Ductal and lobular carcinomas are the two most common types of invasive breast cancer. Whether well-established risk factors are differentially associated with risk on the basis of histologic subtype is not clear. We prospectively investigated the association between a number of hormonal and nonhormonal exposures and risk defined by histologic subtype among 4,655 ductal and 659 lobular cases of postmenopausal breast cancer from the Nurses' Health Study.P value for heterogeneity using a likelihood ratio test comparing models with separate estimates for the two subtypes versus a single estimate across subtypes.Multivariate Cox proportional hazards regression stratified by histologic subtype and time period was used to examine the association between risk factors and the incidence of ductal and lobular subtypes. For each exposure, we calculated the P-heterogeneity (het) = 0.03), age at first birth (P-het < 0.001) and postmenopausal hormone use (P-het < 0.001) were more strongly associated with lobular cancers. The associations with age, nulliparity, parity, age at menopause, type of menopause, alcohol intake, adult body mass index (BMI), BMI at age 18, family history of breast cancer and personal history of benign breast disease did not vary by subtype (P-het ≥ 0.08). Results were similar when we restricted the analyses to estrogen receptor-positive and progesterone receptor-positive tumors.The associations with age at menarche (These data indicate that breast cancer is a heterogeneous disease, and the differential association with a number of risk factors is suggestive of etiologically distinct tumors. Epidemiological analyses should continue to take into account a modifying role of histology. Epidemiologic studies have shown that reproductive, lifestyle and anthropometric exposures are predictive of subsequent breast cancer risk ,2; howevBesides the studies of PMH and breast cancer risk by histology, few large studies have evaluated whether the association of other well-established breast cancer risk factors varies by histology -10. Moren = 92,468). Follow-up has been high in this cohort . The study protocol was approved by the Institutional Review Board at Brigham and Women's Hospital.The NHS was initiated in 1976, when 121,700 female registered nurses between the ages of 30 and 55 and residing in 11 U.S. states completed a self-administered, mailed questionnaire about their medical histories and health-related exposures . Every 2We obtained information on the exposures of interest from one or more of the biennial questionnaires completed by participants. On the baseline questionnaire, we collected information on date of birth, age at menarche, weight at age 18 and current height. The baseline and all subsequent questionnaires requested information on status and duration of PMH use, menopausal status, type of menopause, history of benign breast disease (BBD) and current weight as well as, beginning in 1978, the type of PMH.For the other exposures of interest, questions were included on multiple but not all questionnaires, and we updated the value for each covariate when new information was available or otherwise carried forward the value from the previous follow-up cycle. For the exposures that were collected at a single time point , we carried forward the value throughout the remainder of follow-up. Age at menopause was requested on all questionnaires through 2000 and menopausal status was included on all questionnaires through 2002, at which time the youngest participants were 55 years of age. We assessed age at first birth (AFB) and parity on every NHS questionnaire until 1984 and again in 1996 to update the data on each woman's lifetime pregnancy history. Data on family history of breast cancer in a first-degree relative were collected every 4 to 8 years beginning in 1976. Daily alcohol consumption was first queried in 1980, then in 1984 and 1986 and every 4 years thereafter.in situ were censored. On each questionnaire, we asked whether breast cancer had been diagnosed and, if so, the date of diagnosis. We asked all women who reported breast cancer (or next of kin for those who had died) for written consent to review the pertinent medical records for confirmation. We also searched the National Death Index for breast cancer deaths among women who did not respond to the questionnaires, which accounted for less than 1% of confirmed breast cancer cases. Pathology reports or cancer registry data were obtained for 95% of the cases. Histologic type and ER or PR status were based upon extraction from the medical records. Invasive tumors of mixed ductal and lobular type or of other or unknown histology were censored at the date of diagnosis.The primary end point was the diagnosis of invasive ductal or invasive lobular breast cancer. Carcinomas in situ  or any invasive cancer except nonmelanoma skin cancer , those reporting no year of birth (n = 161) and those who died before 1980 (n = 461). Women were censored at the time of development of DCIS or any type of invasive cancer except nonmelanoma skin cancer. Only postmenopausal women were included in the analysis, because the analysis included many hormonal factors that may operate differently in pre- and postmenopausal women, and we had limited numbers of woman with premenopausal lobular breast cancers. Women who were premenopausal at baseline began contributing person-time to the analysis at the time that they became postmenopausal. Menopause was defined as natural, radiation-induced (very few women had radiation-induced menopause: ~0.14%) or surgical .We excluded the following women at baseline from the analysis: those reporting a previous diagnosis of ductal carcinoma 2), BMI at age 18  and alcohol consumption  as categorical variables. Continuous variables were used to assess P trend. Family history of breast cancer in a first-degree relative and personal history of BBD were modeled as binary variables (yes or no). We carried forward the last self-reported exposure data for one cycle if the data were missing. Otherwise, women with missing information were included in the analysis using indicators for the missing variables. Findings were similar in analyses including only nonmissing data .Participants accrued person-time from the return date of the baseline questionnaire until the date of breast cancer diagnosis, diagnosis of any other cancer (excluding nonmelanoma skin cancer), death or the end of follow-up (2006). Participants contributed person-time only for follow-up periods for which they were postmenopausal. For the reproductive and hormonal exposures, we modeled age, age at menarche and age at menopause as continuous variables to minimize the number of parameters in the model. We used categorical variables to model type of menopause , nulliparous or parous, AFB  and PMH use  <5 years, current estrogen and progesterone (E + P) <5years, current other ≤10 years, current E 5-10 years or current E+P 5-10 years). For analyses of duration of PMH use by type of PMH, we included only PMH use durations of ≤10 years because PMH use longer than 10 years was for the most part limited to E-alone formulations. PMH use for women with use for >10 years was censored. For the nonreproductive exposures, we modeled recent body mass index (BMI)  and 95% confidence interval (CI) of invasive cancer overall for each exposure. We then restricted the analysis to cases with ductal or lobular histology and used Cox proportional hazards regression stratified by type of outcome and time period to allow for different associations by histologic subtype . We usedP value for heterogeneity (P-het) using a likelihood ratio test, with the degrees of freedom equal to the difference between the number of parameters in the full and reduced models. Using a stepwise-down approach, we set exposures with a nonsignificant P-het (P > 0.05) to have a single parameter estimate across subtypes so that the final model estimated two separate associations for exposures that differed significantly by subtype and a single parameter estimate for all other exposures. In the current analysis, we show the results from the model that allowed all the associations to vary (full model). In secondary analyses, we also examined these associations limited to ER-positive and PR-positive tumors.We compared a model that assumed different associations for all exposures by histologic subtype (full model) to a model with a single estimate across histologic subtypes for one exposure at a time (reduced model). We calculated the P values were based on two-sided tests and were considered statistically significant if P ≤ 0.05.All analyses were conducted using SAS version 9.1 software . All At baseline, our analysis included 37,127 postmenopausal women and then expanded to 107,759 women by the end of