Also, women with non-menstrually-related migraine had increased risk ) while women with menstrually-related migraine had decreased risk ) of hormone-receptor-negative (ER−/PR−) cancer, with a significant contrast in estimated effects (P = 0.005). While replication of these subset-based findings will be needed, effect specificity could suggest that while migraine has little overall association with breast cancer, menstrual migraine may be associated with reduced risk of ER−/PR− breast cancer.Migraine headache is often timed with the menstrual cycle. Some studies have reported reduced risk of breast cancer in migraineurs but most of those did not distinguish menstrually-related from non-menstrually-related migraine. To examine the possible associations between breast cancer and migraine overall and between cancer subcategories and the two migraine subtypes, we used a cohort study of 50,884 women whose sister had breast cancer and a sister-matched case-control study including 1,418 young-onset (<50 years) breast cancer cases. We analyzed the two studies individually and also in tandem via a hybrid Cox model, examining subcategories of breast cancer in relation to menstrually-related and non-menstrually-related migraine. History of migraine was not associated with breast cancer overall. Migraine showed an inverse association with ductal carcinoma  Migraine headache is a common and chronic disorder that occurs more often in women than menMigraine can be sensitive to hormones. Approximately 50% of women with migraine report that attacks tend to be synchronized with their menstrual cycle5Breast cancer is also related to hormones: higher rates are seen in women with early age at menarche, late age at first birth, and late age at menopause791112in situ (DCIS), estrogen-receptor/progesterone-receptor (ER/PR) positive versus negative, and hormone receptor negative and HER2 negative (triple negative) versus others) in relation to menstrually-related and other migraine. Our objective was to determine whether migraine per se was associated with the risk of breast cancer and whether that association differed by tumor subtype or was modified by whether or not the migraine was menstrually related. We took advantage of two large studies that had used very different designs: one (Sister Study) was prospective, population-based and required a first-degree family history, while the other (Two Sister Study) was retrospective, family-based and included only about 20% with a first-degree family history. Because the two could be analyzed in a way that ensured statistical independence of findings, we were able to assess reproducibility of findings.An association between migraine and breast cancer risk has been hypothesized. Several studies reported an inverse association, with 10–30% reduction in risk in women with a migraine history1617http://sisterstudy.niehs.nih.gov/English/about.htm), who were age 35 to 74 at enrollment in 2004–2009 and had a sister with breast cancer, but had never been diagnosed with breast cancer themselvesThe Sister Study recruited 50,884 women in the United States and Puerto Rico (http://www.sisterstudy.niehs.nih.gov/English/2sis.htm) is a family-based retrospective case-control study ancillary to the Sister Study. With the help of already-identified Sister Study participants, we enrolled case sisters who had been diagnosed recently (within 4 years) and under age 50. Enrollment took place from September 2008 to December 2010. Both the Sister Study and the Two Sister Study secured informed consent and were carried out with human subjects approval and oversight from the NIEHS Institutional Review Board and the Copernicus Group Institutional Review Board. Both studies were carried out in accordance with the approved guidelines.The Two Sister Study ) were ascertained from medical records (80%–89%) when available, or from self-report (11%–20%). Agreement between these two sources was excellentThe baseline questionnaire included the question: “Has a doctor or other health professional ever told you that you had migraine headaches?” Those who responded “Yes” were then asked the age at which that diagnosis had been made. Responses to the additional question “Have you ever noticed a pattern where your migraine headaches got worse at certain times of your menstrual cycles?” were used to classify migraine as menstrual versus nonmenstrual. Women with both types were categorized as having menstrual migraines. We also collected data on use of migraine medications, for sensitivity analyses. Data were not collected on family history of migraine.Data from the prospective Sister Study cohort was modeled using Cox proportional hazards regression, with age as the primary time scale. Follow-up began at enrollment  and ended at breast cancer diagnosis or (for women remaining without breast cancer) age at most recent follow-up. For assessing associations with specific subcategories of breast cancer, diagnoses of other types or of unknown subcategory were treated as censoring events that truncated time at risk.Cox proportional hazards regression is equivalent to conditional logistic regression with fine stratification on ages at events, and data from the Two Sister Study were also analyzed with conditional logistic regression, but with additional stratification on sibship. For many families the matched control sister was older than their case sister, because eligible case sisters had to have been under age 50 at diagnosis by design. We used “index age” to ensure comparable opportunity for time-dependent exposures in within-sibship comparisons, as previously describedWe also carried out completely separate analyses and used meta-analyses to combine the results of the separately-analyzed two studies (with inverse variance weighting) to confirm that the point estimates based on combined-analysis and meta-analysis were similar.Despite the fact that some of those followed in the Sister Study also served as controls for the Two Sister Study, the two studies provide statistically independent inference. This independence arises from the fact that the overall likelihood is the product of the two likelihoods. The Cox model  treats outcomes at different event times as statistically independent (under a Markov assumption), and controls are used over and over again in the same analysis, until they become cases. One consequence is that the overall likelihood is the product of many separate likelihoods, one for each event time. The control sister for the Two Sister Study was eligible to be a control because she was free of cancer at the age when her sister was diagnosed. Her own subsequent experience with breast cancer risk in the Sister Study follow-up was analyzed prospectively. To ensure that the two studies contributed independently to the analysis, we started the clock for the Sister Study likelihood either at the participant’s age at completion of enrollment or, if she was also serving as a control for Two Sister, at the age when her proband sister was diagnosed, whichever was later. Thus the two designs are separable and provide non-overlapping, statistically independent inference.in situ (DCIS). The invasive cancer subgroup analyses were further divided into tumor-based estrogen receptor/progesterone receptor (ER/PR) status subtypes. Cases missing ER/PR status were treated as censored at diagnosis for the Sister Study and were excluded for Two Sister. We adjusted for the following potential confounders identified by consideration of directed acyclic graphs (DAG)23Migraine history was coded as either a binary variable or a three-level variable . A small number of women who did not specify menstrually-related or not  were treated as nonmenstrually-related, presuming that a relationship with menses would have been noticed. We separately evaluated association with invasive breast cancer and ductal carcinoma All analyses were done using the SAS software, PHREG and LOGISTIC procedures, version 9.3 . All statistical tests were two-sided.Similar percentages of women in the Sister (20.7%) and Two Sister (18.5%) studies reported migraine history and among them similar percentages, 44.5% (Sister) and 45.5% (Two Sister), reported their migraine tended to be timed to the menstrual cycle, referred to as menstrually-related migraine. As shown in P = 0.005) and the same contrasting effect directions were seen in both of the two studies. Again the meta-analysis results were similar to the combined-analysis results  and 0.61  for menstrually-related and nonmenstrually-related migraine, respectively). Similar associations were observed for the subcategory of invasive ER−/PR−/HER2− cancer  for nonmenstrually-related migraine, HR = 1.04  for menstrually-related migraine) . For inv− cancer . We did P = 0.06) (P = 0.044). The risk for other subcategories or DCIS versus non-DCIS did not differ appreciably by migraine type.In a case-only analysis of invasive breast cancer modeling the odds of ER negative cancer, conditional on cancer having occurred, nonmenstrually-related migraine was positively associated with estrogen-receptor negative (ER−) cancer whereas menstrually-related migraine was negatively associated with estrogen-receptor negative (ER−) cancer  . In a moIn a sensitivity analysis, we only categorized women as having migraine if they reported both a positive migraine history and a history of use of migraine medication. Similar, but slightly stronger, associations for DCIS and ER−/PR− cancers were observed with this stricter migraine definition (data not shown). We reanalyzed our data focusing on histological subtypes and did not find any association in either ductal or lobular invasive breast cancer. (Data not shown.).We analyzed a sister-matched case-control study and a cohort study and neither showed an overall association between self-reported migraine headache and breast cancer. There was evidence for an inverse association between migraine and DCIS in the cohort study, and in the combined analysis, but limited evidence for that association in the Two Sister Study. However, the Two Sister Study included few cases with DCIS, and there was considerable overlap in the confidence intervals, indicating no important inconsistency between the two studies.We considered whether medical screening bias could be a factor, since the Sister Study cohort participants all have a first-degree family history of breast cancer, while the majority of cases in the retrospective Two Sister Study did not have a first-degree family history. Women with a sister with breast cancer who themselves have migraine may be more likely, because of their own chronic condition, to have regular medical care and hence also to be screened for breast cancer. However, instead of an inverse association, one would expect to see a positive association between migraine and DCIS if there were screening bias in the Sister Study, whereas the association we saw was negative.Migraine, like breast cancer, is an estrogen-sensitive disorder that primarily affects womenWhen we subcategorized migraine as menstrually-related versus nonmenstrually-related, and considered hormone-receptor-negative breast cancer, patterns emerged that were similar in the two studies. We saw increased estimated risk for hormone-insensitive ER−/PR− breast cancer in women reporting nonmenstrually-related migraine and decreased risk in women reporting menstrually-related migraine. Thus data from both studies are consistent with the possibility that women with hormone-insensitive migraine are at relatively increased risk for the more aggressive hormone-receptor-negative breast cancer.et al.et al. (2010)et al.et al. (2009)et al. (2013)et al.et al.et al. (2010)in situ breast cancer and found an inverse association with migraine, which was not statistically significant but is consistent with our finding. However, Winter et al.19et al. (2015)The existing literature on migraine and breast cancer is mixed. Three case-control1718161916171819et al. (OR = 0.87 (0.56–1.36))et al. (2009) (OR = 0.83 (0.70–0.99))et al. (2010) )et al. )Previous studies that did not categorize migraine by hormone sensitivity showed diverse results regarding the association between migraine and ER−/PR− breast cancer risk. An inverse association was reported by Mathes et al.et al.In our analysis, an association of migraine with breast cancer was not seen in general. However, with further exploration a relationship with ER−/PR− cancer was seen when we categorized migraine by hormone sensitivity. This observation, based on subcategories, would require replication. Among the six previous publications, only Lowry Some limitations of our study are worth mentioning. Information on migraine history was self-reported and some misclassification may exist. Nevertheless, a re-analysis of the data by categorizing women as having migraine only if they also reported use of migraine medication produced similar results to those based on the original self-reported migraine status.We also have used self-reported information on whether their migraine attacks tended to be timed with the menstrual cycle, as “menstrually-related migraine,” rather than the stricter category of “menstrual migraine” defined by the International Headache SocietyFinally, for the Sister Study we used information collected at baseline, without updating it during follow-up. However, considering that 93% of migraine cases are diagnosed before age 50 Our study has several strengths. One is that the findings with respect to ER−/PR− breast cancer were reproduced in two studies with very different designs : a largeIn summary, using data from a prospective cohort study and a sister-controlled retrospective study of breast cancer we found evidence that migraine is negatively associated with DCIS. However, the DCIS association was based on the Sister Study cohort and was not observed in the Two Sister Study.et al.When attention was turned instead to invasive ER−/PR− breast cancer, we identified statistically significant heterogeneity in risk in women with nonmenstrually-related versus menstrually-related migraine, with the same pattern evident in both studies. This observation, while needing future confirmation, suggests that women with hormone-insensitive migraine who develop breast cancer may be more likely to produce a hormone-insensitive ER−/PR− tumor. The inverse observation that a history of menstrually-related migraine appears to be protective against ER−/PR− breast cancer has now been noted twice .


