of associations according to receptor status was assessed using the data augmentation method  in whichAfter a mean follow up of 16.3 years, 391 breast cancer cases were identified in the cohort (362 invasive and 29 in situ). Of these, 282 were ER+ and 82 ER- (27 unknown); 236 were PR+ and 126 PR- (29 unknown); and 62 HER2+ and 273 HER2- (56 unknown).Table 1 according to disease status. Women who developed breast cancer were more educated, used less oral contraceptives, more often had a family history of breast cancer, and overall had a lower intake of B vitamins than those who did not.The distributions of vitamin intake and breast cancer risk factors in the cohort at recruitment are shown in Table 2. Women in highest thiamine intake quartile had a significantly lower risk of breast cancer than those in the lowest quartile . A similar significant effect was seen for riboflavin , which was also present when riboflavin intake was considered as a continuous variable . A similar significant effect was also seen for vitamin B6 , which again was present when vitamin B6 was considered as a continuous variable . Finally, the highest quartile of folate intake was also associated with lower breast cancer risk than the lowest quartile . No significant association of niacin intake with breast cancer was found.Multivariable-adjusted HRs for developing breast cancer by quartiles of B vitamin intake are shown in Table 3 shows associations between B vitamin intake and breast cancer risk according to ER status. High riboflavin intake was associated with significantly reduced risk of ER+ disease, evident both in the quartile  and continuous  models.High vitamin B6 intake was also associated with reduced risk of ER+ disease: with a significant P trend, and significant by the continuous model .High folate intake was also associated with a significantly reduced risk of ER+ disease, evident in both the quartile  and continuous  models.No significant associations of thiamine or niacin with ER+ breast cancer were found; neither were significant associations of riboflavin, folate, thiamine or niacin with ER- breast cancer found, although HR estimates were in the same direction as those for ER+ breast cancer. Vitamin B6 intake was significantly associated with reduced risk of ER- disease in the continuous model only .As regards PR+ disease, high intakes of riboflavin  and of folate  were significantly associated with reduced incidence of this cancer subtype in the quartile models; riboflavin also had a significant effect in the continuous model .As regards PR- disease, high thiamine  and high vitamin B6  were significantly associated with lowered risk of this cancer subtype in the quartile models; vitamin B6 was also effective in the continuous model . The test for heterogeneity between PR+ and PR- for vitamin B6 was significant (P = 0.030). No association of riboflavin, niacin, or folate with PR- breast cancer was found.Table 4 shows associations between vitamin intake with risk of breast cancer subtypes defined by joint ER and PR status. High intakes of riboflavin and folate were significantly associated with lowered risk of ER+PR+ disease, both in the quartile  and the continuous  models.As regards ER-PR- disease, thiamine had a significant effect only in the quartile model  while vitamin B6 intake was associated with lowered risk only in the continuous model . The test for heterogeneity between ER+PR+ and ER-PR- for vitamin B6 was significant (P = 0.040).Table 5 shows associations between vitamin intake and risk of HER2+/- breast cancer. The highest quartile of riboflavin intake, compared to lowest, was associated with significantly reduced risk of both HER2+  and HER2-  disease.The highest quartile of thiamine intake, compared to lowest, was associated with significantly reduced risk of HER2+ disease .Compared to the lowest, the highest quartiles of vitamin B6  and folate  were associated with significantly lowered risk of HER2- disease. Vitamin B6 intake was also significantly associated with reduced risk of HER2- disease in the continuous model . No significant associations of niacin, vitamin B6 or folate with HER2+ disease were found. No significant associations of niacin or thiamine with HER2- disease were found. Tests for heterogeneity between HER2+ and HER2- cancers were not significant for any B vitamin.We further investigated the association of vitamin B with the risk of triple-negative cancers , but found no significant association between dietary intake of vitamin B and the risk of this poor prognosis breast cancer subtype .When the analyses were stratified by BMI, vitamin B6 was significantly associated with reduced risk in lean women whereas thiamine was associated with reduced risk in overweight women. Tests for heterogeneity were not significant (P = 0.088 for thiamine and P = 0.896 for vitamin B6) . In no cIn the present prospective study we found that high intakes of thiamine and B vitamins involved in one-carbon metabolism  were associated with significantly lowered breast cancer risk. Furthermore, high folate intake was associated with reduced risk of ER+, PR+, ER+PR+ and HER2- subtypes; high thiamine was associated with reduced risk of ER-PR- and HER2+ disease; high riboflavin was associated with reduced risk of ER+, PR+, HER2+, and HER2- disease; and high vitamin B6 was associated with reduced risk of ER+, ER-, PR-, and HER2- cancers.We examine first folate. The literature on folate intake and breast cancer is extensive. Recent reviews/meta-analyses do not provide a clear picture ,7. Most The literature (cohort studies) on folate intake and risk of breast cancer subtypes defined by ER and PR status is less extensive,34,36,37To our knowledge, only the EPIC study  has evalFolate plays an important role in DNA methylation ,41 and iMethylation of CpG islands on the ER gene has been associated with lack of ER gene expression in breast cancer cell lines and primary breast cancers –46. HypeAs regards riboflavin and vitamin B6, these are involved in one-carbon metabolism as enzyme cofactors . RiboflaVitamin B6 and riboflavin may protect against breast cancer by mechanisms unrelated to one-carbon metabolism. It is known that chronic inflammation plays a role in the development and progression of several types of cancer  includinAs regards thiamine, this enzyme cofactor is involved in metabolic processes that are often altered in tumour tissue ,58. HoweThe strengths of the present study are its prospective design, and highly complete follow-up. Furthermore, dietary habits, over the year prior to assessment, were assessed using a food frequency questionnaire that was designed to capture the eating habits of the enrolled women by including local recipes and products. The main sources of folate in our cohort were vegetables (28.0%), cereals (17.4%) and fruits (12.2%); for riboflavin they were milk and dairy products (24.5.0%), meat and meat products (21.8%), and vegetables (15.2%); for vitamin B6 they were meat and meat products (28.9%), cereals (16.7%) and fruits (15.3%); for thiamine they were cereals (23.0%), meat and meat products (22.0%), and fruits (14.0%). Given the wide distribution of sources for these micronutrients it is unlikely that the risk reductions can be attributed to a specific dietary pattern (for example a Mediterranean-type diet) or to generic factors such as overall healthy lifestyle, however we cannot exclude these possibilities.A limitation is that only a single dietary assessment was made and any changes in dietary habits since that assessment (20 years ago) will have been missed. Furthermore, we cannot rule out confounding by factors that we were not able to estimate or estimated in a sub-optimal way in our questionnaires.Another limitation is the hormone receptor expression of the cancers was determined using various biochemical and immunohistochemical techniques that may not be completely equivalent to each other, resulting in some misclassification receptor status.To conclude, our study supports the hypothesis that high dietary intakes of folate and other B vitamins involved in one-carbon metabolism reduce breast cancer risk. It also suggests that folate protects against ER+PR+ and HER2- subtypes; and that thiamine protects against be ER-PR- and HER2+ subtypes. However further prospective studies are required to clarify the associations of these vitamins with risk of developing different breast cancer subtypes.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.