follow-up. During 1,774,075 person-years of follow-up, we observed 6,226 incident cases of invasive breast cancer. Of these, 4,655 were ductal and 659 were lobular carcinomas   Table . AlthougP-het = 0.03, <0.001 and <0.001, respectively). Age at menarche was inversely associated with risk of both ductal and lobular cancers; however, the association was stronger for lobular cancers .The associations with age at menarche, AFB and PMH use differed significantly by histology (P-het < 0.001). For example, compared with the reference group , the RRs associated with an AFB between 30 and 34 years old were 1.21  and 2.31  for ductal and lobular cancers, respectively. There was significant heterogeneity when modeling AFB and parity as continuous variables . For ductal and lobular tumors, respectively, the RRs for every 5-year increase in AFB were 1.12 (P trend < 0.001) and 1.48 (P trend < 0.001), while the RRs for each additional birth were 0.97 (P trend = 0.01) and 1.05 (P trend = 0.11).Increasing AFB was associated with an increasing risk of both ductal and lobular cancers, although the results were stronger for lobular cancers (P-het < 0.001). Compared to never users, past use was not significantly associated with risk of ductal or lobular breast cancer . Current use of E alone for <5 years was associated with a statistically significant increase in the risk of lobular cancer  but not ductal cancer , while use of E alone for 5 to 10 years was associated with an increased risk of both cancer types, albeit the risk for lobular tumors was stronger . Current E+P use was associated with increased risks of both subtypes of breast cancer, although we found a stronger RR for lobular than ductal cancers within each duration category. Specifically, the RRs for <5 years of use vs. no use were 1.56  for ductal cancer and 2.16  for lobular cancer, while the RRs for 5-10 years of use were 1.75  and 3.12  for ductal and lobular cancers, respectively.There was significant heterogeneity for PMH use across subtypes (P-het = 0.20) (Table P-het = 0.16). For each five-unit increase in BMI at age 18, there was a significant 23% and 22% decrease in risk of ductal and lobular cancers, respectively. We [P-het = 0.02) with a stronger positive association for ductal vs. lobular tumors . However, the sample size was reduced .BMI was positively associated with risk of both subtypes (vely. We  and othevely. We  have shoP-het = 0.11 for each five-unit increase).The positive associations for family history of breast cancer and a personal history of BBD were similar across the two subtypes Table . There wP-het ≥ 0.16). Nevertheless, there was significant heterogeneity for the relationship with increasing parity when we modeled this exposure continuously (P-het = 0.05). Similar to the analysis including the entire cohort, the protective effect of parity was stronger for ductal vs. lobular tumors. For the nonreproductive exposures, there was significant heterogeneity for the association with BMI at 18 years of age (P-het = 0.03) and increasing daily alcohol intake (P-het = 0.02), with a stronger association for lobular cancers but no heterogeneity of effect for adult BMI, family history of breast cancer or history of BBD (P-het ≥ 0.07).Since lobular tumors are more likely to be ER-positive and PR-positive than ductal cancers, we restricted analyses to ER-positive and PR-positive tumors in secondary analyses to address whether our observations were driven by differential proportions of hormone receptor positivity between ductal and lobular tumors. A total of 2,233 tumors ER-positive and PR-positive tumors were included in this analysis  were 1.24 for ductal cancer and 1.66 for lobular cancer; however, individually, most studies had limited power, and only the Million Women Study reported a statistically significant difference in the RRs by subtype . Phipps  subtype ,21,22. PP values  and the istology ,25,26.To date, 10 case control and 7 cohort studies have examined the relationship between PMH use and risk of developing ductal and lobular carcinoma . Of theset al. [et al. [et al. [Fewer studies have examined the relationship between duration of hormone use and risk ,29,35-38 [et al.  reported [et al. ,36,37. W [et al. . Nonethe [et al. ,40.P-het = 0.008), but no significant associations for the other subtypes [Epidemiological studies have demonstrated a positive association between BMI and postmenopausal breast cancer risk , althougsubtypes . We did To our knowledge, ours is the first study that has evaluated an association between BMI at age 18 and risk of postmenopausal breast cancer by histologic subtype. In general, adolescent obesity is inversely associated with breast cancer risk . In a pret al. [P-het = 0.11). Despite these findings, there was significant heterogeneity for this association when we limited the analysis to ER-positive and PR-positive tumors (P-het = 0.02). Given the inconsistent results, further research is needed for this exposure.Two prior studies reported a significant positive association between alcohol consumption and risk of breast cancer overall, which was stronger for lobular compared with ductal cancer among postmenopausal women (odds ratio (OR) = 1.8 vs. 1.2  and 1.5 et al.  found a et al. [In our analysis, family history of breast cancer and a personal history of BBD were similarly associated with increased risk of breast cancer, regardless of subtype. Three prior studies have evaluated the relationship between family history and risk by histology ,20,26. Ret al. . No confet al. . A previOverall, the relationship between the exposures evaluated in the current study and the risk of breast cancer was within the expected range and both subtypes showed similar directions; however, the associations for age at menarche, AFB and PMH use were stronger for risk of lobular vs. ductal tumors. Since lobular tumors are more often hormone receptor-positive, it is not entirely unexpected that various hormonal or reproductive risk factors may be more strongly associated with this subtype. The proposed mechanism underlying the association between an earlier age at menarche and risk likely is via its effect on the number of lifetime ovulatory cycles, which in turn influences lifetime exposure to endogenous ovarian hormones . Parity Major strengths of our study include the large number of participants and high participation rate, resulting in adequate statistical power to conduct stratified analyses. Further, the prospective nature of the NHS cohort allows for the analysis of repeated measures of most exposures and confounders, limiting the effect of measurement error. In addition, the methods used in this analysis allowed for the estimation of separate associations with each subtype simultaneously, as well as formal tests for differences in risk across subtypes. Although our analysis included a large number of invasive breast cancer cases, we did not have enough cases to assess risk with less common histologic subtypes . Further, our analysis of ER-positive and PR-positive tumors was less well-powered, given that hormone receptor status was not available for all cases. An additional limitation was that we classified histologies on the basis of a review of pathology reports and did not conduct a centralized pathology review. This could lead to nondifferential misclassification of tumor histology and attenuate the associations.In summary, the results from this study provide evidence that some reproductive or hormonal and nonreproductive factors are differentially associated with risk of postmenopausal breast cancer on the basis of histologic subtype. For the most part, our results are consistent with prior reports, complementing the growing body of evidence suggesting etiologic heterogeneity between ductal and lobular tumors. Future risk factor analyses should continue to investigate associations stratified by histology.in situ; E: estrogen; E + P: estrogen and progesterone; ER: estrogen receptor; NHS: Nurses' Health Study; OR: odds ratio; P-het: P value for heterogeneity; PMH: postmenopausal hormones; PR: progesterone receptor; RR: relative risk.AFB: age at first birth; BBD: benign breast disease; BMI: body mass index; CI: confidence interval; DCIS: ductal carcinoma The authors declare that they have no competing interests.JK helped to design, analyze and interpret the data and drafted the initial manuscript. WYC helped to design, analyze and interpret the data and did critical revisions of the manuscript. MAG helped with statistical analysis and data interpretation. SEH and SST both helped analyze and interpret the data and critically revised the manuscript. BAR helped with statistical analysis, interpreted the data and critically revised the manuscript. All authors read and approved the final manuscript.