Several single nucleotide polymorphisms have been identified in cyclooxygenase-2 (COX-2) genes , −1195G>A (rs689466), and 8473 C>T (rs5275)). The association of these SNPs with the risk of different cancer types is still controversial. This study aims to evaluate the correlation between these SNPs and breast cancer risk in different ethnic groups. We have searched PubMed, Web of Knowledge, and Embase for relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the strength of the associations. A total of 13 studies  were eligible for meta-analysis. This meta-analysis showed that COX-2 rs20417 polymorphism was correlated with an increased risk of breast cancer in Caucasians, while rs689466 was associated with a decreased risk of breast cancer in Caucasians. The rs5275 polymorphism had no association with breast cancer risk. Breast cancer is the most common cancer in women worldwide . It is a in vitro and prevented the occurrence of rat breast cancer chemically induced by DMBA  in the COX-2 gene and breast cancer risk.P = 0.03). Moreover, in a stratified analysis by ethnicity using the recessive model, we found that the association remained in Caucasians , but not in Asians. These results suggest ethnic differences in genetic backgrounds and the environment in which they live play a possible role in breast carcinogenesis [A previous study by Yu et al.  failed togenesis .In Zhu et al.'s meta-analysis , they shP = 0.34; heterozygote comparison: OR = 0.99, 95% CI = 0.95–1.04, P = 0.81; dominant model: OR = 1.02, 95% CI = 0.98–1.07, P = 0.33, and recessive model: OR = 1.04, 95% CI = 0.97–1.12, P = 0.27). When stratified by ethnicity, similar results were observed in both Caucasians and Asians.In the present meta-analysis, 13 studies with 15,017 cases and 18,901 controls concerning the rs5275 polymorphism were included. We found no significant association of rs5275 polymorphism with breast cancer risk . In the stratified analysis, when analyzed by the dominant model, the OR was 0.88 (95% CI = 0.83–0.94) (P < 0.0001) among Caucasians.In the previous meta-analysis by Tang et al. , there wSome limitations of this meta-analysis should be noted. Firstly, this meta-analysis was based on pooled data and no individual data was available; thus, we could not assess the risk of cancer according to stratification by age, environment factors, and other risk factors of breast cancer. Secondly, most of the included studies did not investigate the chronic inflammatory condition and the history of taking nonsteroidal anti-inflammatory drugs. Thirdly, the included studies are mainly based on Caucasian background. There were only two studies based on Asian background and one based on African background. Larger scale multicenter studies based on Asians or Africans are warranted to further validate the association between COX-2 polymorphisms and breast cancer risk.In summary, this meta-analysis points to the COX-2 rs20417 C allele as a risk factor for breast cancer among Caucasian subjects. On the contrary, the rs689466 allele has a decreased risk of breast cancer in Caucasians. The rs5275 C status does not seem capable of predicting breast cancer risk in both Caucasians and Asians.


Breast cancer with oestrogen receptor expression is common in older women. Several factors, such as age and reproductive hormone exposure, have been associated with oestrogen receptor expression in breast cancer. However, the association between comorbidities and the oestrogen receptor expression has been poorly studied. We hypothesized that there was an association between burden comorbidity and breast cancer with oestrogen receptor expression in older women.To determine whether oestrogen receptor expression in breast cancer was associated with burden comorbidity in community-dwelling women.A total of 1,707 women with breast cancer registered on the list of a breast cancer registry were included. The recorded data included: age, Charlson Comorbidity Index score≥1, breast cancer characteristics , and breast cancer pathological stage .Breast cancer with oestrogen receptor expression was identified in 1,378 patients (80·7%). The fully-adjusted logistic regression showed that oestrogen receptor expression was associated with Charlson Comorbidity Index score≥1 , progesterone receptor expression , human epidermal growth factor receptor , age , Scarff Bloom Richardson grade II and grade III .Our findings provide new data showing an independent positive association between burden comorbidity and breast cancer with oestrogen receptor expression. This result confirms that evaluation of oestrogen receptor expression in breast cancer should not be limited to hormonal factors stratified by age. Breast cancer (BC) is the most commonly diagnosed cancer in women in the United States (US) and Europe Several factors, such as age and exposure to reproductive hormones, have been associated with ER+ in BC Only a few studies have examined the association between comorbidities and BC with ER+. These studies reported mixed results The study was conducted in accordance with the ethical standards set forth in the Helsinki Declaration (1983). The Angers Ethical Committee approved the study protocol and the study is in compliance with the Strengthening the Reporting of Observational Studies in Epidemiology statement guidelines. The institutional review board waived the need for written informed consent from the participants. Waiving of consent was authorized for this study according to French law.A total of 1,855 women with BC were included in this cross-sectional study. All participants were registered on three cancer registries involving the following French administrative areas: Doubs, Loire-Atlantique, and Tarn. The inclusion criterion for the study was BC diagnosis in 2007. The exclusion criterion was male gender. Information collected by the BC registry came from several databases involving public and private pathology laboratories and hospitals, the regional French National Health System, and Comprehensive Cancer Centres. Because analyses in the present study focused on ER status, we excluded 148 women (8.0%) who had unknown ER status. Therefore, full data were available for 1,707 (92·0%) women in the registry.rd Edition. In addition, the BC pathological-tumour-node-metastasis (PTNM) was assessed using the recommendations of the 5th edition of Union for International Cancer Control. The stages have been grouped into three groups: the first group combined stage 0 and I tumours less than 2 cm without lymph node involvement, the second group combined stage II and III tumours comprising between 2·1 cm and 5 cm, with or without lymphadenopathy, and the third group corresponded to stage IV metastatic tumours. Furthermore, the Scarff Bloom Richardson (SBR) grade, modified by Elston and Ellis, was also measured because this classification of BC evaluates the “aggressiveness” of the tumour by taking into account the speed of tumour development and its management Data collected by the cancer registries and used in this study were age, comorbidities (the number of chronic diseases and their severity), and the BC characteristics coded according to the International Classification of Diseases for Oncology, 3Comorbidities were scored using CCI. The CCI was validated in 1987 by ME Charlson t-test or chi-square (χ2) test, as appropriate. Univariate and multiple logistic regressions were performed to examine the association between the presence of ER (dependent variable) and the CCI score≥1 (independent variable) adjusted for the participants' baseline characteristics. P-values <0.05 were considered statistically significant. All statistics were performed using SPSS .The participants' baseline characteristics were summarized using means and standard deviations or frequencies and percentages, as appropriate. Normality of the data distribution was evaluated using the Skewness-Kurtosis test. As the number of observations was >40 for each group, no transformations were applied to the variables of interest. Participants were separated into two groups based on the presence or absence of ER. Between-group comparisons were performed using an independent sample As shown in The main finding of our study is that a CCI score≥1 is associated with the expression of ER in women with BC. This association was independent of age, other hormonal receptors, PTNM stages, and SBR grades. Furthermore, the grade of tumors and the presence of HER were significantly associated with ER-, whereas the expression of PR and age were related to ER+. Finally, our findings indicate that PTNM stages were not associated with ER expression.The comorbidity burden quantified by the CCI score was an independent factor associated with the expression of ER in the sample of studied women. To the best of our knowledge, no previous studies have examined the association between the comorbidity burden and ER+ in BC. It has been reported that the comorbidity burden is associated with increased mortality and affects prognosis and treatment in all hormonal types of BC Age was significantly associated with ER+ in our study. This association may be considered as clinically relevant. Indeed, the OR was calculated at 1.02, which corresponds to an increase of 2% per year of the association between age and ER+ for a woman of 60.8 years old. Considering periods of 10 years, it means that 20% of women aged 71 years old, or 40% of women aged 81 years old with BC have ER+. This result is in concordance with previous studies in which the number of BC with ER expression increased with age Regarding the other hormonal status in our study, BC with PR expression was positively associated with ER+. This result is in concordance with previous studies Some limitations of the study should to be considered. First, the cross-sectional design of the present study may limit exploring the association between BC with ER+ and comorbidities compared to a prospective cohort design and thus prevent causal inferences. Second, although we were able to control for several characteristics that may have modified the association, residual potential confounders might still be present. Indeed, we were not able to control for factors related to hormonal status, such as nulliparity, metabolic syndrome, age at first birth, and menarche. However, studies showed that a systemic exposure of these factors was associated with the hormonal status of BC In conclusion, our study provides new data showing an independent positive association between a CCI score≥1 and BC with ER+. This result confirms that evaluation of ER expression in BC should not be limited to hormonal factors stratified by age


Percent mammographic density (PD) estimates the proportion of stromal, fat, and epithelial breast tissues on the mammogram image. Adjusted for age and body mass index (BMI), PD is one of the strongest risk factors for breast cancer . InheritSixty-one probes from five chromosomal regions  were significantly associated with PD in MBCFS . A CNV at 3q26.1 showed the greatest evidence for association with PD; a region without any known SNPs. Conversely, the CNV at 17q22 was largely due to the association between SNPs and PD in the region. SNPs in the 8q24.22 region have been shown to be associated with risk of many cancers; however, SNPs in this region were not responsible for the observed CNV association. While we were unable to replicate the associations with PD, two of the five CNVs (3q26.1 and 11p15.3) were also observed in the Mayo VTE controls.CNVs may help to explain some of the variability in PD that is currently unexplained by SNPs. While we were able to replicate the existence of two CNVs across the two GWAS studies, we were unable to replicate the associations with PD. Even so, the proximity of the identified CNV regions to loci known to be associated with breast cancer risk suggests further investigation and potentially shared genetic mechanisms underlying the PD and breast cancer association.The online version of this article (doi:10.1186/s13104-015-1212-y) contains supplementary material, which is available to authorized users. ZNF365, ESR1, LSP1 and RAD51L1, suggesting shared heritability between PD and breast cancer  to be significantly associated with PD after adjusting for age, menopausal status, and BMI in MBCFS  we identified five candidate regions that were significantly associated with PD: 3q26.1 [2 regions], 8q24.22, 11p15.3 and 17q22.A CNV at 3q26.1  has been previously reported to be associated with breast cancer risk in a Japanese population, though the start and end positions are slightly different . We obseThe 8q24 region has been shown to be associated with risk of many cancers, including breast, –42. WhilOur algorithm identified a CNV at 11p15.3 in MBCFS, which was validated in the Mayo VTE samples. However, we only observed a significant association with PD in the MBCFS samples. To our knowledge, this region has not been identified previously.BRCA1  that showed evidence of an association with PD. While three of CNV regions were observed in a second dataset , we were unable to replicate the associations with PD. However, these CNVs have been previously implicated in breast cancer risk as well as other malignancies. Thus, there is a possibility that they did not replicate in the Mayo VTE samples because of the different experimental design, power and/or the different PD measurements. As such, we recommend additional investigations to further examine these CNVs with PD and breast cancer in other populations to better understand genetic mechanisms by which PD may influence breast cancer risk.