Epidemiologic studies exploring causal associations between serum lipids and breast cancer risk have reported contradictory results. We conducted a meta-analysis of prospective cohort studies to evaluate these associations.Relevant studies were identified by searching PubMed and EMBASE through April 2015. We included prospective cohort studies that reported relative risk (RR) estimates with 95% confidence intervals (CIs) for the associations of specific lipid components  with breast cancer risk. Either a fixed- or a random-effects model was used to calculate pooled RRs.Fifteen prospective cohort studies involving 1,189,635 participants and 23,369 breast cancer cases were included in the meta-analysis. The pooled RRs of breast cancer for the highest versus lowest categories were 0.96 (95% CI: 0.86–1.07) for TC, 0.92 (95% CI: 0.73–1.16) for HDL-C, 0.90 (95% CI: 0.77–1.06) for LDL-C, and 0.93 (95% CI: 0.86–1.00) for TG. Notably, for HDL-C, a significant reduction of breast cancer risk was observed among postmenopausal women  but not among premenopausal women. Similar trends of the associations were observed in the dose-response analysis.Our findings suggest that serum levels of TG but not TC and LDL-C may be inversely associated with breast cancer risk. Serum HDL-C may also protect against breast carcinogenesis among postmenopausal women. Cancer and cardiovascular diseases are the leading causes of death in developed countries, and they are expected to be the most important determinants of death in developing countries by 2030 . LifestyCholesterol plays important roles in cellular structure and function and as an obligatory precursor to several biochemical pathways, especially the synthesis of steroid hormones, which are implicated in the etiology of breast cancer , 4. SincTherefore, the objective of this meta-analysis was to systematically evaluate the association between individual lipid components and breast cancer risk in prospective cohort studies.We performed literature searches of the PubMed and EMBASE databases without restrictions through April 2015. The following terms were used: “lipid,” “lipoprotein,” “cholesterol,” “triglyceride,” “dyslipidemia,” “breast neoplasms,” “breast cancer,” “risk,” “incidence,” and “prevalence.” Moreover, we reviewed the reference lists of retrieved articles for additional studies. We followed the MOOSE guidelines to conduct and report this meta-analysis.Studies were eligible for this meta-analysis if they fulfilled the following criteria: 1) the study design was a prospective cohort study, 2) the exposure of interest was serum concentration of at least one of the selected lipid components  measured prior to breast cancer diagnosis, 3) the outcome of interest was the occurrence of breast cancer, and 4)the relative risk (RR) with corresponding 95% confidence interval  were reported. If data were duplicated in more than one study, we included the study with the largest number of cases.Two investigators (H.B.N. and H.X.L.) independently reviewed the articles and extracted the data from all eligible publications. Any disagreement was settled by discussion. The following data were recorded: first author’s surname, publication year, country of origin, ethnicity, study and follow-up periods, characteristics of study population , numbers of cases and participants, ranges of serum lipid levels, RRs from the most fully adjusted model for the highest versus lowest category of serum lipids and the corresponding 95% CIs, and matching or adjustments for confounding factors.The methodological quality of included studies was assessed by the nine-star Newcastle-Ottawa Scale (NOS) , which cRR was used as a common measure of association, and the hazard ratios was deemed equivalent to RRs because the absolute risk of breast cancer is quite low. From each study, we extracted the risk estimates that reflected the comparison of the highest versus lowest categories and the greatest degree of control for potential confounders. Those articles providing results stratified by menopausal status only were treated as two separate reports , 8. For I2 statistic [The homogeneity of RRs among studies was assessed with Cochran’s Q statistic  and quantified using the tatistic . When sutatistic . PrespecWe next conducted dose-response relationships of serum lipids with breast cancer risk based on the method proposed by Greenland and Longnecker  and OrsiPotential publication bias was evaluated with Begg’s rank correlation tests  and EggeThe detailed procedure of our literature search and selection is shown in The main characteristics of the selected studies are summarized in Pheterogeneity = 0, I2 = 72.7%).The multivariable-adjusted RRs for each study and the combined RR for the highest versus lowest TC categories are shown in Pheterogeneity = 0.006, I2 = 65.0%).Seven studies presented results on the highest versus lowest levels of HDL-C and breast cancer risk . The majPheterogeneity = 0.405, I2 = 0.0%).Four studies analyzed the role of LDL-C in breast cancer risk. The results are shown in Pheterogeneity = 0.442, I2 = 0.0%).An association between breast cancer risk and serum TG was reported in six studies. The results of subgroup analyses according to geographic region, ethnicity, follow-up length, number of cases, menopausal status, and adjustment for dietary factors are presented in Pheterogeneity = 0.33, I2 = 13.0%). The influence of each individual data set on the combined risk estimates was not significant for the other lipid components.To assess any impact of study quality on the effect estimates, we performed a sensitivity analysis that only included high-quality studies. The combined risk estimates did not show any substantial difference compared to the overall results. Furthermore, we conducted sensitivity analyses in which one study was removed and the rest were analyzed. The results showed that substantial heterogeneity in TC and breast cancer association was most likely due to the Strohmaier et al study ; excludiPheterogeneity = 0.20) for TC, 0.96  for HDL-C, and 0.95  for TG.Overall, we failed to identify a significant dose-response relationship between any lipid components and breast cancer risk using data from five studies on TC , 19, 27,P > 0.05).There was no evidence of publication bias for individual lipid components based on Begg’s rank correlation and Egger linear regression tests  and minHowever, several limitations of our study should also be acknowledged. First, given the non-randomization design, residual confounders were of concern. We were unable to rule out potential confounding due to unmeasured variables such as family history of other types of cancer, which could exaggerate or obscure the true associations. Moreover, the adjusted covariates, for instance dietary factors , differed in individual studies, which might also increase the risk of confounding bias. Second, we observed substantial heterogeneity that could have been introduced by clinical or methodological differences among studies, including variation in geographic regions, menopausal status, number of cases, follow-up length, and analysis covariate selection. We determined that across-study heterogeneity for serum TC and HDL-C seemed was largely driven by one European cohort study  that didIn summary, the results of this meta-analysis indicate that elevated serum levels of TG may be associated with a reduced breast cancer risk. Among postmenopausal women, serum HDL-C may also play a protective role against breast carcinogenesis. We did not find significant associations between breast cancer risk and serum TC and LDL-C concentrations. Future research with larger sample sizes, detailed menopausal status information and consistent adjustments for confounders, especially among Asian populations, is warranted to extend our findings.S1 File(DOC)Click here for additional data file.S1 PRISMA Checklist(DOC)Click here for additional data file.


According to the “World Cancer Research Fund” and the “American Institute of Cancer Research” (WCRF/AICR) one in four cancer cases could be prevented through a healthy diet, weight control and physical activity.To explore the association between the WCRF/AICR recommendations and risk of breast cancer.973 controls from 17 Spanish Regions. We constructed a score based on 9 of the WCRF/AICR recommendations for cancer prevention:: 1)Maintain adequate body weight; 2)Be physically active; 3)Limit the intake of high density foods; 4)Eat mostly plant foods; 5)Limit the intake of animal foods; 6)Limit alcohol intake; 7)Limit salt and salt preserved food intake; 8)Meet nutritional needs through diet; S1)Breastfeed infants exclusively up to 6 months. We explored its association with BC by menopausal status and by intrinsic tumor subtypes  using conditional and multinomial logistic models respectively.During the period 2006 to 2011 we recruited 973 incident cases of breast cancer and Our results point to a linear association between the degree of noncompliance and breast cancer risk. Taking women who met 6 or more recommendations as reference, those meeting less than 3 showed a three-fold excess risk (OR=2.98(CI95%:1.59-5.59)), especially for postmenopausal women ) and ER+/PR+&HER2- ) and HER2+ ) tumors. Noncompliance of recommendations regarding the consumption of foods and drinks that promote weight gain in premenopausal women ; p for interaction=0.014) and triple negative tumors (OR=2.93(CI95%:1.12-7.63)); the intake of plant foods in postmenopausal women ) and triple negative tumors (OR=3.48(CI95%:1.46-8.31)); and the alcohol consumption in ER+/PR+&HER2- tumors (OR=1.52 (CI95%:1.06-2.19)) showed the strongest associations.Breast cancer prevention might be possible by following the “World Cancer Research Fund” and the “American Institute of Cancer Research” recommendations, even in settings like Spain, where a high percentage of women already comply with many of them. Breast cancer (BC) is the most common cancer among women worldwide and, in spite of the continuous improvements in BC prognosis, this tumor constitutes the leading cause of cancer death among women in medium and high income countries –4. FigurTo our knowledge, only four studies have explored the specific association between these recommendations and BC risk –15 and nThe objective of this study was to explore the association between WCRF/AICR recommendations and BC by menopausal status and pathological tumor subtype in Spain, a country traditionally characterized by healthy lifestyle habits.1017 incident cases of BC diagnosed in the Oncology departments of 23 hospitals members of the Spanish Breast Cancer Research Group (GEICAM: http://www.geicam.org) located in 9 of the 17 Spanish Regions. The participant oncologists invited the cases to participate in the moment of diagnosis. The inclusion criteria for cases were: age between 18 and 70 years old, agreement to participate and ability to understand and answer the questionnaire. Women previously diagnosed with breast cancer and women who were unable to answer the questionnaire due to health, language or educational issues were excluded. Each case was matched with a healthy control of similar age (± 5 years), selected from cases’ in-law relatives, friends, neighbors, or work colleagues residing in the same town.As we previously described , EpiGEICCases were sub classified by the following intrinsic subtypes based on local pathology reports:  1) HER2-23 participating hospitals   = 2.98 (CI95%:1.59–5.59)). The risk was higher in postmenopausal ) than in premenopausal women ), but confidence intervals overlap and the p-value for the interaction term in the continuous model was not statistically significant. The proportion of preventable cases of BC in this population by following 6 or more recommendations was estimated at around 30% for all women and also by menopausal status groups. Regarding specific items, diet related individual recommendations showed the strongest associations. In fact, noncompliance with recommendation 3 “Limit the intake of high density food” had an excess risk of 1.86 , especially in premenopausal women (OR = 2.24 (CI95%: (1.18–4.28); p for interaction = 0.014), while a low intake of plant foods was also associated with BC ), particularly among postmenopausal women ), although the p-value for heterogeneity was not significant. The odds ratio of BC for women with alcohol consumption above the recommended was over 1.30 in all cases, however, none of these estimations showed statistical significance, probably given to the fact that most women (94% of controls and 95% of cases) meet totally or partially this specific recommendation.