Breast cancer is the most prevalent women's cancer, with an age-adjusted incidence of 122.9 per 100,000 US women. Cadmium, a ubiquitous carcinogenic pollutant with multiple biological effects, has been reported to be associated with breast cancer in one US regional case-control study. We examined the association of breast cancer with urinary cadmium (UCd), in a case-control sample of women living on Long Island (LI), NY (100 with breast cancer and 98 without), a region with an especially high rate of breast cancer  and in a representative sample of US women . In a multivariable logistic model, both samples showed a significant trend for increased odds of breast cancer across increasing UCd quartiles . Compared to those in the lowest quartile, LI women in the highest quartile had increased risk for breast cancer  and US women in the two highest quartiles had increased risk . Further research is warranted on the impact of environmental cadmium on breast cancer risk in specific populations and on identifying the underlying molecular mechanisms. Breast cancer is the most prevalent women's cancer worldwide . AlthougIn 2006, McElroy  reportedIn humans, cadmium has an elimination half-life of 12 to 30 years . CadmiumBecause of the relatively high incidence of breast cancer on LI, we looked for associations between urine cadmium and breast cancer in a case-control sample of women living on LI obtained from the Long Island Database Project for Breast Cancer (LIDPBC), a repository of demographic and health data of female residents of LI. The results were compared to a cross-sectional U.S. probability sample, the National Health and Nutrition Examination Survey (NHANES 1999-2008) .In weighted, unadjusted, logistic regression analyses, log-transformed UCd, menopause, and continuous age in years were significantly associated with increased risk of breast cancer in both the NHANES Table  and LIDPIn a weighted, unadjusted, logistic regression model Table , women iIn a common, multivariable-adjusted model Table  (adjusteThe LI never-smoker cases (n=43) and never-smoker controls (n=58) had significantly higher UCd, 0.53 ug/g and 0.46 ug/g, respectively, than the NHANES never-smoker cases (n=55), 0.38 ug/g and the NHANES never-smoker controls (n=1885), 0.33 ug/g . When smokers are included, the LI cases (n=100) also had a significantly higher median UCd, 0.59 ug/g, compared to the NHANES cases (n=99), 0.45 ug/g (p=0.003), whereas the median UCd of the LI controls  was not significantly higher than the NHANES controls  (p=0.224).Despite some differences between the LIDPBC and the NHANES samples with regard to race/ethnicity, age and lifestyle factors, the findings of both studies indicate an increased risk for breast cancer with increased body burden of cadmium, with similar effect estimates. These concordant findings from a cancer registry-based sample from a geographic region with a relatively high incidence of breast cancer and from a cross-sectional, national probability sample support an association between environmental cadmium exposure and risk of breast cancer, as initially reported in a non-occupationally exposed group of women in Wisconsin. Since LTo estimate the potential impact of cadmium body burden on breast cancer risk for the exposed LIDPBC sample, we calculated an attributable risk percent for individuals with UCd ≥0.37 μg/g (weighted median for NHANES sample) based upon relative risk estimated from cross-tabulated frequencies for exposure and breast cancer in the LIDPBC sample. Because causality has not been established, we use the term excess fraction . AssuminA limitation of the NHANES sample is lack of family history of breast cancer. Additionally, self-report of breast cancer diagnosis might introduce a misclassification bias not present in the LIDPBC sample. Renal dysfunction may be induced by cadmium exposure  and by cIn the NHANES sample, the median difference between age at breast cancer diagnosis and age at UCd measurement was 7 years, and ranged from 5-12 years in the LIDPBC sample. Thus, women from both samples may have higher UCd levels than at the time they were diagnosed with breast cancer. To address a potential influence of incremental yearly age with regard to urine cadmium levels, a continuous variable for age in years was substituted for the categorical age group variable in each sample model, a continuous log-transformed UCd variable was substituted for UCd quartiles, and tested for interaction. The LI model showed a statistically significant association between breast cancer and the log-transformed UCd , but the interaction between age and UCd was not statistically significant and the model fit was adequate with main effects . The NHANES model, however, showed a statistically significant interaction (p=0.012). Stratification by median age (54 years) adjusted for year of age, showed that there was no significant association among women older than 54 years and significantly increased risk for women age 54 or younger in the third and fourth UCd quartiles . Confidence intervals were wide due to small sample size. McElroy  also fouThe extent to which urine cadmium reflects long-term cadmium exposure may be influenced by age. Lauwerys  suggesteBreast cancer phenotype is another unmeasured factor, as cadmium has been associated with basal breast cancer cell transformation in tissue culture , and basAlthough smoking is a well-established source of cadmium exposure, we found similar estimates for an association between increased UCd and breast cancer, independent of tobacco use in both samples, as was also reported by McElroy  in a WisThe reason that never-smoking LI residents with or without breast cancer participating in this study have significantly higher total body burdens of cadmium than non-smoking women in the US sample is not known. Furthermore, a larger population-based study of breast cancer as a function of cadmium body burden in long-term residents of LI is needed to determine whether there is greater cadmium exposure in this region than in the US in general. If true, this could be a lead toward understanding at least one factor that may contribute to increased breast cancer risk in certain populations.The molecular mechanisms underlying the ability of cadmium to increase risk of specific cancers remain to be delineated. The fact that cadmium may directly lead to cellular transformation of breast cells to a cancer phenotype and also bind to and activate the estrogen receptor alpha, as well as accumulate in breast adipose tissue, as reported by Antila , are intThe carcinogenic effects of cadmium could also be mediated in part by its ability to interfere with the function of p53, a key regulator of many components of DNA-damage induced defense mechanisms  and by iIn addition, cadmium alters a number of molecular pathways, which regulate cell development and growth including the E-cadherin/β-catenin complex and genes activated in response to mitogens such as c-fos, c-jun, and c-myc and/or are induced by stress ,47. ChenOur findings, like those of McElroy et al , indicatIn addition to breast and other cancers ,57, therFurther research is needed to evaluate the extent of risk that increasing environmental concentrations of cadmium pose for breast cancer and to identify specific sources of cadmium exposure, particularly in geographic areas with high breast cancer rates. Moreover, studies of the interplay between cadmium exposure via particular foodstuffs and gastrointestinal absorption may provThis investigation has been conducted in accordance with the ethical standards and according to the Declaration of Helsinki and according to national and international guidelines and has been approved by the Committee on Research Involving Human Subjects at Stony Brook University, Stony Brook, NY, USA.Data for the case-control study of LI women were obtained from the LIDPBC comprised of 605 women, age 30 years or older, living on LI for, at least, 5 consecutive years prior to entry on study, 373 of whom had histologically documented breast cancer diagnosed after January 1, 1998 through December 31, 2004 and 232 women in the same region without a history of breast cancer. Cases in the LIDPBC had been identified through the cancer registry of Stony Brook University Hospital and contacted by their primary physicians to determine interest in participating. The control group was a purposive sample recruited from the community through local ads, presentations at health fairs, fundraisers for breast cancer research, and word of mouth, primarily through the breast cancer participants. Those providing informed consent completed a demographic, occupational, and health questionnaire under the supervision of a trained interviewer, including family history of breast cancer, use of hormone therapy other than birth control pills, age at first live birth, and menopausal status, provided a blood sample, and agreed to be contacted as to their interest in participating in future studies. For the present cadmium study, enrollees in the LIDPBC were invited to participate by mail. The first 100 women who had had breast cancer and the first 100 women without breast cancer to agree to the study were selected. Participants completed an informed consent, which included permission to use their questionnaire information on file in the LIPDBC, and provided a single urine sample. From 2008-2009, urine was collected in a coded cadmium-free urine container and sent to ARUP Laboratories  for measurement of urine cadmium by