Despite the potential cancer preventive effects of flavonoids and lignans, their ability to reduce pancreatic cancer risk has not been demonstrated in epidemiological studies. Our aim was to examine the association between dietary intakes of flavonoids and lignans and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A total of 865 exocrine pancreatic cancer cases occurred after 11.3 years of follow‐up of 477,309 cohort members. Dietary flavonoid and lignan intake was estimated through validated dietary questionnaires and the US Department of Agriculture (USDA) and Phenol Explorer databases. Hazard ratios (HR) and 95% confidence intervals (CIs) were calculated using age, sex and center‐stratified Cox proportional hazards models, adjusted for energy intake, body mass index (BMI), smoking, alcohol and diabetes status. Our results showed that neither overall dietary intake of flavonoids nor of lignans were associated with pancreatic cancer risk . Statistically significant associations were also not observed by flavonoid subclasses. An inverse association between intake of flavanones and pancreatic cancer risk was apparent, without reaching statistical significance, in microscopically confirmed cases . In conclusion, we did not observe an association between intake of flavonoids, flavonoid subclasses or lignans and pancreatic cancer risk in the EPIC cohort. What's new?Flavonoids and lignans found in plant‐based foods are potent cancer chemopreventive agents but little is known about their effects on pancreatic cancer risk. Here the authors address this question in a large prospective epidemiological study using comprehensively derived dietary data. Their results support growing evidence that there is no association between food‐based consumption of both substances with pancreatic cancer risk. Pancreatic cancer incidence and mortality estimates for the year 2012 in Europe show that the prognosis of this cancer remains poor .via pro‐estrogenic mechanisms or antioxidant effects,Flavonoids and its subclasses  are bioactive compounds with phenolic structures commonly present in fruits, vegetables and plant‐based beverages.in vitro and in vivo studies. These studies suggest that flavonoids inhibit proliferation of various pancreatic cancer cell lines through induction of apoptosis and inhibition of cell growth.The anticancer effects of flavonoids on pancreatic cancer have been widely researched in A compelling argument of a possible lack of association between dietary flavonoids and lignans with pancreatic cancer risk is that fruits, their major food sources, seem not to play a role in the aetiology of this cancer.Our aim was to examine the association between dietary intakes of flavonoids and lignans and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, in which a diverse intake of these compounds was described.The EPIC study is a multicenter prospective cohort study that is being carried out in 23 centers from 10 European countries . Recruitment of over half a million participants, aged 25–70 years, took place between 1992 and 2000. The majority of the participants were recruited from the general population although some centers also constituted their cohorts with local blood donors , vegetarians , women attending breast cancer screening programs , or women belonging to a health insurance scheme for state school and university employees (France). Participants gave their informed consent for participating in the study. The study was approved by the Internal Review Board of the International Agency for Research on Cancer, as well as by local institutions of the participating centers. Methods of recruitment have been described in detail elsewhere.A total of 23,785 participants with prevalent cancer at baseline other than non‐melanoma skin cancer, 4,383 participants with missing or incomplete information on follow‐up, 6,253 participants with incomplete dietary or non‐dietary information, and 9,600 participants with a ratio for energy intake versus energy expenditure in the top or bottom 1% were excluded. The final study sample consisted of 477,309 participants (29.8% men).Record linkage with population‐based cancer registries, as well as with national mortality registries, was performed to identify incident cancer cases and to assess the vital status of the participants. Complete follow‐up data was obtained until at least December 2004 and maximally to December 2008 depending on the EPIC center. Active follow‐up was carried out in Germany (up to December 2008 for Potsdam and June 2010 for Heidelberg), Greece (up to December 2009), and France (up to December 2006) by reviewing cancer, pathology and health insurance records of each participant, and also by directly contacting their next‐of‐kin.n = 40), secondary tumors (n = 67) and tumors of uncertain, benign or metastatic behavior (n = 3) were all censored at the date of their diagnosis. Of all 865 exocrine pancreatic cancer cases, 608 (70.3%) were microscopically confirmed, based on histology of the primary tumor (n = 359), histology of the metastasis (n = 68), cytology (n = 130) or autopsy (n = 51). Diagnosis was based on clinical symptoms, physical examination or imaging results for the remaining cases.Incident pancreatic cancer cases were defined as adenocarcinomas of the exocrine pancreas . Endocrine tumors  were used to inquire the participants about their habitual diet over the previous year, namely: quantitative food frequency questionnaires (FFQs) in Germany, Greece, UK, Northern Italy and The Netherlands, diet history questionnaires in Spain, France and Ragusa , and semi‐quantitative FFQs in Denmark, Naples , Norway, Umea (Sweden). In Malmö (Sweden), quantitative questionnaire with a 7‐day menu book were used.Other lifestyle data were collected at recruitment using standardized questionnaires including self‐reported diabetes mellitus status, lifetime history of smoking and alcohol consumption, physical activity and socio‐economic status. Approximately half of all diabetes self‐reported cases were included in a validation study, which consisted of verifying this diagnosis using additional sources of information, such as use of diabetes‐related medication, repeated self‐report during follow‐up, or linkage to diabetes registries and patient records.Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for intake of total flavonoids, flavonoid subclasses and lignans associated with pancreatic cancer risk. Regression models were stratified by age at recruitment in 1‐year categories, sex and center to additionally control for between‐center differences in the dietary assessment methods used at recruitment and differences in follow‐up procedures. Time at entry was age at recruitment, and time at exit was age at first pancreatic cancer diagnosis for cases and age at censoring for non‐cases . The proportional hazard assumption was satisfied as was verified after including time dependent covariates in the Cox models and testing for a non‐zero slope in a linear regression of the scaled Schoenfeld residuals on functions of time.2 scale to estimate risks associated with a doubling of intake and to normalize the skewed data. We previously examined the shape of the dose–response relationship by fitting Cox models with restricted cubic splines using three knots on the 5th, 50th, and 95th percentile of the distribution of flavonoids and lignan intakes.Intakes were also modelled on a continuous loga priori as factors associated with pancreatic cancer risk and dietary intake of flavonoids and lignans were tested for confounding by comparing models with and without each variable. Those variables that changed estimates >10% or significantly improved the model fit likelihood ratio test were retained in the regression model. Physical activity, educational level, waist circumference and dietary factors possibly associated with pancreatic cancer risk  did not comply with these criteria and were therefore not retained. The associations of dietary flavonoids and lignans intakes with pancreatic cancer risk were examined in crude models , which were further adjusted (Model 1) for energy intake from fat and from non‐fat sources, and additionally (Model 2) for body mass index (BMI), smoking status, alcohol intake, and diabetes status at recruitment.Covariates considered vs. overweight and/or obese, considering WHO criteriavs. moderate and large, considering NCEP/ATPIII criteriavs. former vs. current smoker), median age at diagnosis (<60 vs. ≥60 years), and heterogeneity by country and region (mediterranean vs. non‐mediterranean). The potential interaction between intake of flavonoids and lignans and smoking status was further explored on an additive scale, using a five‐category variable for flavonoids (quintiles) and a three‐category variable for smoking status .We conducted stratified analyses and tested interaction using the log‐likelihood test in regression models with and without multiplicative interaction terms to examine the modifying effect of sex, BMI  to minimize possible misclassification of tumors. We also stratified the associations by diabetes status to explore whether diabetes mediates and/or moderates the possible association between dietary intake of flavonoids and lignans with risk of pancreatic cancer. However, the associations could only be examined in non‐diabetics, including 773 pancreatic cancer cases, due to insufficient number of pancreatic cancer cases with diabetes at recruitment (55 cases).Sensitivity analyses were conducted by excluding the first 2 years of follow‐up (excluding 88 cases) to evaluate whether reverse causation driven by early effects of subclinical disease distorted the associations, and excluding the microscopically non‐confirmed cases . Statistical significance was based on two‐sided −1, respectively. Intakes were highest in the UK, possibly due to the high proportion of health conscious participants and tea drinkers in this cohort, and lowest in Norwegian women and Swedish men and women. For lignans (median intakes: 1.46 mg day−1 in men and 1.23 mg day−1 in women), a similar pattern was observed. The main contributors to the intake of total flavonoids were flavanols (82.1%) followed by flavonols (6.1%) in men, and flavanols (80.8%) followed by anthocyanidins (6.8%) in women. The composition of flavonoids subclasses in the diet differed by country, with flavanols being overall the most frequently consumed flavonoid subclass  were documented after 11.3 years of follow‐up. Median intake of flavonoids in men and women was 335.0 and 332.2 mg dayThe characteristics of the study population are described in Table 2 transformation = 1.03, 95% CI: 0.95–1.11 and 1.02; 95% CI: 0.89–1.17, respectively) . Risk of pancreatic cancer risk tended to decrease with higher intake of flavanones , but not so after multivariable adjustment (p trend = 0.24). The associations were all not statistically significant on the continuous scale. Adjustment for smoking status affected the associations most, while adjustment by the other variables had barely an effect.Neither dietary intake of total flavonoids nor of lignans were associated with risk of pancreatic cancer (HR for a doubling of intake after a logp = 0.21) and lignans (p = 0.81) with pancreatic cancer risk; the same applied for the analyses by regions. Interactions for total flavonoids and lignan intake were also not observed for sex (p = 0.64 and p = 0.39), BMI (p = 0.67 and p = 0.26), smoking status (p = 0.14 and p = 0.15), waist circumference (p = 0.83 and p = 0.66) and age (p = 0.47 and p = 0.89). There was also no evidence for interaction by these variables for any of the flavonoids subclasses (data not shown). An inverse association between intake of flavanone and pancreatic cancer risk was apparent, though