[0–3[vs[6–9] = 3.60  and OR[3–4[vs[6–9] = 2.18 ) and HER+ tumors ). Triple negative tumors were also associated with the WCRF/AICR score in the lower category ). The highest preventable effect of the WCRF/AICR guidelines was observed for ER+/PR+&HER2- ) and HER+ ) tumors while such effect was not significant for the triple negative subtype. Again, for individual items, diet-related recommendations seemed to be the most important, particularly the consumption of foods and drinks that promote weight gain above the recommended which showed OR ranging from 1.68 for ER+/PR+/HER2- tumors to 2.93 for triple negative tumors, though the p-value for heterogeneity was not statistically significant. Low consumption of plant foods seemed to be specifically associated with triple negative tumors (OR = 3.48 (CI95%:(1.46–8.31)), with a p-value of heterogeneity of 0.148 while consumption of alcoholic drinks was only significantly associated with ER+/PR+&HER2- tumors (OR = 1.52 (CI95%:(1.06–2.19)) ) .The exploration of non-linear associations using fractional polynomials revealed that the linear model was the best fit when a continuous association was found .Sensitivity analyses gave similar results leading to the same conclusions  Tables.Our results suggest that WCRF/AICR recommendations may help to prevent overall BC risk, especially among postmenopausal women and women with ER+/PR+&HER2- or HER+ tumor subtypes. Diet related individual recommendations seemed to be the factors more strongly associated with BC risk, especially a high consumption of high density foods or alcohol and the low intake of plant foods.To our knowledge only four studies have explored the association between BC risk and the WCRF/AICR recommendations: two in the US, one in Canada and another using the European EPIC cohort, showing similar results to ours –15. All Specific literature exploring the individual items that compose the WCRF/AICR score in relation with breast cancer, has pointed through a negative or non-significant effect of BMI or physical activity on the incidence of BC in premenopausal women and a positive association with postmenopausal breast cancer ,11,28–30The evidence of an association between consumption of red meat and processed food and BC is still weak ,37,38, bRegarding the potential preventability of the WCRF/AICR recommendations observed in our study, it is in concordance with the results published in the Policy and Action for Cancer Prevention Report  whose esRecall bias is always a concern in case-control studies; however, the validity and reproducibility of FFQ was satisfactory ,22 and tExcept for the cases of the specific subrecommendations related to moldy cereals or pulses, we were able to operationalize all general and specific WCRF/AICR recommendations applicable to this population. No previous studies have been able to operationalize all the recommendations with their data and only one was able to explore the individual association between BC risk and 6 out of the 9 recommendations. On the other hand, this is the first study that explores such associations by menopausal status and BC pathological subtype including ER, PR and HER2 status.Finally, Spain is a country that has traditionally maintained healthy dietary habits. In fact, almost 60% of the control population met 5 or more recommendations and 90% of our women accomplish somehow the most important recommendations on food (R1 and R4) and alcohol consumption (R6) . HoweverBC prevention might be possible by following the WRCF/AICR recommendations, even in settings like Spain, where a high percentage of women already comply with many of them. Despite the fact that especial benefit can be obtained by avoiding the consumption of foods and drinks that promote weight gain, limiting alcohol intake and increasing the consumption of plant foods, our results indicate that a good level of satisfaction with most of the recommendations is more important than any single recommendation.S1 Fig(PDF)Click here for additional data file.S1 TableComplete case analysis.(DOCX)Click here for additional data file.S2 TableComplete case analysis.(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.


The global burden of breast cancer in women is substantial and increasing. Efforts to address breast cancer have focused on primary prevention, reduction of modifiable risk factors, early detection, timely referral for appropriate treatment, and survivorship. Environmental and lifestyle factors that increase breast cancer risk include ionizing radiation, exogenous hormones, certain female reproductive factors, alcohol and other dietary factors, obesity, and physical inactivity. A variety of chemical exposures are purported to be associated with breast cancer.In this article, we summarize the influence of the natural, social, built, and policy environments on breast cancer incidence and cancer recurrence in women based upon bibliographic searches and relevant search terms.Despite a lack of conclusive evidence from epidemiologic studies, exposures to chemicals with estrogenic or other properties relevant to sex steroid activity could influence breast cancer risk if the exposures occur at critical life stages or in combination with exposure to other similar chemicals. Results from several studies support an association between shift work and disruption of the circadian rhythm with breast cancer risk. The social environment likely influences breast cancer risk through several mechanisms including social norms pertaining to breast feeding, age at first live birth, parity, use of oral contraceptives and replacement estrogens, diet, and consumption of alcohol. Social norms also influence body weight, obesity, and physical activity, which have an effect on risk of breast cancer incidence and recurrence. Obesity, which is influenced by the social, built, and policy environments, is a risk factor for the development of postmenopausal breast cancer and certain other cancer types.The natural, social, built, and policy environments affect breast cancer incidence and survival. Effective health care policies can encourage the provision of high-quality screening and treatment for breast cancer and public education about the value of proper diet, weight control, screening and treatment. Additional research and policy development is needed to determine the value of limiting exposures to potentially carcinogenic chemicals on breast cancer prevention. The global burden of breast cancer in women, measured by incidence, mortality, and economic costs, is substantial and increasing. Efforts to alleviate this burden have focused on primary prevention and modifiable risk factor reduction, on early detection and timely referral for appropriate treatment, and on breast cancer survivorship issues. Various factors, genetic and environmental, or the interaction between the two, increase the risk of breast cancer incidence and recurrence. Environmental and lifestyle factors that increase breast cancer risk include ionizing radiation, exogenous hormones, certain female reproductive factors, alcohol and other dietary factors, obesity, and physical inactivity. The increasing prevalence of obesity in the U.S. and many other countries and the independent association of obesity with cancer incidence have prompted interest in identifying environmental influences on risk of obesity and breast cancer. Obesity, a risk factor for the development of postmenopausal breast cancer and certain other cancer types, is associated with poorer response to cancer therapy and cancer reoccurrence.Breast cancer is a leading cause of morbidity and mortality among women in the U.S. and many other countries. Maintaining a healthy body weight reduces a woman’s risk of cancer recurrence, diabetes and cardiovascular diseases. Breast cancer-related environmental factors, however, extend beyond individual exposures to include the natural, built, social, and policy environments.Among women who have already been diagnosed with breast cancer, obesity is associated with breast cancer recurrence and poorer survivalIn this article, we reflect on the influence of natural, social, built, and policy environments on breast cancer incidence and cancer recurrence in women, discuss remaining challenges in this area, and offer suggestions for additional research and policy development. As described by Juarez et al. (2014), the natural, built, social, and policy environments play important roles in health and disease including racial and ethnic disparities in breast cancer.http://community.cochrane.org/cochrane-reviews) and the U.S. Institute of Medicine and reviewed the references of reports and review articles.Our review is based upon bibliographic searches in PubMed and Google Scholar and relevant search terms. For example, we identified articles published in English in recent years using the following MeSH search terms and Boolean algebra commands:  or (weight loss or weight gain or body weight or exercise weight or weight management)) and women). We also identified articles using the following combination of MeSH search terms: ). The searches were not limited to words appearing in the title of an article. Information obtained from bibliographic searchers  was used to determine whether to retain each article identified in this way. In addition, we identified reviews included in Cochrane reviews , dioxins, and pesticides such as dichlorodiphenyl-trichloroethane (DDT), lindane and hexachlorobenezene, have not been consistently associated with breast cancer risk–16. Although use of DDT and PCBs has been banned in the United States since the 1970s, organochlorine compounds have accumulated and persisted within the environment, and some are still used in some low- or middle-income countries. As a result, measurable amounts of these chemicals can be found in human tissues. Because some organochlorine compounds are estrogen agonists or antagonists, as determined in cell culture and animal studies, a possible link between breast cancer risk and organochlorine exposure has been hypothesized. Although results from some studies support this hypothesis, most epidemiological studies do not. While these compounds may have other adverse environmental or health effects, organochlorine exposure is not believed to be causally related to breast cancer. In the California Teachers Study, no associations were found between residential exposure to ambient estrogen disruptors and overall breast cancer risk or hormone receptor-positive breast cancer risk, or among targeted subgroups of participants . Among never-smoking non-movers, however, elevated risks for hormone receptor-negative tumors were noted for higher exposure to cadmium compounds and possibly to inorganic arsenic. The risk of breast cancer from exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been reviewed by various authors and expert panels who found no consistent evidence of an increased risk. In a recent prospective study in France, no association was found between estimated dietary dioxin exposure and breast cancer. Despite the lack of conclusive evidence from epidemiologic studies, exposures to chemicals with estrogenic or other properties relevant