inductively coupled plasma-mass spectrometry (ICP-MS)and measurement of urine creatinine.Data were obtained from NHANES, a cross-sectional, random household survey of the civilian population based on a probability sampling design  for survst quartile (Q1), UCd<0.22; 2nd quartile (Q2), 0.22≤UCd<0.37; 3rd quartile (Q3), 0.37≤UCd≤0.60; 4th quartile (Q4), UCd≥0.60. In addition, a dichotomous UCd variable, for values below and above the median UCd, was created for the LIDPBC sample using UCd frequency distributions for LIDPBC controls: UCd≤0.40 and UCd >0.40 μg/g. Three age groups were analyzed: 30-54; 55-68; and 69 and older. For the NHANES sample, Medical Examination Center subsample weights for participants with urine cadmium measurements and Taylor linearization methodology were used for analysis of the NHANES sample in accordance with complex survey design. For each variable in the two study samples, univariate logistic regression analysis was performed to evaluate its association with breast cancer status. The analyses were based on weighted data for NHANES sample and unweighted data for LIDPBC sample. For the LIDPBC sample, comparisons between the LIDPBC cases and controls were also made using two-sample t-tests for geometric mean of UCd and arithmetic mean of age, Mann-Whitney U-statistic for median of UCd, and Chi-square and Fisher's exact tests (when applicable) for proportions, such as age group, smoking status, etc.The NHANES and LIDPBC study samples were summarized by unweighted descriptive statistics: medians, means (arithmetic and geometric) and standard deviations for continuous variables, and frequencies and proportions for categorical variables. Quartiles for creatinine-adjusted UCd were generated using weighted frequency distributions for the entire NHANES sample and used to evaluate the relationship between cadmium exposure and breast cancer in both the NHANES and LIDPBC samples. The quartiles were: 1To evaluate the association between urinary cadmium and breast cancer, a series of logistic regression models were fitted to each sample including an unadjusted logistic model, an age-group adjusted logistic model, and a common logistic model, which adjusted for the same set of variables in both samples, and excluded variables with a p value >0.15 in univariate logistic regression analysis with breast cancer in both datasets. A final multivariable logistic model incorporating dataset-specific information, i.e., breast cancer family history, was also explored for the LIDPBC data, and race/ethnicity was added to the final NHANES model. Interactive effects between UCd and major covariates in association with breast cancer were also considered. We conducted further analysis of the sample stratified by the covariate, if the interaction term had a p-value ≤ 0.05. Odds ratios and their 95% confidence intervals (CI) were summarized. The linear association between UCd quartiles and breast cancer was analyzed by trend test. Models for complex survey design met the convergence criterion and case-control models met Hosmer-Lemeshow test for goodness of fit. Stata version 8.2 was used to perform t-tests. All other statistical analyses were performed using SAS version 9.2. A two-sided p value of less than 0.05 was regarded as statistically significant.


There are breast cancer epidemiological and tumor behaviour disparities between black women in sub Saharan Africa and their counter parts in western high resource countries. In Uganda, the incidence of breast cancer has nearly tripled in over a four decades for uncertain reasons. High serum estradiol is a known risk factor for breast cancer among women in high resourced nations. The objective of this study was to establish whether high serum estradiol is an associated risk for breast cancer amongst a group of black Ugandan women.A case control study, conducted over eight month period with incident breast cancer as cases and the controls were without breast cancer but at risk and representative of the population from which the cases were chosen. Questionnaires were administered, clinical examination was done, serum estradiol level estimation was done using cobase immunoassay analyzer using Electro chemiluminescence Immuno assay (ECLIA). Data was analyzed using logistic regression model, and a p - value of less than 0.05 was considered significant. IRB approval was secured.A total of 140 women participated, 70 cases and 70 controls. The median estrogen levels was 43.2 pg/ml with IQR of 18.48 to 75.8 pg/ml, the value was higher among premenopausal women than those without cancer but with no statistical significance. No association was found between level of estradiol and breast cancer (p 0.647). The median oestrogen levels were significantly higher than normal levels in Caucasian women.There was no association between level of estradiol and breast cancer. This is yet another disparity between women of African origin and the non Africans in high resourced countries. There is need to explore more to explain this disparity. Breast cancer is the most common type of cancer diagnosed in women world wide, excluding skin cancer. Globally almost one third 32%) of all cancers diagnosed in women are breast cancer . In Ugan% of all High oestradiol exposure (≥ 8.03pg/ml) has been found to be a strong indicator for development of breast cancer, women with high levels have an up to 3.6 fold greater risk for breast cancer compared to women within the low levels .The purpose of this study therefore was to explore associations between high estradiol level and breast cancer among Ugandan women, as part of the mission to understand the apparent disparities between women in low resourced sub-Saharan Africa and the western high resourced nations. Ultimately the understanding of underlying biological mechanisms may contribute to novel therapeutic interventions.A case control study.Mulago hospital is a national referral and teaching hospital for Makerere University in central Uganda 2km from the city center. It has a bed capacity of 1500. The study was done at the Breast unit. It is the only public institution with comprehensive specialist-based and free breast cancer screening and care facilities. The unit receives at least three cases of incident breast cancer and five patients for the screening per week; an outpatient clinic runs once a week, the other services, radiotherapy, surgery, chemotherapy run through out the week. Primary care physicians recognize this center as the only free medical facility with comprehensive breast cancer specialists.Women who came to the breast unit with suspected breast cancer or those screened for breast cancer at Mulago Hospital during the six months study period who met the eligibility criteria and given an informed consent to participate in the study.All women presenting with incident breast cancer, confirmed by histology who were able to give relevant information for the study and consent to participate in the study were the cases. Women without breast diseases and had normal mammographic findings, who were able to give relevant information and consent for the study were the controls selected from patients that presented for screening and breast health care. All women with benign breast lesions, severely ill or unable to give relevant information, or pregnant, on HRT, contraceptive pills or diagnosed with any form of cancer were excluded. In the clinic patients were screened, history and physical examinations were done to exclude other conditions. Those without breast lump but within the age group for breast cancer screening were sent for mammography and are reviewed with mammography results. Those with lesion detected by mammography, went for Fine Needle Aspiration Cytology (FNAC). Those with clinically palpable masses were sent for mammography and FNAC. Further management followed depending on the results of the test. Needle and excision biopsies were the main procedures done in the clinic. When participants had consented and had gone through examination and investigations. They were divided into 2 groups, Women with a histological diagnosis of breast cancer were recruited in the study as cases while those with normal breast, were recruited in the study as controls. All information was recorded in a data collection form. The data collection method was an interviewer-administered questionnaire. The patients were recruited from the breast clinic.Serum specimens were obtained from all participants who adhered to a fat-free diet during the night and morning before the sample collection to minimize lipemia that could interfere with assays. Blood was drawn (phlebotomy), after the participant had consented. 