not statistically significant, in smokers . Additionally controlling for smoking duration or intensity did not affect the risk estimates (Supporting Information Table 1). The combined effect of flavonoids and lignans with smoking on the risk of pancreatic cancer did not appreciably alter the associations with increasing intakes among never or former smokers with respect to smokers with the lowest category of intake (data not shown).No statistically significant heterogeneity between countries was observed for the associations of total flavonoids (p trend = 0.045), although statistical significance was not reached on the continuous scale . On the other hand, the positive trends observed for flavonols, flavan‐3‐ol monomers and theaflavins were all attenuated . The associations in nondiabetics weakened overall. Exclusion of cases diagnosed in the first 2 years of follow‐up had a minor impact on risk estimates.In the sensitivity analyses Table , the assThe results of the present study do not support an association between dietary intakes of total flavonoids, flavonoids subclasses or lignans with risk of pancreatic cancer. Intake of flavanones tended to be inversely associated with pancreatic cancer risk only when microscopically confirmed cases were considered, but the results were not statistically significant. No other variables exerted a differential effect on these associations.in vitro and in vivo animal studies have implicated the anticarcinogenic activity of flavonoids via various biological mechanisms influencing cell signalling, cell‐cycle regulation and angiogenesis, such as down regulation of NF‐kB activity with suppression of Akt activation, induction of apoptosis on BxPC‐3 in MIA PaCa‐2 and PANC‐1 cells, or inhibition of glucose uptake through down regulation of GLUT‐1 in CD18 cells.p trend = 0.02), and with a stronger association observed in smokers . A dietary pattern regarded as rich in flavonols was also found to decrease pancreatic cancer risk in smokers participating in the MEC study, but this was not confirmed in a validation study conducted within the EPIC cohort.n = 306 cases).The beneficial effect of fruits and vegetables against cancer has been attributed to fiber, vitamins and to flavonoids because of their well‐established antioxidant, antimutagenic, and antiproliferative properties.n = 230 cases),n = 130 cases).n = not reported),n = 29 cases),p trend = 0.001).Other prospective studies did not find any association between intake of flavonoids and risk of pancreatic cancer. For instance, the largest prospective study conducted so far, which included 2,379 pancreatic cancer cases of the NIH‐AARP cohort, concluded that intake of flavonoids was not associated with pancreatic cancer risk .e.g. databases on flavonoids content in food, the number of food items used for the evaluation of intake of flavonoids, and whether the influence of food processing on flavonoids content was taken into consideration.in vivo and in vitro effects of flavonoids disagree with data from epidemiological studies might be due to the poor bioavailability of these compounds, to dietary intakes at levels that are under the threshold of their biological activity,Comparison between these studies is, to some extent, limited by several issues in relation to (Supporting Information Table 3): differences in the study populations, varying ranges of intake and in dietary assessment methods used, A large proportion of the pancreatic cancer cases in our cohort were microscopically confirmed. An inverse association of borderline significance became apparent between flavanones and pancreatic cancer risk after restricting the analysis to these cases. The positive trend we observed for flavan‐3‐ol monomers, flavonols and theaflavins, was not consistent in all our analyses nor statistically significant, and is also not supported by the fact that the major food sources of these subclasses  are not linked to pancreatic cancer risk.Stratified analyses by diabetes status revealed that flavonoids and lignans were not inversely associated with pancreatic cancer in nondiabetics. In a previous study within the EPIC‐InterAct study, an inverse association between these subclasses and risk of type 2 diabetes was observed.n = 55).Flavonoids and lignans may reduce the long‐term damaging effects of diabetes by improving insulin secretion, increasing glucose uptake and reducing insulin resistance,Several strengths of this study merit consideration. The large sample size and long follow‐up enabled stratified analysis by smoking status and other potential effect modifiers with sufficient statistical power. Another major strength and distinguishing feature of our study is that we were able to minimize bias due to misclassification of cases after restricting the study population to microscopically confirmed pancreatic cancer cases. The influence of prediagnostic disease on the associations is unlikely since exclusion of cases diagnosed within the first 2 years of follow‐up did not alter the associations. Our study also benefits from an exhaustive quantification of intake of flavonoids, at a combined and individual basis for seven subclasses.In conclusion, this study does not support an association between dietary intakes of total flavonoids, flavonoids subclasses, or lignans and pancreatic cancer risk in the EPIC cohort.Supporting InformationClick here for additional data file.Supporting InformationClick here for additional data file.Supporting InformationClick here for additional data file.Supporting InformationClick here for additional data file.


FATS, formerly known as C10orf90), a regulator of p53-p21 pathway has been involved in the onset of breast cancer. Recent data support the idea that the crosstalk between FATS and p53 may be of physiological importance for reproduction during evolution. The aim of the current study was to test the hypothesis that FATS genetic polymorphism can influence the risk of breast cancer.The fragile-site associated tumor suppressor  in fragile-site gene FATS genotyping in breast cancer prevention.Our findings suggest the role of FATS-p53 signaling cascade in suppressing pregnancy-related carcinogenesis and potential application of The online version of this article (doi:10.1186/s12885-015-1570-9) contains supplementary material, which is available to authorized users. Breast cancer is both the most common malignancy and the one causing the highest number of cancer deaths in women worldwide. For most sporadic breast cancers, it has been suggested that genetic polymorphisms, especially single nucleotide polymorphisms (SNPs) in low-penetrance susceptibility genes in concert with environmental exposures may be more important. The p53 tumor suppressor protein, through its downstream target p21, plays a key role in sustaining cell-cycle checkpoints after DNA damage to maintain the genomic stability –9. HowevFATS, aka C10orf90), a regulator of p53-p21 pathway, has been identified at a common fragile site (CFS) FRA10F mapped to 10q26, a genomic region susceptible to DNA damage and frequently deleted in tumor genomes  supplemented with lysozyme  and incubated on ice for 15 minutes. Just before sonication, 1 mmol/L DTT, 10 mmol/L MgCl2, 1 mmol/L phenylmethylsulfonylfluoride (PMSF), and 1 % Sarkosyl (Sigma) were added to the cell lysate and mixed thoroughly. The cell lysate then was sonicated at maximum intensity for 20 seconds. Triton X-100 (2 %) was added, and the cell lysate was mixed gently for 30 minutes to help the fusion protein dissolve. After centrifugation, the GST-fusion protein was purified by Glutathione Sepharose 4B (Amersham Biosciences) and eluted with buffer [50 mmol/L Tris (pH 8.0)] containing 10 mmol/L glutathione .MCF-7 cells were transfected with plasmid DNA using a Nucleofector kit (Amaxa) or Lipofectamine 2000 (Invitrogen), according to manufacturer’s instructions.Cells were washed with cold PBS twice and collected in lysis buffer . Let cells sit in lysis buffer on ice for 30 minutes to ensure complete lysis. Spin cells at 12000 g for 10 minutes at 2-4 °C. The supernatant was saved as whole cell lysates.The cell lysates were separated by SDS-PAGE and transferred to PROTRAN nitrocellulose membranes . For immunoblot experiments, 20 to 50 μg of lysates in SDS loading buffer were separated by SDS-PAGE. Western blot analysis was exposured to X-ray film for autoradiography.4) were transfected with 250 ng of firefly luciferase reporter (pGL3-FATS-luc), 20 ng of the transfection control Renilla vector (pRL-TK) and 100 ng of p53-expressing vector in combination with 500 ng of FATS-expressing vector. At 24 h after transfection, cells were lysed in 1x passive lysis buffer (Promega), and reporter activity was measured using the Dual-Luciferase Reporter Assay System (Promega). Each assay was tested in triplicate in three independent experiments.Cells  at 30 °C for 90 min. The reactions were stopped by adding 2 x SDS loading buffer and heating at 95 °C for 5 min. Ubiquitinated p53 proteins were detected by immunoblotting using a p53-specifc antibody. In the absence of p53, the assembly of poly-ubiquitin was examined by Western blot using an ubiquitin antibody.The ubiquitination assay was performed as described previously . In brie2 test was used to examine the differences in demographic variables and genotype distribution of FATS polymorphisms between patients and controls. A Hardy–Weinberg equilibrium test was performed for the genotype distribution in the controls to evaluate possible selection bias and genotyping errors. The multivariate logistic regression method was used to assess the association between breast cancer risk and FATS gene SNP. Odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated with adjustment for known risk factors of breast cancer, such as age, BMI, age at menarche, birth number, duration of breast-feeding, menopause status, oral contraception, smoking status (ever/never), exercise, benign breast disease, and family history of cancer (first/second degree). For cases only, we also performed stratified case-series analysis of the genotype data by clinical phenotypes. All statistical tests were two-sided and a P value < 0.05 was considered statistically significant using SAS v9.0 software .The Kruskal-Wallis H Test was used to analyze the differences of mRNA expression between breast tumor samples and normal breast tissues. A χFATS SNP and breast cancer risk from the Discovery and Replication cohorts was estimated by the I2 , which was ranked as “no-” (0 % ≤ I2 < 25 %), “moderate-” (25 % ≤ I2 < 50 %), “large-” (50 % ≤ I2 < 75 %) and “extreme-” (75 % ≤ I2 ≤ 100 %) heterogeneity between these two cohorts . A random-effects model (DerSimonian and Laird method) or fixed-effects model (Mantel-Hansel method) was used to calculate the pooled OR in the presence (P ≤ 0.10) or absence (P > 0.10) of heterogeneity, respectively [Heterogeneity of the association between ectively , 19. AnaFATS expression to breast cancer. Consistent to the sample set from our previous report [FATS mRNA was silent or down-regulated in 100 % matched breast tumor tissues (n = 38), compared with that in normal tissues  and found that the average level of FATS mRNA even in pathologic stage–I breast tumors was 10-fold lower than that in normal control  gene contains 9 exons whose coding protein consists of 699 amino acid residues  that included 1532 breast cancer cases and 1573 healthy controls. The study subjects in this cohort were all recruited from Tianjin, a metropolis in North China . We did not observe a difference in the genotypic frequencies of rs11245007 between patients and controls (P = 0.907), and the results of a case-only analysis indicated that the rs11245007 genotypes were not significantly associated with mean