to sex steroid activity could influence breast cancer risk if the exposures occur at critical life stages or in combination with exposure to other similar chemicals,17. Results from several studies support an association between shift work and disruption of the circadian rhythm with breast cancer risk. Levels of serum melatonin, which may have a protective effect, decrease when people are exposed to light at night.The natural environment includes physical, chemical, and biological factors. Here we consider the natural environment broadly to include synthetic chemicals that occur in nature due to human activities. Exposure to ionizing radiation, which can induce mutations in DNA is an established breast cancer carcinogen. Social norms also influence body weight, obesity, and physical activity, which in turn influence risk of breast cancer incidence or recurrence. Other aspects of the social environment that affect breast cancer risk include cultural beliefs and attitudes  and the availability of social networks and community organizations and agencies that help provide access to information and resources for breast cancer prevention, early detection, treatment, and survivorship. In many traditional cultures, including parts of the Middle East, Africa, and Asia, efforts are underway to combat cultural attitudes that deter women from talking about breast cancer or seeking care.The social environment likely influences breast cancer risk through mechanisms that include social norms pertaining to breast feeding, age at first live birth, parity, use of oral contraceptives and replacement estrogens, diet, and consumption of alcohol. Proximity to recreational facilities, bike lanes, walking and running paths, and stores and markets that offer nutritious and affordable foods  can contribute to reduction in risk of chronic disease,24. In addition, population studies have identified neighborhood effects and aspects of the built environment that may influence breast cancer incidence and mortality,26.Affecting breast cancer are several aspects of the built environment including the availability of transportation to and from clinics and hospitals that provide screening and treatment services. The location of diagnostic and treatment facilities outside of low-income, minority neighborhoods can also pose a barrier to receiving health care services. Several studies have examined commuting time in relation to receipt of breast cancer screening servicesHealth policies at the national, state or provincial, and local level impact breast cancer incidence and survival. Effective health care policies can encourage the provision of high-quality screening and treatment for breast cancer and public education about the value of proper diet, weight control, screening and treatment. Organized approaches for delivering breast cancer screening should be accompanied by programs and policies that provide access to timely and appropriate diagnostic follow-up and treatment services. In many countries, large numbers of women lack access to screening mammography services or to high-quality oncology care. Public policies aimed at providing equitable health care coverage and addressing inequities in socioeconomic status and health can contribute to alleviating the burden of breast cancer and other serious illnesses.,24,27–30.Public policies at the community level and in work-places can encourage development of health promotion strategies, including those that promote physical activity  or eating a healthy diet. Expert panels have begun to address the daunting tasks of identifying, characterizing, and elucidating the mechanisms of endocrine- disrupting chemicals in breast cancer in order to produce a comprehensive model that will facilitate preventive strategies and public policy.The policy environment also determines permissible exposures to endocrine-disrupting chemicals that may be linked to breast cancer but for which the evidence from epidemiologic studies is inconclusive. The U.S. Environmental Protection Agency estimates that there are 10,000 endocrine-disrupting chemicals among the common daily exposures that could affect risk of disease,21. Results from epidemiologic studies indicate that greater body fatness and alcohol consumption are associated with a higher risk of several chronic illnesses including postmenopausal breast cancer. According to the American Institute on Cancer Research (AICR), eating a healthy diet, maintaining a healthy weight, and being physically active can prevent about one-third of the most common cancers in the U.S. To reduce risk of recurrence, the AICR recommends that cancer survivors adhere to cancer prevention guidelines.The natural, social, built, and policy environments affect breast cancer incidence and survival. Effective health care policies can encourage the provision of high-quality screening; treatment for breast cancer; and public education about the value of diet, weight control, screening, and treatment. It is likely that, in addition to genetic and biological factors, a variety of social, structural, and environmental factors influence breast cancer incidence and survivalDespite a lack of conclusive evidence from epidemiologic studies, exposures to chemicals with estrogenic or other properties relevant to sex steroid activity could influence breast cancer risk if the exposures occur at critical life stages or in combination with exposure to other similar chemicals. Results from several studies support an association between shift work and disruption of the circadian rhythm with breast cancer risk. Additional research and policy development are needed to assess the value of limiting exposures to potentially carcinogenic chemicals for breast cancer prevention. Further, synthetic chemicals that have not been causally linked to breast cancer may pose hazards for the development of other chronic illnesses and adverse reproductive health outcomes.


Despite continuous argument about the efficacy of breast self-examination; it still could be a life-saving technique through inspiring and empowering women to take better control over their body/breast and health. This study investigated Malaysian female university students’ knowledge about breast cancer risk factors, signs, and symptoms and assessed breast self-examination frequency among students.A cross-sectional survey was conducted in 2013 in nine public and private universities in the Klang Valley and Selangor. 842 female students were respondents for the self-administered survey technique. Simple descriptive and inferential statistics were employed for data analysis.The uptake of breast self-examination (BSE) was less than 50% among the students. Most of students had insufficient knowledge on several breast cancer risk factors.Actions and efforts should be done to increase knowledge of breast cancer through the development of ethnically and traditionally sensitive educational training on BSE and breast cancer literacy. Developing countries are observing alarming rates of breast cancer, particularly among young women .Not only the advantages associated with early detection of breast cancer and cognitive factors influencing preventive behaviors for breast cancer but also women’s knowledge on breast cancer signs, symptoms and risk factors is critical to the improvement of breast cancer interventions. Despite a few studies on breast cancer literacy in Malaysia, our knowledge about breast cancer knowledge of female university students in Malaysia is imperceptible.A recent study carried out among 10,242 undergraduate university students in 24 countries across Asia, Africa and America revealed that 35.4% of the women were not aware of any risk factors  influencing breast cancer .In Malaysia, educational level influences the knowledge of breast cancer signs, symptoms, and risk factors. However, breast cancer literacy is not the same in several ethnicities among Malaysian women. For instance, a study on 320 women from different age groups and various ethnicities in Sungai Petani, Kedah revealed that Chinese women had a better knowledge towards breast cancer, but Malay women had a better knowledge on the risk factors of breast cancer .Ethnicity, employment status, and educational level were also the strongest predictors of breast cancer knowledge and literacy . PreviouFurther, breast cancer is a progressive disease, small tumours are more likely to be at an early stage, and therefore early detection is more likely to have more effective treatment and a better prognosis . LiteratGiven the previous literature on the frequency of breast self-examination and knowledge of breast cancer, signs, symptoms and risk factors; breast cancer literacy might be a noticeable factor in cancer early detection. Though, information is still limited regarding differences in women’s breast cancer literacy and self-exam practices by several socio-demographic status, location, and specific racial/ethnic groups in Malaysia. This study aimed to evaluate breast cancer literacy among young female university students in the Klang Valley and Selangor, Malaysia. The main goal of the study is the need for the development of a new assessment tool for breast cancer literacy and to present tailored intervention plans and programs in the future. The most important ambition of the study is to involve health care providers in decision making process for the development of breast cancer education for low-literacy women in Southeast Asia.The participants in the study were female students in the selected public and private universities in the Klang Valley and Selangor, Malaysia. Details of this study has already been published somewhere else . In summThe initial sample size was assessed based on the number of students at the designated universities with absolute precision of 5%. The participants aged ranges between 17 - 52 years old . Majority of the participants were undergraduate students (84.6%).A self-administered paper questionnaire was applied to collect the data from students after explaining the survey purpose. The questionnaire was adopted and adapted from other published studies dealing with same subject matter . QuestioSocio-demographic characteristic used in this study were age, education level, major of study, marital status, occupation, monthly family income, race, religion, and family history of breast cancer and etc. The frequency of breast self-examination (BSE) was asked for two different situations: BSE in the past year and intention to practice BSE in the next year. Knowledge about the risk of breast cancer along with breast cancer signs and symptoms were assessed by selected questionnaire items. A positive answer was assigned one point, whereas a negative answer was given zero.The Statistical Package for Social Sciences (SPSS21) was used for data processing. Simple descriptive and inferential statistics were used for data analysis and frequency with percentage distribution applied for categorized variables. Using the median value as a cut-off point, respondents were categorized into two groups: low level group (with scores less than the median) and satisfactory level group  . The medThe study participants consisted of 842 Malaysian female university students which is majority of them were aged below 29 years old (92.3%) and were undergraduate students (84.6%) . Most ofMost of the participants (86.8%) have no occupation which means they were full-time students while 9.6% of the participants were working. 64.1% of the participants were from urban areas and more than half of all the participants had monthly family income less than RM2500 (55.5%). In terms of ethnic background, Malay comprised the majority of the participants (65.8%), followed by Chinese (21.6%), and then Indian (8.60%). 