3ml of venous blood was taken in a vacuum container with coagulant. For pre-menopausal women blood was taken only within the first seven days from the first day of menstrual flow since this period the estrogen level is not under the influence of physiology of menstruation.Serum was immediately analyzed or frozen, at negative 20°C. The sample was safe at this temperature for six months. Assays were performed concurrently on serum specimens from cases and controls. Cobase immunoassay analyzers using Electro chemilumine scence Immuno assay (ECLIA). Reagents used streptauidia coated micro-particles (M), anti estradiotab-biotin 9(R1) and estradiol-peptide-RU (bpy) R2. The lab was blinded to the case status. Reproducibility was determined using elecsys agents. Pooled human sera and controls in a modified protocol in a modified protocol (EP5-A) of the NCCLS .The questionnaire was pre tested to check whether it extracts the desired information. Data was checked for completeness before the participants are discharged from the study. Analysis was done using SPSS version 16 logistical regression model used, p-value Sample size calculation for estimation of association of serum estradiol with breast cancer; we determined it by Fleiss method with the correction factor  that 70 Informed consent was obtained from the participants. Appropriate ethical approval was sought.All 140 participants were female; 70 were cases and 70 controls. Pre tested questionnaires were administered, participants were from various parts of the country with majority being the Bantu ethnic group. The average age of the respondents was 45 year in the cases and 44 years in the controls .The distribution of factors in both the cases and the controls was mostly the same . HoweverCases had significantly lower body mass index than the controls. The age at menarche was significantly between the cases and controls however the numbers of cases were very small. There were no cases in the ever taken hormonal replacement therapy. Fewer cases than controls had ever been diagnosed with benign breast disease. Alcohol intake was greater in the control group than the cases.There was no difference in the median serum estradiol levels in the cases and controls. We could thus say that the median serum estradiol level in the study population was 43.2 pg/ml with interquartile range of 18.48 to 75.8 pg/ml. In this the control group is taken as the normal population representation , Table 3No difference was noted in the estradiol levels in the breast cancer cases and their controls in the premenopausal and the post menopausal though the post menopausal women had significantly lower estradiol levels in both the cases and the controls.The odds ratio (OR) of developing breast cancer disease increased by 1.02  for each unit increase in body mass index (BMI). Late onset of menarche associated had an Odds Ratio of 0.68  for developing breast cancer compared to women with early menarche, but this was not significant. History of having had hormonal replacement therapy was associated with an OR of 0.60 (95% CI 0.34 – 1.06) of developing breast cancer disease. History of having diagnosed with a benign breast disease is associated with OR of 0.65 (95% CI) for developing breast cancer disease. Alcohol intake was associated with OR of 0.73 (95% CI 0.55 – 0.96) of developing breast cancer .The central role of hormones in the etiology of breast cancer is support by multiple sources of evidence. In several epidemiology studies the role of endogenous hormones in risk of breast cancer among postmenopausal women has been delineated. A strong positive association between breast cancer risk and circulating levels of oestrogen has been well confirmed among postmenopausal women. Evidence among premenopausal women is more limited .In this study we found that high serum estrodial levels conferred no risk to both pre and post menopausal women in this sub Saharan African region but we also found that the serum oestrodiol levels in the control group was higher than that recorded in studies among Caucasian women in general.Breast cancer is considered to be associated with various documented risk factors. In this study the body mass index, age of menarche, history of ever been diagnosed with benign breast disease and alcohol intake were found to be associated with breast cancer disease.High BMI was associated with a marginally increase risk of breast cancer, this finding is supported by other previous studies done . This isEstrogens levels have shown great variations across different continents and ethnic populations world wide , 14. TheHigh levels of estradiol is associated with an increase in breast cancer risk in different parts of the world with serum estradiol ≥29.4pmol/L having 2.9 to 3.6 relative risk for breast cancer compare to those on the lower quartile ≤18.4pmol/L . In thisSingle samples were collected and analysed once, this may have introduced variations since dynamic changes in estradiol levels occur across a normal menstrual cycle therefore there was additionally limited ability to evaluate associations within specific parts of the cycle. Another factor that may have introduced bias and was not controlled for is the body mass index. Being a hospital based study; both the cases and controls may not be generalizable to the entire country's population, also recall bias may have been an issue perhaps compromising the accuracy of history given. Choice of controls using mammography is affected by the low sensitivity of mammography. It's also difficult to establish a causal relationship since we do not know whether the cause preceded the effect.No association was found between level of estradiol and the risk for breast cancer disease among this group of black women in eastern Africa, however the serum oestradiol levels were comparatively high in the normal (controls) compared to studies among Caucasian women, raising the question of enhanced aromatase activity and therefore requiring further studies in this indigenous African context.


We examined differences in knowledge and socioeconomic factors associated with 3 types of breast cancer screening  among African American, Arab, and Latina women.Community health workers used a community-based intervention to recruit 341 women  in southeastern Michigan to participate in a breast cancer prevention intervention from August through October 2006. Before and after the intervention, women responded to a previously validated 5-item multiple-choice test on breast cancer screening (possible score range: 0 to 5) in their language of preference . We used generalized estimating equations to analyze data and to account for family-level and individual correlations.P < .001).Although African American women knew more about breast cancer screening at the baseline , all groups significantly increased their knowledge after participating in the breast cancer prevention intervention (posttest median scores were 5 for African American and 4 for Arab and Latina women). Generalized estimating equations models show that Arab and Latina women made the most significant gains in posttest scores (Racial/ethnic differences in knowledge of breast cancer screening highlight the need for tailored information on breast cancer screening for African American, Arab, and Latina women to promote adherence to breast cancer screening guidelines. Despite growing interest in factors associated with cancer-related disparities and interventions to reduce disparities, information is still limited regarding differences in screening practices by geographic location and effective tailored interventions for specific racial/ethnic groups. African American and Latina women have disproportionately higher death rates due to breast cancer yet nationally lower incidence rates than those of their non-Hispanic white counterparts . AlthougAs women's screening rates for breast cancer increase nationally, barriers to screening remain for African American, Arab, and Latina women from poor backgrounds. Multiple factors are associated with breast cancer screening rates among these groups of women, including socioeconomic status, health insurance coverage, usual source of care, perceptions and fears about breast cancer, race, ethnicity, age, and knowledge of breast cancer screening -8.A special edition of the Michigan Cancer Behavioral Risk Factor Survey (BRFS) conducted in 2006  disaggreWe studied differences in knowledge of and socioeconomic factors associated with breast cancer screening and assessed baseline and postintervention test scores on the knowledge of breast cancer screening practices among African American, Arab, and Latina women who participated in the Kin Keeper Cancer Prevention Intervention, a family-focused educational intervention for women . We hypoThe Michigan State University institutional review board approved this study. The locations of the community-based study were southeastern Michigan, in the cities of Detroit and Dearborn. Detroit is the largest city in Michigan and the 11th most-populated city in the United States. Approximately 80% of the residents are African American and 5% are Latino/a, according to the 2000 US Census. The 2006-2008 US Department of Treasury American Community Survey data for Michigan indicates that the city's median annual household income is $29,526 compared with Dearborn's $44,650. Nearly 33% of the residents in Dearborn are Arab; the city has the largest Arab population outside of the Middle East.Study participants came from 1 of 3 community-based organizations affiliated with the Detroit Department of Health and Wellness Promotion: 1) Village Health Worker Program, 2) Community Health and Social Services (CHASS), and 3) the Arab Community Center for Economic and Social Services (ACCESS). Although the health department serves all racial/ethnic groups, for the purposes of this study, it was asked to recruit only African American and Latina women through its healthy lifestyle program. CHASS, known for its specialized services to Latinos/as in Detroit, recruited Latinas from the REACH Detroit Partnership (a diabetes prevention and complications program). ACCESS, which is located in Dearborn, recruited Arab women from its healthy lifestyle program. The organizations had credibility in the community and employed community health workers (CHWs). We used the Kin Keeper model to recruit women and