age at diagnosis, lymph node metastasis, and expression status of estrogen receptor (ER) or progesterone receptor (PR)   in P = 0.0053) (Table P = 0.0289), compared with the CC genotype. Paradoxically, the TT genotype was not significantly associated with a decreased breast cancer risk in women with family history  , we found that both the rs11245007 CT and TT genotypes were associated with a decreased risk of breast cancer in subjects who had given birth more than three times, compared with the CC genotype. When combined together, the protective effect of the T allele (CT + TT genotype) was more pronounced in subjects with parity > =3 . The subjects in this cohort were recruited from Guangzhou, a major city in South China where is 1 493 miles away from Tianjin, excluding the probability of repetitive recruitment , and such protective effect was significant for CT  and TT  genotypes in triparous women . Genotypes with T-allele (CT + TT genotype) was associated with a decreased overall risk of breast cancer compared with the CC genotype . Further, this protective effect of the T allele was more pronounced in subjects with parity > =3  and with family history of cancer .Considering the sampling error and random error due to geographic difference between these two cohorts, meta-analyses were used to evaluate the potential heterogeneity between these two cohorts and to calculate the pooled association between SNP and breast cancer risk with ORs from these two cohorts  variant, regulating p53 function, did not affect the overall risk of breast cancer in our study population. Similarly, the genetic variants in Tp53 do not show effect on the risk of breast cancer [Tp53 or FATS on breast cancer would be very small or possibly confined to subgroups. Indeed, although BRCA1, BRCA2 and TP53 mutations confer susceptibility to breast cancer, common variants in these genes have not been shown to confer measurably increased risks of breast cancer [FATS rs11245007 variant on breast cancer risk was confined to women with parity ≥3. Both the rs11245007 CT and TT genotypes were associated with a decreased risk of breast cancer in subjects who had given birth more than three times as compared with the CC genotype, in both the Discovery and Replication cohorts. The stronger activation of p53 mediated by FATS 262 N would be physiologically important to suppress carcinogenesis of breast tissues undergoing repetitive and extensive changes during pregnancy for triparous women, and even a small protective effect of FATS-p53 signaling cascade may contribute significantly to decrease the risk of breast cancer as parity increases. The protective effect of FATS-p53 signaling cascade on breast cancer risk may be confined to the subgroup of triparous women. Although rs11245007 T allele (CT + TT) in FATS conferred a reduced risk of breast cancer in individuals with a family history of cancer in Tianjin Discovery cohort, such effect was not replicated in the Replication set of Guangzhou cohort, possibly due to the relatively smaller number of the Replication cohort, particularly for the stratification analysis.Interestingly, t cancer , suggestt cancer . UnexpecFATS gene  that is associated with susceptibility to breast cancer in a parity-dependent manner. Functional analysis demonstrated that FATS-262 N significantly increased the p53 activity in breast cells, resulting from more pronounced polyubiquitination of p53 by FATS-262 N. These findings provide the emerging physiologic evidence in support of the role of FATS as an E2-independent E3 toward p53, in addition to pinpointing a genetic marker with potential value in predicting breast cancer risk in women with parity ≥3. Once this genetic variant is validated by larger studies in different ethnicities, FATS genotyping for 905C > T may have application in breast cancer prevention.In summary, we have identified for the first time a genetic variant in the


Few studies have systematically reported the relationship between the risk of breast cancer and family history of other cancers. This study was designed to systematically determine the relationship between breast cancer risk and family history of other cancers in first-degree relatives.Between January 2006 and June 2011, 823 women diagnosed with breast cancer were included, and age-matched women diagnosed with benign breast disease were selected as controls. Family history of other cancers in first-degree relatives was recorded by trained reviewers. Multivariate logistic regression was applied to analyze the relationships.A family history of esophagus cancer , lung cancer (OR: 2.49 95% CI: 1.10 – 5.65), digestive system cancer  and any cancer  in first-degree relatives was directly associated with increased breast cancer risk. In subgroup analysis, the risk of hormone receptor positive breast cancer was increased in subjects with a family history of lung cancer , while the risk of hormone receptor negative breast cancer was increased in subjects with a family history of esophagus cancer , uterus cancer , digestive tract cancer  and gynecology cancer . Additionally, a significant increase in breast cancer was observed with a family history of digestive system cancer for subjects 50 y and younger , not for subjects 50 y older .Breast cancer aggregates in families with several types of cancer especially for digestive system cancer. The influence of a family history of other cancers seems more likely to be limited to hormone receptor negative breast cancer. Breast cancer is a prevalent malignant disease in the world and the leading cause of death in women , 2. PlenImportantly, several studies have suggested that an increased breast cancer risk is observed in subjects with a family history of other cancers, including colon cancer, prostate cancer, ovarian cancer and some other cancers –11. To oAccording to estrogen receptor (ER) and progesterone receptor (PR) status, breast cancer can be divided into two subgroups: hormone receptor positive and negative breast cancer. Hormone receptor positive and negative breast cancer may share disparate genetic risk factor profiles –19. To oGiven poor reliability of the recall of cancer in second-degree relatives , only fiAs previously described , eligiblThe present case-control study was performed with the approval of the ethics committee of The First Affiliated Hospital with Nanjing Medical University, and this study was also in compliance with the Helsinki Declaration of the World Medical Association. All patients included in this study provided written informed consent for their clinical data to be reviewed by us.The interviews of family history for all cases and controls were performed before diagnose. The clinical data were reviewed by trained interviewers. The family history of other cancers and potential risk factors were extracted from medical record review. As described previously , the folBesides, ER and PR status were reviewed and recorded. Immunohistochemical analyses on paraffin-embedded material were used to determine the ER and PR status. The cut-off positivity was 10% tumor cells for the evaluation of ER and PR. Hormone receptor positive was defined as ER positive and/or PR positive, and hormone receptor negative was defined as both ER and PR were negative. Of 823 cases, 514 were identified as hormone receptor positive, 214 were identified as hormone receptor negative, and hormone receptor status could not be identified in 95 cases.≤ 50 years, and patients diagnosed with breast cancer > 50 years. The candidate explanatory variables in the multivariate logistic regression analysis were: age , age at menarche , previous childbearing  and menopausal status . The categories of age, age at menarche, and previous childbearing were described previously [Median, percentiles, range, and standard deviation (SD) were analyzed for each continuous variable. Univariate and multivariate analyses were applied to estimate odds ratio (OR) and 95% confidence interval (CI) for the association between family history of other cancers and breast cancer risk. In addition, multivariate logistic regression was also applied to estimate OR and 95%CI for the association between family history of other cancers and risk of subtype-specific breast cancer, including hormone receptor positive breast cancer, hormone receptor negative breast cancer, patients diagnosed with breast cancer eviously . All varP > 0.05). Cases and controls in this study were very well matched on age. The other basic characteristics of all included subjects were described previously [A total of 823 women with breast cancer and 823 age-matched controls were studied. Age distribution of all participants was shown in Table eviously .Table 1The number of cases and controls with a history of selected cancers was shown in Table In univariate analysis Table , a signiP > 0.05). Furthermore, no significantly increased breast cancer risk was observed in subjects with two or more family histories of other cancers .When age, age at menarche, childbearing, and menopause status were adjusted Table , a signiIn subgroup analysis Table , a signiImportantly, a significantly increased breast cancer risk was observed with a family history of any other cancer for women both younger  and older  than 50 y (Table In this hospital-based case-control study, the risk of breast cancer was increased in subjects with a family history of esophagus cancer, lung cancer and digestive system cancer in first-degree relatives. In subgroup analysis, the risk of hormone receptor positive breast cancer was increased in subjects with a family history of lung cancer, while the risk of hormone receptor negative breast cancer was increased in subjects with a family history of esophagus cancer, uterus cancer, and gynecology cancer. Additionally, a significant increase in breast cancer was observed with a family history of digestive system cancer for subjects 50 y and younger, not for subjects 50 y older.Previous studies have reported that family history of colon, prostate, ovarian cancers has been associated with an increased breast cancer risk , 19. HowThe relationships between having a family history of breast cancer and risk of subtypes of breast cancer defined by hormone receptor status are inconsistent , 19, 33,Jiang and colleagues find that women with a family history of breast cancer were more likely to have hormone receptor negative breast cancer than women without a family history, and the association was limited to cancers diagnosed before age 50 . SimilarOur study was the systematic investigation of all other cancers in first-degree relatives and the subsequent breast cancer risk. The strengths of this study are described as following. First, previous studies suggest that the recall of cancer in second-degree is less reliable , 42. OnlHowever, several potential limitations of this study should be considered when interpreting these results. First, the information on other potential risk factors of breast cancer such as diet, smoking, body mass index, and number of siblings, was unavailable. Some of the significant associations could be attributed to chance. Moreover, number of first degree relatives  was not In conclusion, a family history of esophagus cancer, lung cancer, and digestive system cancer in first-degree relatives was directly associated with breast cancer risk. In subgroup analysis, the influence of having a family history of other cancers seems more likely to be limited to hormone receptor negative breast cancer. An increased breast cancer risk was observed in subjects 50 y and younger with a family history of digestive system cancer in first-degree relatives. Future cohort studies with a larger sample are still needed to confirm our findings and consider other risk factors.