62.9% of the participants admitted that they have a health insurance.The majority of the participants (99%) stated that they were not smoking at all. Among the participants, 675 (80.5%) had a normal menstrual cycle, 19 (2.3%) had an abortion history, and 63 (7.5%) had a breastfeeding history. The percentage of students with a family history of breast cancer (11.9%) in the study is also considerable .Breast Self-Examination (BSE) was asked for two different periods; breast self-examination practice (BSE) in the last year and intention to conduct breast self-examination (BSE) in the next year. Out of 842 participants, 54.5 % (459) “never applied” BSE in the past year and 32.5% (274) applied BSE “whenever it came to their mind”. In addition, 18.5% (156) of the respondents declared no intention to practice BSE in the next year and 25.2% (212) of them admitted that they will apply BSE monthly.With regard to BSE in the past, the ANOVA results showed that there was statistically significant differences between participants regarding different levels of education, ethnicity, and age groups (P<0.05). The ANOVA analysis also revealed that there was a significant difference in race between Malay, Chinese and Indian and age groups on BSE intensions (P<0.05). The results of the ANOVA tables for demographic characteristics and BSE behaviors and intentions have already been published in our recent study . In factThe rate of BSE (45.5%) is the same as the percentage of BSE in the other studies such as Turkish female teachers (43.9%), and Turkish midwives (52%) . HoweverIn contrast to our results, another study reported that Malay women were more likely to perform BSE . BesidesParticipant’s knowledge about items related to risk factors of breast cancer was asked. The percentages of those responded correctly for each items were presented in Meanwhile, 28.1% of the participant answered correctly about consumption of spicy foods. A small number of participants replied correctly on personal hygiene (19.5%) and having benign breast disease (4.2%).Participants showed deprived understanding of major breast cancer risk factors such as over –weight, oral contraceptive, breast feeding, late menopause, and early onset of menses. Similarly, in another study among Muslim women in the Middle East, participants had also limited knowledge about breast cancer risk factors such as obesity, oral contraceptive, late menopause, and early onset of menses . PreviouOur results on students’ knowledge about the risk factors of breast cancer also supported the interpretation of why 54.5 % (459) of female university students in the study never applied BSE in the last year.The percentages of those replied correctly for each items of breast cancer signs and symptoms were also presented in The uptake of breast self-examination (BSE) was less than 50% among selected students. Results also portrayed that 32.5% of the respondents did not routinely perform breast self-exams and most of the students had insufficient knowledge on several breast cancer risk factors. However, students’ knowledge on breast cancer signs and symptoms were higher than median score. The results of this paper denote that it is not an easy task to focus on breast cancer prevention/screening, even among educated people in Malaysia the same as a number of other countries in the Southeast Asia region.The findings on breast cancer literacy highlighted the need for a new assessment tool for Muslim women in Southeast Asia to advocate their adherence to breast cancer screening standards. Besides, new approaches to cancer prevention programs should involve the targeted audiences  in pursuing to change their wrong perceptions, negative cultural beliefs and social taboos about cancer.This analysis will postulate health care providers with the conceptual basis to realistically compare breast self-examination frequency and cancer literacy among various populations while also serving as a guide for further tailored interventions for breast cancer prevention among young women. A larger sample from rural and urban areas in others states in Malaysia should be included in the others studies to investigate the differences and similarities among varied ethnicities and age groups of women to develop an exclusive breast cancer literacy assessment tool.We do accept that this study characterised with some limitations. On the contrary of this study, the majority of breast cancer studies regarding breast self-exams believed these exams as a part of treatment for patients suffering from breast diseases. Similar to other studies, we used to implement the adaptive questionnaire design in the survey. Our respondents were more under-graduates, quite fluent in English, and from urban areas. Nevertheless, the implication of the study would be the need for appropriate interventions/campaigns to raise the women’s awareness of breast cancer signs, symptoms, risk factors, and common misconceptions about the respective items.


Breast cancer risk prediction models are used to plan clinical trials and counsel women; however, relationships of predicted risks of breast cancer incidence and prognosis after breast cancer diagnosis are unknown.Using largely pre-diagnostic information from the Breast Cancer Surveillance Consortium (BCSC) for 37,939 invasive breast cancers (1996–2007), we estimated 5-year breast cancer risk  with three models: BCSC 1-year risk model ; Breast Cancer Risk Assessment Tool (BCRAT); and BCSC 5-year risk model (BCSC-5). Breast cancer-specific mortality post-diagnosis  was related to predicted risk of developing breast cancer using unadjusted Cox proportional hazards models, and in age-stratified  models adjusted for continuous age, BCSC registry, calendar period, income, mode of presentation, stage and treatment. Mean age at diagnosis was 60 years.Of 6,021 deaths, 2,993 (49.7%) were ascribed to breast cancer. In unadjusted case-only analyses, predicted breast cancer risk ≥1.67% versus <1.0% was associated with lower risk of breast cancer death; BCSC-1: hazard ratio (HR) = 0.82 (95% CI = 0.75–0.90); BCRAT: HR = 0.72 (95% CI = 0.65–0.81) and BCSC-5: HR = 0.84 (95% CI = 0.75–0.94). Age-stratified, adjusted models showed similar, although mostly non-significant HRs. Among women ages 55–69 years, HRs approximated 1.0. Generally, higher predicted risk was inversely related to percentages of cancers with unfavorable prognostic characteristics, especially among women 35–44 years.Among cases assessed with three models, higher predicted risk of developing breast cancer was not associated with greater risk of breast cancer death; thus, these models would have limited utility in planning studies to evaluate breast cancer mortality reduction strategies. Further, when offering women counseling, it may be useful to note that high predicted risk of developing breast cancer does not imply that if cancer develops it will behave aggressively. Improving methods to predict risk of developing breast cancer and communicating this information to women would enable them to make more informed screening and prevention choices.–3 ModelsBreast cancer risk factor associations vary by tumor subtypes., 15–17 GThis analysis includes data collected by the BCSC in seven population-based U.S. mammography registries as compiled and analyzed at the Statistical Coordinating Center (SCC). The BCSCin-situ or use of chemoprevention were excluded. Of the 43,489 women, we excluded 3,484 with a self-reported history of cancer at risk assessment and 609 lacking follow-up vital status. Race and ethnicity were available via self-report and cancer registries. We excluded 1,457 women with discrepant race and ethnicity information from these two sources, leaving 37,939 women for analysis. Each registry and the SCC received institutional review board approval for active or passive consenting processes or a waiver of consent to enroll participants, link data, and perform analytic studies. All procedures are Health Insurance Portability and Accountability Act (HIPAA) compliant and the registries and the SCC received a Federal Certificate of Confidentiality and other protection for the identities of women, physicians, and facilities involved in this research.We identified 43,489 women aged 35 to 89 years diagnosed with a first primary invasive breast cancer from 1996 to 2007 for whom risk factor information (mainly pre-diagnostic) was available (see below). Women with a history of ductal carcinoma BCSC registries collected similar questionnaire data at each mammography examination, including demographic information, zip code of residence, height, weight, reproductive history and menopausal hormone use. Income was defined as annual median values for zip codes of residence based on 2000 census data.Radiologists recorded breast density, assessed visually, according to the Breast Imaging Reporting and Data System (BI-RADS) in categories of increasing risk: a) almost entirely fat; b) scattered fibroglandular densities; c) heterogeneously dense and d) extremely dense.Visits at which records indicated that a mammogram was performed for screening, and which were not preceded by a mammogram within 9 months, were classified as screening visits. We estimated 5-year absolute breast cancer risk using questionnaire data (and BI-RADS density when included within a risk model) collected at the last screening visit prior to diagnosis or if unavailable, at another pre-diagnostic visit. We preferentially used risk factor data from the last screening visit 1–2 years prior to breast cancer diagnosis  or if unavailable, at a screening visit performed 2–5 years prior to diagnosis . Otherwise, we used data collected at the screening visit closest to the date of diagnosis within the interval from within one year prior to 30 days post-diagnosis . When questionnaires were unavailable for these visits, we used information collected with any mammogram during these periods using the same prioritization: 1–2 years prior to diagnosis , 2–5 years prior to diagnosis (n = 827) and one year prior to 30 days post-diagnosis .5] as previously reported.[We estimated absolute 5-year risk of developing breast cancer according to the BCSC-1 model  were collected. Treatment data included surgical procedure and administration of adjuvant therapy (yes/no).Breast cancer size, histological grade, estrogen receptor (ER) status, lymph node status and American Joint Committee on Cancer Collaborative Stage  or state records. Deaths were ascertained through 2008 or 2009, depending on registry. Women without death records were presumed to be alive through the last date of ascertainment.Absolute 5-year risks of developing breast cancer were estimated per model and grouped categorically: <1.0%; 1.0–1.66%; and ≥ 1.67% . To assWe computed hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of breast cancer death and death from unrelated causes after breast cancer diagnosis using Cox proportional hazards models. Proportional hazards assumptions were checked by examination of marginal survival plots.In unadjusted analyses, we compared breast cancer mortality  in each of the two highest categories of predicted risk of developing breast cancer to those in the lowest category (1.0% — 1.66% versus <1.0% and ≥1.67% versus <1.0%). Given that breast cancer death may show a non-linear dependence on age, we fit separate Cox models by categories of age of diagnosis: 35–44, 45–54, 55–69 and 70–89 years. Since the models predict risk of developing breast cancer, rather than risk of developing fatal breast cancer, we performed additional analyses to assess if observed associations are independent of factors related to prognosis that are not included in the models. We also assessed the association of the model predictions with risk of non-breast cancer death (i.e. competing risks). Of possible factors, age is most critical, because breast cancers among older women are generally less aggressive and these patients are more likely to die of unrelated causes.  