deliver breast cancer education in the homes of a family member (the kin keeper) -13.The Kin Keeper Cancer Prevention Intervention is community-based; it uses CHWs to educate groups of female family members about breast or cervical cancer or both -13. In 2This model has a unique recruitment method: CHWs recruit clients/kin keepers and kin keepers recruit female family members. It begins with cross-training CHWs  in the basics of breast and cervical cancer prevention and control and recruitment of clients into the study ,13. AfteEach family unit received 2 home visits. At the first home visit, participants signed informed consent forms and completed pre-intervention (baseline) sociodemographic forms and a 16-item assessment of breast cancer literacy. Both the sociodemographic and the cancer literacy assessments were administered orally; participants followed as the CHW read in the preferred language. Latina and Arab CHWs were bilingual and at some visits had to read in both English and the preferred language, which allowed us to measure participants' actual knowledge about screening for breast cancer regardless of their ability to read and comprehend the assessment items. From the second home visits, 333 women were retained , resulting in an overall sample retention rate of approximately 98%.The 16-item assessment tool for breast cancer literacy has 3 domains: 1) cancer awareness, 2) knowledge and screening, and 3) prevention and control. It uses a multiple-choice and true-or-false format, and has been validated  . For theAfter completing the intervention pretest to assess breast cancer literacy, participants received the education followed by a posttest. The home visit lasted 1.5 to 2 hours. CHWs who needed to speak in 2 languages took longer. At the end of the first home visit, the second home visit was scheduled for 1 to 3 weeks later. At the second home visit, the second posttest was administered before the second educational session. During the second educational session, CHWs cleared up myths, answered questions, and reviewed basic points. Then they administered a third posttest and worked with participants to complete a personal action plan.We analyzed 5 binary outcome variables in this study, each corresponding to a response on the knowledge and screening domain of the assessment tool for breast cancer literacy (1 if correct and 0 if incorrect). We used baseline and postintervention responses  to compare racial/ethnic differences in knowledge of breast cancer screening, which allowed us also to assess changes in knowledge of breast cancer screening for each race/ethnicity.2 and Fisher exact tests were performed to test for categorical association. For these preliminary analyses, familial association was ignored. We used SAS version 9.1  to perform all statistical tests and modeling. Statistical significance was set at P < .05.We graphed the distributions of the pretest and posttest scores and computed descriptive statistics for the whole sample and by racial/ethnic group. Sociodemographic characteristics were analyzed by race/ethnicity. Two-sided χTo analyze differences in women's knowledge of breast cancer screening by race/ethnicity and across time, we considered generalized estimating equations (GEE) models -19 accoukfij is given by the following equation:The probability of answering each question correctly was modeled separately, controlling for age, income, highest level of education attained, marital status, employment status, and health insurance status. The basic GEE regression model for the binary outcome wEquationlog(pr(wkfij=1)1−pr(wkfij=1))=βjk+γCkfij,kfij be the binary variable defining whether the question under consideration is answered correctly (wkfij = 1) or not (wkfij = 0), for woman i of family f of race k at time point j (j = 1 for baseline test and j = 2 for postintervention test). Parameter jkβ represents the log odds of answering correctly a question at time point j for race k, adjusted for covariates in the design vector kfijC. The standard error of the estimate of jkβ is typically computed from the sandwich estimator of the variance-covariance matrix of the parameter vector estimate, which takes into account the longitudinal nature of the binary outcomes and the familial clustering.Let wP < .001). Overall, 61% of the women were aged 40 years or older, the age category of women recommended for yearly mammography screening (P < .001), as depicted by distribution, which is relatively skewed compared with the pretest distribution in Sociodemographic characteristics differed significantly by race/ethnicity . Africancreening . Scores creening  and postcreening  were comIn the pretest, Arab women had lower odds of correctly answering the first question (who does a breast self-examination?) than did African American women , adjusted for other sociodemographic variables . SimilarFor Latinas, pretest results were somewhat similar to those of Arabs. The GEE-based analysis showed that Latinas had lower odds of correctly answering each question in the pretest than African Americans, except for questions 3, 4, and 5, in which the GEE-based odds were not significant. Latinas had significantly lower odds of knowing the differences between breast self-examination, clinical breast examination, and mammogram than did African Americans.Posttest GEE estimates show that, compared with African American women, Arab women had lower odds of correctly answering questions 1 and 4, whereas Latina women had significantly lower odds of correctly answering question 4.To our knowledge this is the first study to empirically compare knowledge of breast cancer screening types among African American, Arab, and Latina women. It yielded 3 major findings: 1) knowledge of breast cancer screening practices was highly associated with race/ethnicity; 2) Arabs and Latinas had similar patterns of knowledge and lower levels of education and insurance coverage compared with African American women; and 3) knowledge of breast cancer screening significantly increased for Latinas and Arabs after community-based intervention, as evidenced by posttest scores.Overall, the results show that, controlling for sociodemographic characteristics, Arab and Latina women had lower pretest and posttest scores for breast cancer screening knowledge compared with African American women, despite significantly improving their scores in the posttest. Respondents did not fully understand the differences in breast cancer screening types.African American women's socioeconomic characteristics were highly associated with their higher knowledge levels. Overall, women with higher education levels had higher baseline knowledge of breast cancer screening and reported higher levels of breast cancer screening regardless of race/ethnicity. This finding is consistent with the results of previous studies that show education and access to health care are major predictors of cancer screening knowledge and practices ,21.The higher scores on knowledge of breast cancer screening among African American women may also be a result of benefits they received from earlier cancer disparities research that focused on African Americans and breast cancer screening awareness campaigns conducted in English. For non–English-speaking Latinas and Arabs, breast cancer awareness campaigns using Spanish and Arabic messages and materials ,22 have Irrespective of a woman's education level, posttest scores increased among the 3 groups; Latina and Arab women achieved the largest gains in knowledge of breast cancer screening. These findings demonstrate that information on breast cancer screening can be effectively provided when interventions address barriers. The Kin Keeper intervention mitigated 3 barriers: low education levels, literacy, and limited English language proficiency . If the For Arab women, community-based interventions are necessary to reduce disparities, given that they are more likely than non-Hispanic white women to have irregular screenings and cancer that is detected at later stages . LanguagAlthough CHWs completed the same training  and had Methodologic cautions are warranted in terms of instrument and identification of populations. As observed, future research needs to include definitions of medical screening procedures for women to ensure their understanding of survey questions being administered, particularly for low-income women with limited proficiency in English. A community-based study, by design, represents the unique needs of a particular geographic area and designated population groups. Therefore, the results are not meant to be applicable to the general US population. Other limitations include lack of longitudinal data to report knowledge retention and length of residency status of Latinas and Arabs who selected a language other than English.The inclusion of Arab women presented several challenges. Although the Arab world comprises various countries, including 10 in Africa , Arabs hBecause of the complexity of cancer disparities, education interventions must be developed that are appropriate to the linguistic, health literacy, and cultural needs of participants. Population-specific materials need to be administered in conjunction with community-based participants such as CHWs. Increasing women's knowledge about breast cancer screening is an important first step, but moving women in the direction of adherence to breast cancer screening guidelines and assuring their access to health care services would reduce disparities in breast cancer death and illness.