Breast cancer is an increasing public health problem. Substantial advances have been made in the treatment of breast cancer, but the introduction of methods to predict women at elevated risk and prevent the disease has been less successful. Here, we summarize recent data on newer approaches to risk prediction, available approaches to prevention, how new approaches may be made, and the difficult problem of using what we already know to prevent breast cancer in populations. During 2012, the Breast Cancer Campaign facilitated a series of workshops, each covering a specialty area of breast cancer to identify gaps in our knowledge. The risk-and-prevention panel involved in this exercise was asked to expand and update its report and review recent relevant peer-reviewed literature. The enlarged position paper presented here highlights the key gaps in risk-and-prevention research that were identified, together with recommendations for action. The panel estimated from the relevant literature that potentially 50% of breast cancer could be prevented in the subgroup of women at high and moderate risk of breast cancer by using current chemoprevention  and that, in all women, lifestyle measures, including weight control, exercise, and moderating alcohol intake, could reduce breast cancer risk by about 30%. Risk may be estimated by standard models potentially with the addition of, for example, mammographic density and appropriate single-nucleotide polymorphisms. This review expands on four areas: (a) the prediction of breast cancer risk, (b) the evidence for the effectiveness of preventive therapy and lifestyle approaches to prevention, (c) how understanding the biology of the breast may lead to new targets for prevention, and (d) a summary of published guidelines for preventive approaches and measures required for their implementation. We hope that efforts to fill these and other gaps will lead to considerable advances in our efforts to predict risk and prevent breast cancer over the next 10 years.The online version of this article (doi:10.1186/s13058-014-0446-2) contains supplementary material, which is available to authorized users. BRCA2) founder mutation in Iceland increased fourfold over the last century, and the cumulative incidence of sporadic breast cancer by age 70 also increased fourfold, from 2.5% to 11% of the population, over the same period [BRCA1 and BRCA2 in other countries [Breast cancer remains a major public health problem. The incidence is rising in most countries and is projected to rise further over the next 20 years despite current efforts to prevent the disease -4]. The. The4]. ountries ,7]. The. TheBRCAountries . Given gountries , or by bountries  and anasountries .A paradigm for preventative therapy (chemoprevention) is cardiovascular disease (CVD). The introduction of drugs that suppress cholesterol synthesis, modify platelet aggregation, or lower blood pressure has led to a steady decline in CVD over the past three decades, such that deaths from CVD in women less than 85 years old fell below those for cancer in 1999 . The carThe fraction of breast cancer cases attributable to lifestyle and environmental factors in the UK was estimated to be 26.8% in 2010 , and a rThis review is an expansion and update of a brief review published in the Gap Analysis in 2013 of breast cancer research overall . Co. CoBRCA1ver time  and scortic test ,19]..BRCA1/2 Of relevance to all women, several models have been developed to predict risk of breast cancer over time . These predict the probability that a woman in the population with a particular combination of risk factors will develop breast cancer -16]. Th. Th16]. The Gail model includes these risk factors: age at menarche, age at first live birth, number of previous breast biopsies, benign breast disease, and number of first-degree relatives with breast cancer. Studies indicate that the Gail model is well calibrated in regularly screened American women  and whenAlthough current models can give an accurate estimation of lifetime risk , we cannot tell her whether she is the one who will develop the disease or whether she is one of the two women who will not. To fill this gap in our knowledge, there is great interest in adding other risk factors to current models, such as mammographic density ,31], si, si31], The available data on mammographic density in relation to breast cancer risk have been reviewed recently ,31]. De. De31]. Four studies have already assessed whether adding a measure of mammographic density improves risk estimation compared with the estimation using standard models alone. A standard measure of improvement of risk assessment is the C-statistic. This is the area under the receiver operating curve (AUC), which in turn is a reflection of the sensitivity and specificity of the model. The higher the C-statistic (AUC), the greater the discriminatory accuracy of the model. An AUC of 0.5 identifies a model whose discriminatory accuracy is no better than chance alone, whereas an AUC of 1.0 identifies a model with perfect discriminatory accuracy. In practice, AUCs of 0.7 or 0.8 are consistent with good discriminatory accuracy .P <0.01). Barlow and colleagues +[−[60], +. Th. Th67]. The use of hormone measurements in breast cancer to incorporate into risk models is attractive. However, measurement, particularly in post-menopausal women, is problematic because of assay variation related to low hormone levels and other unknown causes of variation in hormone levels over time . NeverthNew biomarkers for risk prediction are likely to come from measures in blood or tissues by a variety of techniques. At present, it appears that none of these is ready for incorporation into the standard models, but given the pace of advance they are likely to be in the near future. Examples of some current approaches include the development of assays for serum antibodies against epithelial antigens , gene ex+ cancers , ch, ch+ can cancers ,84], an, an+ can cancers ,86]. Th. Th+ canThere is probably sufficient evidence from the randomized trials for the use of SERMs and AIs for use in women at high and moderate breast cancer risk ,11] and and11] ain situ) using tamoxifen 20 mg per day was 38% (P <0.0001) . In. In93]. n weight . In the n weight . There in weight . It is in weight ,98] and and2 incn weight ,100]. M. M2 incr– breast cancer but not with the risk for ER+ disease. This topic requires further investigation . W. W– breatigation , adherentigation .Adherence to dietary types may also affect risk. For example, in the California Teachers Study, data from 91,779 women were analyzed according to predominant dietary pattern by using principal component factor analysis . A greatMore than half of the US population does not meet the recommended PA guidelines. In addition, the most recent Health Survey for England  showed tIt is estimated that breast cancer risk is increased by 7% to 10% for each one-unit increase in intake of alcohol per day . In the Nurses’ Health Study, women who consumed 4 to 9 units per week were 15% more likely to develop breast cancer compared with never drinkers . Women wIt is important to be aware that lifestyle prevention includes not only middle- and late-age women but younger women after menarche. Animal experiments and modeling of the reproductive events in women indicate that the most susceptible period for carcinogenesis is during the period between menarche and first pregnancy ,123]. I. I123]. in utero and at puberty, particularly in the rodent mammary gland, have been discovered and are summarized in recent reviews . T. Tin uteThe experiments outlined above cannot be performed in humans. However, another approach to the development of prevention is understanding the biological mechanisms of risk factors for breast cancer. Here, we discuss some examples which support this view with respect to estrogen and the breast, early and late first pregnancy, menopausal involution of epithelial cells, mammographic density, and mechanism of the effects of energy restriction and exercise.The most successful preventative approach to breast cancer to date, reducing the effects of estrogen on the breast, has come from an understanding of the biology of the ER and the knowledge that estrogen is synthesized in the breast and elsewhere after ovarian function decreases at menopause. These data have led to the introduction of the SERMs  and the potential introduction of AIs (exemestane and anastrozole) for breast cancer prevention. Tamoxifen acts by blocking the ER but under certain circumstances can change to being a partial agonist via the ER and this may limit its preventive utility since in some women at increased risk it appears to increase mammographic density . The dev+ and progesterone receptor-positive (PR+) cells in the normal breast rarely proliferate . R. R+ and partment . These dpartment .Observational data have linked diet and growth in height in childhood and dietary exposures during early adulthood . These studies have either used retrospective recall of early life exposures from adults or prospectively assessed short-term effects on surrogate risk markers like benign breast disease . StudyinBRCA1 tumor-suppressor gene, earlier differentiation of breast tissue , b, b137], t tissue , subsequt tissue , and a st tissue . Increast tissue . Likewist tissue  and benit tissue , which it tissue .Late pregnancy is a major driver of the worldwide increase in breast cancer incidence. Over half of women in the UK have their first pregnancy over the age of 30, and thus understanding the mechanism of its effect on risk is of great importance. It seems likely that the breasts of older fertile women harbor early pre-cancerous lesions. One mechanism in which these may be stimulated is as a result of immunological processes that occur during post-partum breast involution. Lyons and colleagues  demonstrThe lobules of the breast undergo involution after menopause. However, Wellings and colleagues  reportedSome studies show that the rate of the well-known decline of mammographic density with age is slower in some women and indicates higher breast cancer risk ,160]. M. M160]. Gene expression profiles of fibroblasts derived from dense and non-dense areas of the breast indicate marked differences in expression. Expression of genes associated with inflammation  and several signaling pathways is upregulated and suggests the use of, for example, JNK inhibitors, already in the clinic for treatment of overt disease ,163]. S. S163]. Energy restriction is well known to increase longevity in several types of organisms, in part by reducing the incidence of cancer. It acts predominantly by reversing the effects of obesity on inflammation, certain signal transduction pathways, and insulin/IGF-1 . ObesitySeveral biological mechanisms have been proposed to explain the inverse association between PA and breast cancer risk. Although regular exercise may delay the onset of menarche, increase the length of the menstrual cycle, or increase the number of anovulatory cycles, hence reducing exposure to sex hormones, prospective intervention studies suggest that high levels of exercise may be needed to induce menstrual cycle changes ,174]. O. O174]. PA could also influence breast cancer risk through its effect on weight loss and reduced levels of body fat. This means that distinguishing the independent effects of PA on breast cancer risk is difficult because body fat reduction impacts a range of putative breast cancer risk markers, including circulating levels of sex hormones, insulin-like growth factors, adipokines, and inflammatory mediators . ElevateThe studies outlined above indicate the interactions which occur between epithelial cells and between them and stromal cells such as macrophages, fibroblasts, and adipocytes Figure . They inSeveral guidelines advise how we might apply the knowledge that we have gained concerning hormonal prevention  and lifestyle factors  to populations of women. Hormonal chemoprevention is suggested for women at increased risk, whereas lifestyle factors can be applied to all women since all are at some risk of breast cancer, and even at low risk, lifestyle factors are similar to those which help prevent other conditions such as CVDs and diabetes.in situ, or lobular carcinoma in situ. They advise use of the Gail model to assess risks and a cutoff of 1.66% 5-year risk. However, taking toxicity into account, they suggest that a threshold for advising treatment of 3% 5-year risk may be more appropriate and advise use of the tables published by Freedman and colleagues . I. I191]. For lifestyle change, the goals for breast cancer prevention are the same as those required to solve the obesity epidemic. These are very well highlighted in the goals set by the US Institute of Medicine report on ‘Accelerating Progress in Obesity Prevention: Solving the Weight of the Nation’ . The goaColditz and colleagues  recentlyOne conclusion of this review is that the application of measures that are already available, such as chemoprevention and lifestyle prevention, would result in appreciable reductions in breast cancer risk. A second conclusion is that the pace of advance of our understanding of the biology of breast cancer risk and development is highly likely to give rise to new avenues for prevention over the next 10 years. A major problem is applying what we already know concerning the efficacy of prevention to appropriate populations of women. To apply chemoprevention, we need to have measures in place to assess risk and to explain the pros and cons of treatment and for prescription of appropriate therapies. Lifestyle change is a population problem which involves publicity concerning its risks and benefits of change and providing mechanisms to support women in their choices throughout society as highlighted in the US Institute of Medicine documents.