AccordinAnalyses were conducted using SAS software, version 9.2 .Patient and tumor characteristics are presented in Outcomes over a median of more than 5 years of follow-up (range per model 5.4–5.6 years) included: BCRAT: 6,021 total deaths, with 2,993 (49.7%) related to breast cancer; BCSC-1: 5,742 total deaths, with 2,785 (48.5%) related to breast cancer and BCSC-5: 3,859 deaths, with 1,910 (49.5%) related to breast cancer.For descriptive purposes, we visually assessed relationships of patterns of predicted risk of developing breast cancer and selected clinicopathological tumor features  Tables. In unadjusted analyses, reflecting the application of models as developed, and including women with missing factors specified in models, women with the highest predicted risk of developing breast cancer (≥ 1.67%) were at significantly lower risk of breast cancer death than those at lowest predicted risk (<1.0%): BCSC-1: HR = 0.82 (95% CI = 0.75–0.90); BCRAT: HR = 0.72 (95% CI = 0.65–0.81) and BCSC-5: HR = 0.84 (95% CI = 0.75–0.94) . AnalyseRelationships of predicted risk of developing breast cancer were compared to breast cancer mortality by risk model, stratified by age at diagnosis and adjusted for continuous age, income, registry, year of diagnosis, mode of detection, stage and treatment . None ofRisk of developing breast cancer was not related to risk of non-breast cancer death in age stratified and adjusted models  Figs.This analysis evaluates whether risks of developing incident breast cancer, as assessed with three models, is related to risk of death among cases. These data have implications for both clinical practice and research.Clinically, the discussion of a new breast cancer diagnosis is stressful for both patients and clinicians, especially if a patient has received prior information about risk of developing breast cancer and used this information to decide about participating in screening and preventive interventions . Our anaOur case-only analysis demonstrates that the predicted risk of developing breast cancer, as estimated with any of three models used in the U.S., was inversely associated with risk of breast cancer death among cases, over a median follow-up of more than 5 years post-diagnosis. Consistent with these results, increased risk of developing breast cancer was associated with better prognostic features related to mode of detection, tumor size, grade, stage and ER status. Unadjusted analyses were based only on the risk scores generated with the models as originally developed. However, in evaluating mortality, we used adjustments for additional factors. With increasing age, breast cancer incidence increases, prognosis generally improves, and non-breast cancer deaths increase . Thus, tTools to identify women at increased risk of fatal breast cancers would facilitate prevention studies aimed at reducing mortality by guiding specification of inclusion criteria and determination of sample sizes. In the IBIS-1 trial, which employed a risk assessment tool not included herein based on family history and prior diagnosis of benign breast disease, administration of 20 mg of tamoxifen daily reduced breast cancer incidence by 29% compared with placebo. Nonetheless, a mortality benefit was not demonstrated, most likely (as the authors note) because the analysis was severely underpowered. AlthoughDeveloping models to predict clinically aggressive forms of breast cancer will be challenging, and was not the intent of this report. The development of a model to predict absolute risk of developing fatal breast cancer, would necessitate modeling of both the risk of incident cancer and the prognosis of such cancers. There is considerable evidence that breast cancer risk factors vary by tumor subtype and that different subtypes vary in clinical behavior, suggesting links between risk and tumor aggressiveness.  Given thStrengths of this study include the large database with detailed information about screening, prospectively collected risk information and pathological outcomes. Although some analyses were limited by missing data, this largely reflected the scope of the questionnaires employed at different registries, rather than systematic biases among individuals; sensitivity analyses restricted to women with complete data did not change overall conclusions. Although HRs were adjusted for treatment in broad categories, treatment would only confound associations if women with high risk scores, as evaluated prior to diagnosis, received less effective treatment. Attribution of cause of death may be misclassified, but unless non-random and frequent, it would be unlikely to alter our conclusions. Although ER-positive cancers may recur more than five years post-diagnosis, our power to assess these endpoints was limited. Finally, our conclusions are restricted to the three models evaluated, and are based on relating risk of developing cancer to fatality, only among cases.In summary, this analysis demonstrates that higher predicted risk of developing breast cancer, was not associated with higher risk of breast cancer mortality among cases, and was possibly related to lower mortality among some women with breast cancer. This information may be important to communicate to women who have received information about risk of developing cancer in the past and are now receiving a new breast cancer diagnosis. In addition, the development of models to predict risk of potentially fatal breast cancers could facilitate efficient planning of research to reduce breast cancer deaths through targeted early detection or prevention.S1 Fig(DOCX)Click here for additional data file.S2 Fig(DOCX)Click here for additional data file.S3 Fig(DOCX)Click here for additional data file.S4 Fig(DOCX)Click here for additional data file.S5 Fig(DOCX)Click here for additional data file.S6 Fig(DOCX)Click here for additional data file.S7 Fig(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.


Alcohol consumption is associated with higher breast cancer risk. While studies suggest a modest association between alcohol intake and mammographic density, few studies have examined the association in racial/ethnic minority populations.We assessed dense breast area and total breast area from digitized film mammograms in an urban cohort of African American (42%), African Caribbean (22%), white (22%), and Hispanic Caribbean (9%) women . We examined the association between alcohol intake and mammographic density (percent density and dense area). We used linear regression to examine mean differences in mammographic density across alcohol intake categories. We considered confounding by age, body mass index (BMI), hormone contraceptive use, family history of breast cancer, menopausal status, smoking status, nativity, race/ethnicity, age at first birth, and parity.2, drinkers consuming >7 servings/week of alcohol had a 17% increase in percent density compared to nondrinkers  and there was no association in women with a BMI ≥ 25 kg/m2  after adjusting for age and BMI (continuous).Fifty percent currently consumed alcohol. Women who consumed >7 servings/week of alcohol, but not those consuming ≤7 servings/week, had higher percent density compared to nondrinkers after full adjustments  1.8, 14.6; ≤7 β = -0.5, 95% CI -3.7, 2.8). There was a positive association between high alcohol intake and dense area after full adjustments . We did not observe race/ethnicity modification of the association between alcohol intake and percent density. In women with a BMI of <25 kg/m2, had higher percent density.In a racially/ethnically diverse cohort, women who consumed >7 servings/week of alcohol, especially those with a BMI < 25 kg/m Breast density, or mammographic density, is one of the strongest intermediate markers for breast cancer - women with high mammographic densities have a 4-6 fold increase risk of developing breast cancer in comparison to those with low mammographic densities . Unlike Alcohol intake has been consistently associated with breast cancer in the range of a 7-12% increased relative risk for every 10 grams per day of ethanol intake ,4. With Alcohol consumption is a modifiable breast cancer risk factor that may impact breast cancer risk via mammographic density. Breast cancer incidence and tumor characteristics show substantial variation by race/ethnicity, with Hispanic and African American women having lower odds of early stage breast cancer diagnosis and African American women experiencing higher incidence of invasive breast cancer in younger ages ,26,27. ANew York City Multiethnic Breast Cancer Project is a collaborative study between Columbia University in Manhattan and Long Island University and Long Island College Hospital in Brooklyn (for details see .Studies are inconsistent as to whether mammographic density varies across race/ethnicity ,32-42. W2 than in women with higher BMI. This is consistent with multiple breast cancer studies that show the positive association between lifetime alcohol intake and breast cancer risk is strongest in leaner women [2 were women of African descent, this may explain why we do not see a strong association between high levels of alcohol intake (>7 servings/week) and mammographic density in women of African descent. Fat tissue can contribute to estrogen production which can lead to increased breast cancer risk [Limited studies ascertain the association between alcohol and multiple measures of mammographic density . While oer women -68. In aer women . In a muer women . If assocer risk -71. Ther2; these two analyses may be capturing similarities and in fact for women consuming >7 servings/week of alcohol with a BMI < 25 kg/m2, 4 of the 5 women were white. Further, we are unable to examine the associations between alcohol intake and mammographic density stratified by nativity given the small number of women that consume high amounts of alcohol (>7 servings/week) and are born outside the US (n = 2). We also did not assess levels of alcohol intake in earlier life periods; however, many studies have shown that current alcohol, and not past alcohol intake, is associated with increased mammographic density [Limitations of our study include the possibility of information bias due to self-reported alcohol intake. However, women being screened likely did not know their mammographic density resulting in non-differential bias. People are also known to under-report alcohol intake, which would result in an under-estimation of the magnitude of association. Our study is limited in the number of women who reported consuming >7 servings/week (n = 14), which contributed to large confidence intervals. However, when we modeled alcohol intake as a continuous variable we confirmed the positive relationship between alcohol intake and mammographic density. We also acknowledge that given the estimates observed for white women are similar to the estimates observed for women with a BMI < 25 kg/m density ,19,50.Mammographic density is one of the strongest intermediate markers for breast cancer risk and is regularly clinically screened at mammography visits. With over one-third of states passing a version of the Breast Density Notification Law that mandates release of high mammographic density information to women, women may begin to seek information on how to modify their mammographic density to reduce their breast cancer risk. Alcohol consumption has been consistently associated with breast cancer risk and our study supports an association with increased mammographic density. Future studies should evaluate whether decreasing alcohol intake is associated with a reduction in mammographic density. Identifying women at higher risk of breast cancer because of their mammographic density would be an important time to reinforce prevention messages about alcohol intake. Further, investigating differences in alcohol and mammographic density association in women with different body size and racial and ethnic backgrounds can inform etiologic research as well as prevention efforts.