Lars Holmberg and Andrew Vickers discuss the importance of ensuring prediction models lead to better decision making in light of new research into breast, endometrial, and ovarian cancer risk by Ruth Pfeiffer and colleagues.Please see later in the article for the Editors' Summary PLOS Medicine:This Perspective discusses the following new study published in doi:10.1371/journal.pmed.1001492Pfeiffer RM, Park Y, Kreimer AR, Lacey JV Jr, Pee D, et al. (2013) Risk Prediction for Breast, Endometrial, and Ovarian Cancer in White Women Aged 50 Years or Older: Derivation and Validation from Population-Based Cohort Studies. PLoS Med 10(7): e1001492. Ruth Pfeiffer and colleagues describe models to calculate absolute risks for breast, endometrial, and ovarian cancers for white, non-hispanic women over 50 years old using easily obtainable risk factors.PLOS Medicine, Ruth Pfeiffer and colleagues present risk prediction models for breast, endometrial, and ovarian cancer In this week's issue of Ruth Pfeiffer and colleagues present models for absolute risks and thereby avoid the common mistake of proclaiming a substantial relative risk as clinically relevant without considering the background risk. For example, a relative risk of 3.0 corresponding to a risk increase from 1% to 3% may have quite different implications than an increase from 10% to 30% clinical decision-making—situations such as primary treatment of early prostate cancer or choice of adjuvant chemotherapy for early breast cancer—the emphasis on decision-making is laudable. What we want from models is that they help us make better decisions, leading to better outcomes for our patients. This raises the question of how to evaluate whether a model does indeed improve decision-making.The key claim of the paper is that the models “may assist in clinical decision-making.” While the examples in the paper predominately concern prevention, rather than what many readers would intuitively think of as x%, close to x will indeed have the event of interest. Calibration concerns average risk in a population and a well-calibrated model may assist in prevention decisions, but a miscalibrated model may lead to situations where an individual at high risk is assigned a low predicted probability, and thus forgoes effective preventive intervention. However, calibration is necessary but not sufficient for clinical utility, as the example of mammography screening shows: breast cancer risk prediction models are rarely used to determine eligibility for screening, which is instead based predominately on age, because very large differences in risk between women would be needed to justify separating women into higher versus lower intensities of mammography.As the authors state, good calibration is essential for good decision-making. A model is well calibrated if, for every 100 individuals given a risk of The statistical measure of how well a model separates risk is known as discrimination. But traditional analyses of risk factors are, on their own, not well suited to discriminate prognostic groups in a way that is useful for clinical decision-making http://www.decisioncurveanalysis.org).The paper by Pfeiffer and colleagues raises the critical issue of how we should determine the clinical utility of a model, whether it changes decisions, and whether those decisions are good ones. This is an issue that touches a variety of different areas in medical prediction, including comparisons of models and the value of novel molecular markers. Recent years have seen numerous methodological developments, going above and beyond a clear recommendation that clinical utility should be formally assessed Thus, there are now quantitative techniques available that can determine whether a model does more good than harm given reasonable assumptions about the consequences of false negatives compared to false positives. This takes us substantially further than the (unsolved) debate about whether model evaluation should prioritize calibration or discrimination The paper by Pfeiffer and colleagues is one of many current papers illustrating the need for quantitative evaluation of the clinical value of prediction models, needed to arm us to transfer rapidly growing medical knowledge to sound decision-making to the benefit of patients. Hopefully, we can have models and model evaluations that illuminate the whole spectrum, from public health decisions for groups of people to the vision of individualized medicine with individually tailored treatments.


The perception of breast cancer risk held by women who have not had breast cancer, and who are at increased, but unexplained, familial risk of breast cancer is poorly described. This study aims to describe risk perception and how it is related to screening behaviour for these women.BRCA1 or BRCA2 mutation had been identified in their family. Data collection consisted of an audio recorded, semi-structured interview on the topic of breast cancer risk and screening decision-making. Data was analysed thematically.Participants were recruited from a population-based sample . The ABCFS includes women diagnosed with breast cancer and their relatives. For this study, women without breast cancer with at least one first- or second-degree relative diagnosed with breast cancer before age 50 were eligible unless a A total of 24 interviews were conducted, and saturation of the main themes was achieved. Women were classified into one of five groups: don't worry about cancer risk, but do screening; concerned about cancer risk, so do something; concerned about cancer risk, so why don't I do anything?; cancer inevitable; cancer unlikely.The language and framework women use to describe their risk of breast cancer must be the starting point in attempts to enhance women's understanding of risk and their prevention behaviour. It has been argued that health and risk have replaced illness and disease as the domains of interest for medicine ,2. 'The It is increasingly recognised that risk perception is complex, multi-dimensional, and incompletely understood, and that research has failed to reach consensus on a model for measuring risk perception -9. ColliEven when people are able to recall an 'objective' risk estimate given to them by a health professional, in their day-to-day deliberations they might not utilise this estimate but instead rely on their own personal 'subjective' risk estimate . Lee  was diagnosed I started to have mammograms. ... at least if you feel that you've, been conscientious about, about monitoring all those things then, then that kind of removes that element of, of concern. Um, but other than that I'm not particularly tuned into it I don't think.She goes on to say,I don't think about it for eleven, eleven months and three weeks, and stupidly, I suppose I, I don't think about it until I go for the mammogram ... And I'm reasonably conscientious - in case you think I am absolutely hopeless - so I do the examination each month and, you know, or, as soon as someone starts talking about it. Um, but I don't worry about it otherwise.removes that element of concern,' so for her, it may be that screening does alleviate anxiety. There was evidence that these women sensed that they may be judged on the basis of their response to their risk of cancer; for worrying either 'too much' or 'too little'; or for not doing the recommended screening. These women wanted to show that they had achieved the 'right' balance, by not worrying excessively, and by adhering to the appropriate screening practices.This group all had one or two first-degree relatives diagnosed with breast cancer before the age of 50 years and, while they could identify that they were at higher than average risk, they were keen to emphasise that they were not overly concerned about their risk. Each was doing regular screening, based on the advice they had been given by a health professional. It was not possible to determine whether it was the freedom from concern that allowed them to pursue regular mammograms, or whether the regular mammograms alleviated anxiety, although Marcia indicates that being conscientious about monitoring her body 'do something about it'. For all of these women, yearly mammograms (starting before age 50) were performed in order to detect cancer at an early stage, but they also described the other strategies they used to reduce their risk. They talked about having a healthy lifestyle, reducing stress and monitoring their bodies through breast self examination. They could be described as 'vigilant' in the way they managed their risk, and some of these women used this term to describe themselves. For this group, the vigilance was inspired by their concern about their cancer risk, and the belief that their actions could reduce their risk of breast cancer. They admitted their concern about their risk, unlike the women in Group 1 who were keen to point out that they did not worry about cancer. Details of each participant displaying this risk management style are summarized in Table Six women were more comfortable expressing concern about their risk of breast cancer, and their response to the risk and concern was to 'Bev was asked to describe her risk of cancer,I always -- you know, I check my breasts ... I'm not um, you know, once a month and all that sort of stuff, but