Epidemiological studies have examined breast cancer risk in relation to sex hormone concentrations measured by different methods: “extraction” immunoassays , “direct” immunoassays (no prior extraction or column chromatography), and more recently with mass spectrometry-based assays. We describe the associations of estradiol, estrone and testosterone with both body mass index and breast cancer risk in postmenopausal women according to assay method, using data from a collaborative pooled analysis of 18 prospective studies. In general, hormone concentrations were highest in studies that used direct assays and lowest in studies that used mass spectrometry-based assays. Estradiol and estrone were strongly positively associated with body mass index, regardless of the assay method; testosterone was positively associated with body mass index for direct assays, but less clearly for extraction assays, and there were few data for mass spectrometry assays. The correlations of estradiol with body mass index, estrone and testosterone were lower for direct assays than for extraction and mass spectrometry assays, suggesting that the estimates from the direct assays were less precise. For breast cancer risk, all three hormones were strongly positively associated with risk regardless of assay method (except for testosterone by mass spectrometry where there were few data), with no statistically significant differences in the trends, but differences may emerge as new data accumulate. Future epidemiological and clinical research studies should continue to use the most accurate assays that are feasible within the design characteristics of each study. Results have now been published from ∼20 such studies since the late 1980s. The first such studies measured hormones with in-house radioimmunoassays, which generally used a relatively large volume of sample and incorporated an organic extraction step and usually also purification by column chromatography. In the 1990s and 2000s the use of commercially produced immunoassays without extraction or chromatography (“direct assays”) became popular with many epidemiologists because these assays were easier to perform (and therefore faster and cheaper) and use less sample than the extraction assays. Some of the direct assays provided results considered adequate for epidemiological studies, which seek mainly to rank individuals rather than to provide accurate estimates of hormone concentrations The aim of this paper is to describe the relationships of circulating estradiol, estrone and testosterone in postmenopausal women with body mass index (BMI) and breast cancer risk according to the type of assay used, using data from the international Endogenous Hormones and Breast Cancer Collaborative Group 22.1Studies were eligible for the collaborative re-analysis if they included data on endogenous hormones and breast cancer risk using prospectively collected blood samples from postmenopausal women, as described previously 2.22), together with their 95% confidence intervals (CIs), were calculated using the predicted values from analysis of variance models, adjusted for study, age at blood collection , and type of menopause . Partial correlations of estradiol with estrone, testosterone and BMI were computed using study-specific standardized values: (jkx − jm)/js where jm and js denote the mean and standard deviation of the log-transformed hormone concentrations in study j and jkx is an observation from that study. These standardized values were adjusted for age at blood collection and type of menopause (same categories as above).For the analyses of hormones and BMI, hormone concentrations were logarithmically transformed to normalize the distributions. Geometric mean hormone concentrations by categories of BMI  for breast cancer in relation to serum/plasma hormone concentrations, categorizing women in each study according to the quintiles of hormone concentration for the controls in that study. Adjustments were not made for reproductive, anthropometric or lifestyle risk factors for breast cancer because hormones may mediate the effects of some of these risk factors and previous analyses have shown that adjustments for these risk factors do not materially change the associations of hormones with breast cancer risk in postmenopausal women For the studies using mass spectrometry, we used the values for unconjugated steroids, where available; for B∼FIT, the mass spectrometry data for estradiol and estrone were available for total steroids, which sums the sulphated, glucuronidated, and unconjugated forms, but not for unconjugated steroids, and are not included in the analyses of steroids by BMI.P < 0.05. All analyses were performed using Stata Statistical Software release 10 .All statistical tests were two-sided, and statistical significance was taken as 33.1Eighteen studies contributed data, eleven in the USA, two in the UK, one each in Australia, Italy, Japan and Sweden, and the multi-centre European study EPIC. Geometric mean hormone concentrations in controls are shown in 3.23.34The findings from the different assay types  were broadly similar. For all three hormones examined, the largest amount of data was from direct assays. Where enough data were available, all three assay methods showed that BMI was strongly positively associated with the estrogens and moderately positively associated with testosterone, and all three hormones were strongly positively associated with breast cancer risk, regardless of assay method.The cross-sectional analyses of geometric mean hormone concentrations in relation to BMI showed that on average the direct assays give concentrations that are substantially higher than those from the other assay methods. This difference has been discussed previously, and may be in part due to cross-reactivity between steroids in the direct assays leading to estimated absolute concentrations which may be greater than the true value The relative risk analyses showed strong positive associations of all three hormones with breast cancer risk, as previously reported by this collaborative group In conclusion, the existing data from prospective studies show that estrogens are strongly associated with breast cancer risk, regardless of the assay method. Direct assays are in general less accurate than extraction assays or mass spectrometry assays


The American Society of Clinical Oncology (ASCO) held its annual meeting this past June. As usual, participants had the opportunity to learn and discuss the latest in oncology research findings. Although I didn’t attend the meeting in person, I noted the daily reports with interest. I was particularly appalled by the results of a study examining 80,000 patients in early breast cancer trials and their outcomes based on several factors, including obesity.P < .00001). After the investigators adjusted for additional tumor aspects, the positive association was clearly significant in only 20,000 of the pre- and perimenopausal women with ER-positive breast cancer, demonstrating an increased risk for worse outcomes, including death. When subdivided by age, obesity was significant only to approximately age 55.The results demonstrated that in 20,000 women with ER-negative disease, there was a minimal association between BMI and breast cancer mortality, but that in 60,000 women with ER-positive tumors, BMI was associated with disease mortality in pre- and perimenopausal women, as well as postmenopausal women (each 2Journal of the National Cancer Institute highlighted the breast cancer risk for women based on increased BMI, stating that this risk was largely the result of increased serum concentrations of bioavailable estradiol stemming from obesity (Most clinicians are strongly aware of the risks of smoking and the many different types of cancer associated with that habit, yet most of us do not completely understand obesity and cancer risk. However, a 10-year-old study published in the  obesity .It is especially disconcerting to see that the prevalence of obesity in several countries is increasing. The phenomenon has been termed a global epidemic, causing an estimated 3 to 4 million deaths in 2010 . ObesityAs advanced practitioners, we are charged with safely guiding our patients through newly diagnosed disease, implementing treatment protocols and managing symptoms throughout their illness and therapy. Survivorship is an equally important part of our care. Yet I can’t help but wonder whether we are doing a good job of educating our patients regarding the specific hazards of obesity. This recently reported research on premenopausal patients with ER-positive breast cancer should give us pause. Are we doing a thorough job of educating our patients regarding the true risk of obesity and its potential to affect overall outcomes from this disease? Can we treat our patients throughout their chemotherapy and hormonal therapies and neglect the importance of additional risk factors that can affect disease recurrence?Advanced practitioners should arm themselves with the knowledge from this important study and engage in discussions about obesity with appropriate patients at the start of the diagnosis and treatment plan. Dietary assistance should be enlisted where appropriate, and milestones should be assessed at each visit. Obesity is a modifiable risk factor. As such, counseling regarding this factor should be considered an important part of the overall treatment protocol and survivorship plan.If you haven’t signed up to attend JADPRO Live at APSHO 2014, please do so! This conference will give you 3 days of focused education aimed specifically at the advanced practitioner’s level, plus an extra day of preconference workshops. The conference takes place October 30 through November 2, 2014, and will be held at the Loews Royal Pacific Hotel at Universal Orlando, Florida. You can view the conference agenda and preconference workshops at www.apsho.org/jadprolive. The conference offers the opportunity to earn up to 20 CE credits/contact hours for advanced practitioners in oncology, including nurse practitioners, physician assistants, pharmacists, physicians, and other providers. As this will also be the first official APSHO meeting, new members will receive a significant discount to the conference. I hope to see you there!