Multigene panels can be a cost- and time-effective alternative to sequentially testing multiple genes, especially with a mixed family cancer phenotype. However, moving beyond our single-gene testing paradigm has unveiled many new challenges to the clinician. The purpose of this article is to familiarize the reader with some of the challenges, as well as potential opportunities, of expanded hereditary cancer panel testing.CDH1, TP53, PMS2, PALB2, CHEK2, NBN, and RAD51C.We include results from 348 commercial multigene panel tests ordered from January 1, 2014, through October 1, 2014, by clinicians associated with the City of Hope’s Clinical Cancer Genetics Community of Practice. We also discuss specific challenging cases that arose during this period involving abnormalities in the genes: BRCA1, BRCA2, MSH6, PMS2, TP53, APC, CDH1), the results would have been positive only 6.2% of the time, instead of 17%. Results returned with variants of uncertain significance (VUS) 42% of the time.If historically high risk genes only were included in the panels  can be accessed to better clarify counseling and management for the patient and family. For pathogenic variants in low and moderate risk genes, empiric risk modeling based on the patient’s personal and family history of cancer may supersede gene-specific risk. Commercial laboratory and patient contributions to public databases and research efforts will be needed to better classify variants and reduce clinical ambiguity of multigene panels. An interdisciplinary medical practice that employs a growing arsenal of genetic and genomic tools to identify individuals and families with inherited cancer risk , geneticMoving beyond single-gene testing has unveiled new challenges to the clinician involved in providing GCRA. Since the implementation of multigene panels, significant gaps in our gene-specific phenotypic knowledge base have been identified. The prevalence of variants of uncertain significance (VUS), unexpected findings, such as “off-phenotypic-target” gene mutations, and pathogenic findings in low and moderate risk genes challenge the established counseling repertoire. Even in the case of mutations in highly actionable genes, expanded panel testing can lead to unexpected findings. The purpose of this article is to illustrate some of the challenges and opportunities associated with expanded hereditary cancer panel tests, many of which include both well-characterized and lesser known cancer-associated genes. We also provide a conceptual framework according to evidence for clinical utility to help classify low, moderate, and high risk cancer predisposing genes Figure ; Table 1Since the advent of lower-cost next-generation sequencing, multigene panels now include 5–60 genes –74. SomeThe City of Hope Division of Clinical Cancer Genetics (CCG) includes a cancer screening and prevention program, cancer genetics education program, and research program. The Clinical Cancer Genetics Community of Practice (CCGCoP) was established as a multifaceted program of GCRA training and ongoing distance-mediated practice support for community-based clinicians, funded by the NCI R25CA171998) , 80. Mem5CA171998The results from 348 commercial multigene panel tests ordered from January 1, 2014, through October 1, 2014, are shown in Figure MUTYH-associated polyposis or attenuated familial adenomatous polyposis (AFAP), a multigene cancer panel was chosen to try and better understand potential hereditable cancer risk. He was found to carry a pathogenic mutation in CDH1, designated c.283C > T.Case 1 is a 48-year-old male of Chinese ancestry diagnosed with metastatic left-sided adenocarcinoma of the colon at age 45. Given his young age at onset he was referred for GCRA. His family history was devoid of other cancers Figure . In the CDH1 is a tumor suppressor gene that encodes epithelial cadherin. Germline mutations have been associated with hereditary diffuse gastric cancer (HDGC), a rare autosomal dominant condition historically thought to be highly penetrant, with evidence to suggest a cumulative diffuse gastric cancer risk of 80% by 80 years. Women with HGDC also have a 39–52% risk for lobular breast cancer , or the familial penetrance of gastric cancer is low with this mutation; similar to the above family previously reported in the literature  could be another possibility. Either way, in this situation testing for all first-degree relatives was recommended to clarify if there are other individuals at elevated cancer risk. His children were recommended to have testing between the ages of 18 and 21. For individuals identified with the mutation, gastrectomy would need to be considered since DGC surveillance has unproven value  is a hereditary cancer syndrome associated with heterozygous germline mutations in TP53 –85. LifeTP53 . AlthougTP53 , 87. TheTP53 ; 18/33 uTP53 . For aduTP53 . This stTP53 , 86. PreTP53 . Howeverde novo finding, or hematological or other malignancy. No additional information from the laboratory or literature regarding the specific variant was available. Concern about apparent clonal hematopoiesis with a TP53 mutation as a manifestation of an occult hematological malignancy led to recommendations for a baseline CBC , as well as annual screening CBC. There were no available living family members to help clarify the results any further. Given that constitutional mosaicism for the TP53 mutation could not be excluded, it was decided that high risk breast screening with addition of breast MRI and clinical breast exams every 6 months was justified. This approach was also supported by the fact that empiric risk model estimates indicated that the patient had moderately elevated breast cancer risk (>20%) based on her family history . Meeting the National Comprehensive Cancer Network (NCCN) hereditary breast and ovarian cancer syndrome (HBOC) genetic testing criteria , the patPMS2 mutations are associated with LS, a condition that increases the risk for developing CRC, uterine, ovarian, hepatobiliary, urinary tract, brain, skin, and other gastrointestinal malignancies  . Limited data exist regarding the exact risk estimates of other extra-colonic cancers  . In addi cancers , 96, 97.PMS2 mutation if there was papillary serous histology vs. endometrioid. Nonetheless, she was counseled that the detected mutation confers modestly elevated risk for CRC for her, and that testing other family members was recommended. Recommendations were made for a colonoscopy with repeat every 1–2 years per NCCN guidelines  following CRC among women with MMR gene mutations; however, the majority of the MMR genes in the report were MSH2 and MLH1 (both thought to be associated with greater cancer risk) . Therefoidelines , 99. ConPALB2 gene mutation .Case 4 is an 80-year-old woman of Northern European ancestry referred for GCRA after her daughter was found to carry a pathogenic PALB2 cause Fanconi Anemia type N, characterized by growth retardation, developmental disabilities and a high risk for pediatric solid tumors   interacts with BRCA2 in the repair of DNA double strand breaks. Biallelic mutations in d tumors . Monoallt cancer , 32, 101 cohorts –104. Antfamilies , 106. ThR = 5.9) , 108, whPALB2 mutations to recommend consideration of risk-reducing bilateral mastectomy, especially in a post-menopausal patient. Furthermore, there is no consensus at this point regarding consideration of risk reduction salpingo-oophorectomy or application of pancreatic surveillance in PALB2 carriers. She was recommended to continue enhanced breast cancer surveillance. Given the lack of other cancers in the family, her ovarian cancer risk was estimated at 5–10%, and her pancreatic cancer risk was estimated to be <5%. Given the strong history of CRC and polyps in the family, the patient’s sisters were recommended to pursue their own GCRAs on the assumption that there may be a separate genetic issue for them. Despite uninformative (negative) genetic testing for the LS genes  in the patient’s daughter, she was recommended to pursue MSI and IHC for the respective MMR proteins on her CRC to help delineate the tumor phenotype, as a small proportion of such cases can show a defective MMR profile due to acquired (somatic) MMR mutations, or rarely, suggest a germline gene mutation undetectable by standard testing techniques.The patient was the only one in her family with a breast cancer diagnosis. At this point, there is insufficient evidence about new primary breast cancer risk associated with BRCA1 and BRCA2 testing, a multigene panel that included other breast cancer predisposition genes was offered and completed. Testing revealed a suspected deleterious splice site mutation in CHEK2, designated c.846 + 1G > A.Case 5 is a 55-year-old woman of Northern European ancestry with a recent history of an estrogen receptor positive (ER+) invasive lobular breast cancer and atypical ductal hyperplasia in the contralateral breast. She underwent bilateral mastectomy and was prescribed Tamoxifen. Her family history Figure . Given tCHEK2 encodes the checkpoint kinase 2 protein, and germline CHEK2 mutations have been associated moderately elevated risk for breast cancer, with an odds ratio of 2.7 for unselected breast cancer cases . E. ECHEK2 carriers , 55. Howommended . Moreovesk model . TherefoCHEK2 will change the care for family members who have elevated empiric risks already, it may illuminate cancer risks that are not apparent based on the family history alone. For example, the twofold elevated risk for CRC associated with a CHEK2 mutation prompted a recommendation for enhanced surveillance with colonoscopy every 5 years beginning at age 40, in addition to the recommendation for annual breast MRI , a rare autosomal recessive disorder associated with immunodeficiency, dysmorphic features, and high risk of lymphoid malignancy , is part of the RAD51 gene family and is essential for homologous recombination repair. Biallelic mutations in this gene can cause a Fanconi anemia-like phenotype, and current evidence suggests that monoallelic mutations confer a moderately increased risk for ovarian cancer  . HoweverRAD51C mRNA, therefore, it could potentially interfere with RNA processing, hence protein production/function; or it may do nothing at all to