Women with evidence of high intake ratios of the marine omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) relative to the omega-6 arachidonic acid have been found to have a reduced risk of breast cancer compared with those with low ratios in some but not all case–control and cohort studies. If increasing EPA and DHA relative to arachidonic acid is effective in reducing breast cancer risk, likely mechanisms include reduction in proinflammatory lipid derivatives, inhibition of nuclear factor-κB-induced cytokine production, and decreased growth factor receptor signaling as a result of alteration in membrane lipid rafts. Primary prevention trials with either risk biomarkers or cancer incidence as endpoints are underway but final results of these trials are currently unavailable. EPA and DHA supplementation is also being explored in an effort to help prevent or alleviate common problems after a breast cancer diagnosis, including cardiac and cognitive dysfunction and chemotherapy-induced peripheral neuropathy. The insulin-sensitizing and anabolic properties of EPA and DHA also suggest supplementation studies to determine whether these omega-3 fatty acids might reduce chemotherapy-associated loss of muscle mass and weight gain. We will briefly review relevant omega-3 fatty acid metabolism, and early investigations in breast cancer prevention and survivorship. Although the predominant driving force in breast carcinogenesis has been thought to be hormonal, cytokine production and inflammation are also being recognized as important in breast cancer development and progression ,2. A proThe long-chain omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are important in generating bioactive lipid mediators important in inflammation resolution . As key Interest in the use of supplementary omega-3 fatty acids to reduce risk of cancer and other chronic debilitating conditions, including cardiovascular disease and cognitive impairment, stems from several longstanding avenues of investigation: 1) an increased incidence of breast cancer and heart disease in western societies with low omega-3:omega-6 fatty acid intake ratios; 2) a very low incidence of these two conditions in populations with high marine omega-3 fatty acid intake (Japan and natives of Alaska and Greenland); 3) a dramatic increase in the incidence of breast cancer and cardiovascular disease in cohorts from low-incidence populations who migrate to western countries and/or adopt a western diet ,17; and Although the ideal total omega 3:omega-6 intake ratio has not been defined, a ratio approaching 1:1 or 1:2 similar to that of precivilized man is generally accepted as associated with a low incidence of diseases characterized by chronic inflammation, and therefore is desirable ,20. By tWe will briefly review omega-3 and omega-6 fatty acid metabolism and function, preclinical mechanistic and prevention studies, as well as selected case–control and prospective cohort studies, and ongoing trials relevant to breast cancer prevention. Reports dealing with omega-3 fatty acids and breast cancer recurrence as well as other relevant survivorship topics including insulin resistance and obesity, cardiovascular disease and cognition will also be discussed.Omega-3 and omega-6 fatty acids are a group of essential polyunsaturated fatty acids (PUFAs) that play important roles in cell membrane structure, fluidity, and cell signaling . The desWhether ingested or synthesized, PUFAs are either oxidized for fuel, stored in triacylglycerol, taken up in phospholipid membranes for eventual use as substrates by cyclooxygenase (COX) and lipoxygenase (LOX) enzymes, or used as ligands for G receptors . NeitherThe omega-6 PUFA AA and its derivatives are important in a diverse set of physiologic functions including initiation and sustainment of inflammation , platelet aggregation, endothelial adhesion molecules, ovulation, parturition, and muscle strength. The omega-3 fatty acids EPA and DHA and their derivatives are important for retina and brain development, cognitive function, and in the production of minimally inflammatory eicosanoids as well inflammation resolving mediators termed resolvins and various tissue protectins ,22. Alth2 and other series-two prostaglandins and thromboxanes [Upon inflammatory stimulus, the enzyme phospholipase A2 releases AA from phospholipid membranes of monocytes and predominantly proinflammatory derivatives are produced  reduces mammary cancer incidence and multiplicity by 20 to 35% ,32,37-41nic mice ,40, the nic mice . The minnic mice . Severalnic mice , or celenic mice .Results of case–control and cohort studies have to date been variable, probably reflecting the heterogeneity of cohorts, methods used to assess omega-3 and omega-6 exposure, time from exposure when measures were taken, dose, and response endpoint.Omega-3 and omega 6 fatty acids are incorporated at different rates in different tissues and tissue components. Levels as a percentage of total fatty acids vary tremendously between tissues/organs although, with supplementation, levels of EPA and DHA rise in a fairly proportional manner . SubstanFor clinical trials, chronic exposure is generally assessed by measuring EPA, DHA, and AA RBC phospholipids, although some investigators feel that monocyte or platelet phospholipid measures are superior to those in RBCs .Results of case–control studies, particularly when questionnaires are used as the primary measure of exposure, are mixed, probably reflective of the accuracy of recall and food frequency questionnaires in estimating dietary intake. There is no significant association between total fish intake and breast cancer particularly in populations where total fish and fatty fish consumption tends to be low ,49. EPA Measurement of the fatty acid composition in blood cell membranes (phospholipids) and adipose is thought to be a good indicator of chronic exposure to omega-3 and omega-6 fatty acids and thus avoids some of the problems with dietary recall. A nested case–control study within a prospective cohort of women in Shanghai China, a population with relatively high fish intake, found that total omega-3 fatty acids and EPA in red cells were associated with significantly lower risk of proliferative breast disease and breast cancer ,53. SimiA meta-analysis of 16 prospective cohort studies examining marine omega-3 intake suggests a reduction in breast cancer risk when individuals with highest intakes are compared with those with lowest intakes of marine PUFA  in the diet or the diet plus supplements . The metEight studies were available for dose–response analysis, which showed that a 0.1 g/day increment and/or 0.1% of energy intake increments were associated with a 5% reduction in breast cancer risk . In thisA recent meta-analysis combined six prospective nested case–control studies and five cohort studies in which the omega-3:omega-6 intake ratio and/or omega-3:omega-6 ratio in serum phospholipids was known. There were over 274,000 women, and more than 8,300 breast cancer events. Their conclusions were that each 1/10 increment in the dietary n-3:n-6 ratio was associated with a 6% reduction in breast cancer risk, and amongst US subjects each 1/10 increment in the serum n-3:n-6 phospholipid ratio was associated with a 27% reduction in breast cancer risk .Although one is not likely to achieve EPA + DHA intake in human trials at the same percentage of calories as in animal prevention trials, doses of EPA and DHA ethyl esters up to ~7 g/day given to healthy women are well tolerated . A dose P = 0.08) but no change in interleukin-6 [Human studies in healthy individuals show little effect of marine PUFA on blood inflammatory biomarkers, although a recent randomized trial in healthy young adults given 0, 300, 600, 900, or 1,800 mg/day EPA + DHA for 5 months showed a marginal decrease in serum tumor necrosis factor alpha  4 g, Lovaza™ 4 g + raloxifene 30 mg, or no intervention in postmenopausal women with >25% breast density. No change with Lovaza™ has been found in the first 46 women in secondary endpoint blood risk biomarkers such as insulin-like growth factor I and insulin-like growth factor-binding protein 3 or the inflammatory marker high-sensitivity C-reactive protein .We have completed separate pilot studies of 3.4 g/day EPA + DHA ethyl esters (4 g Lovaza™) administered for 6 months to explore effects on benign breast tissue risk biomarkers for breast cancer in premenopausal and postmenopausal women at increased risk for breast cancer. Favorable modulation of several tissue risk biomarkers for breast cancer was observed ,68.A study of particular interest is the ongoing VITAL trial (NCT01169259) which aims to randomize over 28,000 men and women to vitamin D3 , omega-3 fatty acids (840 mg EPA + DHA), both, or none, with a primary outcome of reduction in risk for cancer, stroke, and other diseases. Eligible women must be age 55 years and over.There is also interest in EPA and DHA for improvement of outcomes after a diagnosis of breast cancer. Breast cancer recurrence, cardiovascular events, weight gain and obesity, bone density loss, and chemotherapy-associated cognitive impairment and peripheral neuropathy are common concerns during the survivorship period. Although there is little in the way of definitive interventional trials, we will review here some of the more interesting preliminary results.Higher intakes of EPA and DHA from dietary sources were reported to be associated with a 25% reduction in breast cancer recurrence and improved overall mortality in a large cohort of over 3,000 women with early stage breast cancer followed for a median of 7 years . One reaCardiac events are the second most common cause of mortality in women with breast cancer, and the most common cause of death for women with stage I breast cancer over the age of 65. EPA and DHA reduce triglycerides and platelet aggregation and are thought to have an anti-arrhythmic effect. EPA and DHA supplementation have been noted to be associated with reduced cardiac deaths in the general population ,76. A hiLoss of bone density and increased fracture rate are a side effect of premature menopause caused by cytotoxic chemotherapy or surgical ovarian ablation in premenopausal women or use of aromatase inhibitors in postmenopausal women. EPA and DHA probably inhibit RANK ligand and osteoclast formation . A smallEPA and DHA help prevent obesity and insulin resistance particularly in animal models fed a high-fat diet ,86, but Cognitive abnormalities are observed in 20 to 70% of women after chemotherapy depending on the agents used, intensity and duration of treatment, predisposing factors, and type and scoring of cognitive tests ,91. DHA The inflammation-resolving properties and favorable effects of EPA and DHA on oncogenic proteins, as well as on the cardiovascular, bone, and central nervous system, make them excellent candidates for primary and secondary breast cancer prevention trials for individuals at increased risk as well as breast cancer survivors. Interventional trials in these cohorts are ongoing.