the protein. The patient was counseled about the uninformative result and ambiguous interpretation. Given the absence of ovarian cancer in the family, the ambiguous test result, and her young age, we did not recommend bilateral salpingo-oophorectomy. Additionally, we did not recommend further testing for this variant within her family at this time. A plan was made to see her again in 2–3 years, with the hope that more information will be known about this particular finding and the absolute cancer risks associated with RAD51C. The patient remained understandably concerned about her personal and family’s risk for future cancers, especially ovarian.Regardless, VUS should be treated and reported to the patient as an uninformative finding until more information is known. However, this particular mutation was reported as a variant of intermediate significance rather than a VUS. The variant lies in the non-translated region of the CDH1, TP53, PMS2 cases above) the results can be particularly challenging. Findings that are “off-phenotype” (not known to be associated with the particular underlying cancer) may suggest rare or novel genotype–phenotype correlations, mosaic or de novo findings, limitations in family structure or simply incidental findings from broad panel testing. However, one is usually compelled to make management recommendations based on genotype when pathogenic mutations in high cancer risk genes are discovered, instead of on the family history or phenotype alone. However, as in the mosaic TP53 case above, the finding of a pathogenic variant in a highly penetrant hereditary cancer syndrome gene in only a subset of the patient’s DNA added another level of management complexity. In that particular case, after a thorough discussion with the patient regarding her various options, management was based mainly on familial empiric risks, instead of genotype alone. The heterozygous PMS2 case demonstrates the importance of providing thorough pre-test counseling and informed consent for unanticipated results, especially when pan-cancer multigene panel testing is pursued. This case also demonstrates the obstacle of redirecting the patient’s focus on cancer risks that may not have been expected prior to testing.The above cases highlight the complexities inherent in the use of multigene panels that include low and moderate cancer risk genes, as well as the potential that a higher risk variant discordant with the personal or family cancer phenotype may be detected in some patients. GCRA, counseling, and management recommendations are often complicated by a lack of family information and mutation tracking information, a crucial component for pedigree-based studies. When pathogenic mutations in high risk genes are incidental  . Currently, it is not clear how to use low cancer risk genes in management and risk counseling , since recommendations should be based either way on the personal and family history of cancer.Will it change medical and/or surgical management? Can screening and/or surveillance be altered? Currently, consensus guidelines to answer these questions are lacking for many moderate and low risk cancer predisposing genes included in many commercially available multigene panels. Figure CHEK2 and NBN cases above, outside of specific founder mutations, cancer-related risks for these genes remain ambiguous. Even though ATM is considered a moderate risk (20–25%) breast cancer predisposition gene, two specific mutations (c.7271T > G and IVS10-6T > G) were estimated to confer a 60% cumulative lifetime risk of breast cancer  has been associated with an eightfold risk for ovarian cancer . In challenging cases, patient follow-up every 1–3 years may be prudent until the patient and family recommendations can be better clarified. Multigene panels are here to stay, therefore, we must collectively continue to clarify the absolute and relative cancer risks, delineate genotype–phenotype correlations, and reclassify variants of unknown significance. This can only be done with laboratory transparency of testing results and through the help of collaborative research studies that merge genetic findings with phenotypic data.In summary, multigene hereditary cancer panel testing can lead to unexpected and complex findings. This stresses the importance of appropriate pre-test counseling and informed consent by a knowledgeable genetics professional . AdditioThe 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.Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Numbers P30CA33572 and R25CA171998 (Pls: KRB and JNW) and RC4CA153828-01 (PI: JNW). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Health.


We examined the association between low-to-moderate alcohol intake and breast cancer subtypes by tumor hormone receptor status.Alcohol is a well-established risk factor for breast cancer, but pathways involved in alcoholA hospital-based case-control study was performed in 585 cases and 1,170 controls. Information on alcohol intake and other risk factors was collected via a questionnaire. Logistic regression was used for analyses. All statistical tests were two-sided.The odds ratio of breast cancer was 1.75  in women who consumed ≤5 drinks/week, and 3.13 (95% CI: 1.81–5.43) in women who consumed >5 drinks/week, both compared with non-drinkers for ≥10 years, after adjustment for age and other confounders. The association of alcohol intake with estrogen receptor-positive breast cancer was stronger than with estrogen receptor-negative: the odds ratio per 1 category increase was 2.05 (95% CI: 1.49–2.82) and 1.29 (95% CI: 0.85–1.94) (P-heterogeneity = 0.07). There was no evidence of an interaction between alcohol intake and menopausal status (P = 0.19) in overall group; however, it was significant in estrogen receptor-positive breast cancer (P = 0.04).Low-to-moderate alcohol intake is associated with the risk of estrogen receptor-positive breast cancer with the strongest association in postmenopausal women. Since alcohol intake is a modifiable risk factor of breast cancer, every woman should be informed and advised to control alcohol use. Many epidemiological studies have investigated the relationship between alcohol consumption and breast cancer risk . An incrThe underlying biological mechanism of the relationship between alcohol intake and breast cancer is not clearly defined . HoweverA significant increase in risk of estrogen receptor-positive (ER+) and/or estrogen receptor- and progesterone receptor-positive (ER+/PR+) breast cancer due to alcohol intake has been reported, but no increase in risk of estrogen receptor-negative (ER-) and/or estrogen receptor- and progesterone receptor-negative (ER-/PR-) breast cancer –5, 20–23This case-control study aimed to explore the association of low-to-moderate levels of alcohol consumption with risk of breast cancer subtypes defined by tumor hormone receptor status.We performed a hospital-based case–control study of breast cancer in the Hospital of Lithuanian University of Health Sciences. The cases  were women aged 28–90 years with new histologically confirmed breast cancer (C50 and D05 according to ICD10) diagnosed between 1 March 2007 and 10 January 2011, who required surgical intervention at the Department of Surgery and were free from other cancer diagnosed in the past. The controls  were women without a personal history of cancer hospitalized to other departments  of the hospital within the study period. Controls presented with a wide spectrum of non-neoplastic disorders and diseases of (a) eye , (b) ear-nose-throat , (c) nervous , and (d) cardiovascular  systems. Controls were individually matched to cases by age (±5 years) in a 2:1 ratio. The study protocol was approved by the Kaunas Regional Biomedical Research Ethics Committee . Written consent to complete the questionnaire and collect biological media specimens was received from each individual.Both cases and controls completed a self-administered structured questionnaire previously demonstrated to be valid and reliable for collection of demographic and socioeconomic characteristics, medical history, height and weight, family history of cancer, reproductive history, and lifestyle characteristics .Alcohol consumption was assessed by a question about the frequency/quantity of the use of three different types of alcoholic beverages such as spirits , wine, and beer. The frequency of consumption was assigned to one of seven categories of never, once per two months, 1–3 times a month, once a week, 2–3 times a week, 4–6 times a week, every day. We also asked about quantities for each type of alcoholic beverage consumed in milliliters (ml). Assessment of alcohol consumption was based on an individual’s usual drinking habits. A recall period was set at one year before cancer diagnosis (cases) or the last admission to hospital (controls). We also ascertained alcohol consumption habits by the responses: “yes”, “gave up… years or… months ago”, “no, I have never used” to a question “Do/did you drink alcoholic beverages?” Therefore, if there was any recent change in habits or quitting drinking, information was sought on the respondent’s habits before the change.3] for spirits or 120 ml [0.12 m3] for wine or 250 ml [0.25 m3] for beer, i.e. an amount of a specific alcohol type that contains about 10 g [0.01 kg] of alcohol  of spirits or 120 ml [0.12 m3] of wine or 250 ml [0.25 m3] of beer  of pure ethanol that was in 32 ml [0.032 m of beer . However of beer . Neverth of beer , for theIn conclusion, this study provides evidence that the association between low-to-moderate alcohol intake and risk of breast cancer differs by tumor hormone receptor status, with a stronger risk demonstrated for estrogen receptor-positive breast cancer. The results show that alcohol/estrogen receptor-positive breast cancer association differs by menopausal status. Further studies are necessary to define whether the association with alcohol consumption varies by menopausal status independently of other risk factors. Since alcohol intake is a modifiable risk factor of breast cancer, the findings are very important to public health and primary health care workers that could inform and advise women to control alcohol consumption.S1 Data(DTA)Click here for additional data file.