I do check them and I have regular -- the last mammogram I had they did an ultrasound. I hadn't had an ultrasound before that, and everything came back clear and um, so I'm pretty vigilant with it.Instead of describing her risk, Bev goes straight into a description of the things she does to manage risk. Vera had a similar response when asked to describe her own risk of cancer,Well I try and do the right thing ... as far as don't drink too much ... try and look after my diet, so I feel that perhaps it's sort of middle road, I wouldn't class myself as a high risk I don't thinkLAK: So what do you think puts people at that higher risk?Well perhaps if they don't go and have their mammograms. Um, ah, don't look after their health in general.vigilant' prevention behaviour like mammography and breast self examination. All women in this group conducted yearly mammography to manage the risk, even though not all had a first-degree relative diagnosed before the age of 50 years, and five of the six women were in their forties. Four of the woman in this group were also coded as 'one' for health services use, as they all had both a regular GP and a regular specialist, while two had only a GP, and accessed mammograms through their GP or BreastScreen.These two issues of risk and risk management were very closely linked for the women in this group to the extent that, for both Vera and Bev, the two concepts were interchangeable. For them, appropriate prevention behaviour had the effect of reducing their perceived risk. Therefore the concern they felt about their breast cancer risk was alleviated by 'why don't I do anything?' They said they knew they should be having mammograms, and gave a range of reasons for not doing so. Details of each participant displaying this risk management style are summarized in Table one in three', Trish felt embarrassed about her weight, and did not want a mammogram until she could lose weight. She had not had a mammogram for seven years. Isabelle described being in shock after her brother's death, and also being too busy to have a mammogram. Two women said that they 'would know' if they had breast cancer and gave this as a justification for not having mammograms. However, all the women in this group expressed disappointment in themselves for not being more vigilant (referring to themselves as 'slack' or 'stupid'). They all had had their first mammogram at a very young age (between the ages of 22 and 34 years) but none had managed to continue with routine mammograms since then, and described themselves as 'not doing enough.'Four women expressed concern about their risk of breast cancer due to a family history; but almost in the same breath asked themselves, 'Anne describes her feeling about her chances of getting cancer as,I'm not paranoid that I'm going to get it, but I'm still -- I'm not, I'm not sitting back and thinking ... I don't think I'll get it,slack' about prevention behaviour. Anne felt that she was 'pretty in tune' with her body and would 'know when there's something's wrong'. She describes her approach;But she described herself as 'And maybe that's why I'm a bit slack, maybe I think I'll know when there's - and actually I think that's what it is, I'll know when there's something wrong with my body...Connie seemed to be very concerned about breast cancer, so LAK asked her how often cancer would come to mind,I think weekly ... Which is a concern isn't it? That I don't do anything about it. Just worrying about it.not paranoid' but also as not thinking 'I don't think I'll get it.' Here she is articulating the range of risk perceptions available to her, and identifying herself somewhere in the middle of the continuum. Connie admits to thinking about breast cancer weekly, and to worrying about it. Along with their concern about breast cancer was the feeling that they were not doing what was expected of them to manage their risk. The women in this group were able to admit that they had not adhered to the 'ideal' model for managing their breast cancer risk, which would involve more vigilance (as demonstrated in the previous group), and all attempted to explain or justify their behaviour. Once again, their comments reveal women's sense that there are social expectations about the appropriate management of breast cancer risk, and that women would be judged  according to this perceived expectation.While Anne was able to articulate a reason for not doing her screening, and Connie could not, both were concerned about their risk of breast cancer, and both were able to recognise and articulate the inconsistency between their thoughts and behaviour. Anne described herself as 'For five participants, their familial history of cancer was interpreted as meaning that they were going to get breast cancer. They did not describe a level of risk, but instead talked about the inevitability of breast cancer. For some this meant they had regular mammograms in order to pick up the cancer early, for others a sense of fatalism led them to neglect screening. Details of the five participants displaying this risk management style are summarized in Table Alexandra described her risk of breast cancer as a 'time bomb' and therefore felt that there was little point doing anything to manage her risk. LAK asked her if she thought her smoking would influence her risk of getting breast cancer,Oh, probably ... But I figure it's probably gonna happen anyway, sooner or later - with our family history. I just go "oh, well, if it's gonna happen, it's gonna happen"Sue was distressed about her risk of breast cancer, and felt it was inevitable for her and her remaining sisters. This left her unable to undergo regular mammograms due to fear that it would lead to a cancer diagnosis.Sue    Well I think that breast cancer's going to get us all in my family. All the girls in my family.LAK   Do you think definitely?Sue    Um, yeah. I'm very bitter about breast cancer.//LAK   How much do you think about the risk of cancer?Sue    It's there all the time. I think about my kids growing up without a mum everyday.LAK   Really?Sue   All the time. Sorry. (crying)//LAK   So what about mammograms?Sue    Oh, I've been slack with them. It's always the thing that I'm scared of the results but I had one a few weeks agoLAK   How long would it have been since you had one before that?Sue   Ten years.Women in this group were convinced that they would get cancer. Rather than seeing breast cancer as an event with a level of probability attached to it, they saw breast cancer as a certainty in their life. This certainty had the potential to lead to fatalism and the sense that nothing they did would make any difference (for Sue and Raelene). However, three women in this group  were able to combine the sense that cancer was inevitable with regular screening mammography, showing the different consequences, depending on how they interpreted and responded to their risk perception.silly'. Neither had attended a specialist regarding their breast cancer risk. Details of the two participants displaying this risk management style are summarized in Table Finally, two women were convinced that they were not going to get breast cancer, despite their family history. Both women were uneasy about sharing their risk perception during the interview and prefaced their statements with the adjective 'Carly stated at several different points during the interview that she did not think that she was going to get cancer,I have...no this sounds silly, and I'll fall over if it happens...but I feel the, the three out of four got it, and for some reason I was blessed that I didn't get it, and for a long time there I felt so guilty -- that I didn't get it, you know//No, I don't feel that I'll get it. But when we moved down here and I went to the doctor and he started asking about family history and then sent me off to get a mammogram and speak to a breast specialists and things like that, but that was probably two years ago and I haven't done anything else.//I check myself every now and then, but not properly because I send positive thoughts,//So no, I don't think I'll get it.Lorna also thought she was not at risk of breast cancer, but she still had mammograms.Um, [sister] tended to take after mum's side of the family, I take after dad's side of the family. That's probably a very silly comment, but I mean I do have mammograms, but breast cancer is something that's never worried me.Both Lorna and Carly were reluctant to reveal their belief that they were not going to get cancer, as they appeared to understand that this was not a socially acceptable position for women with a strong family history of breast cancer. However, both were able to articulate the reason for their belief, and despite describing a similar perception of risk, they responded to it differently, one having mammograms, the other avoiding them when possible.Given the high level of unexplained familial risk participants were managing, it is of concern that half of these women had only ever seen a general practitioner about their risk and that only a quarter were consulting a specialist on a regular basis. The evidence of an effect of genetic counselling on risk perception or cancer worry is contradictory ,25, howeWhile women are generally able to tick a box, or mark a line to indicate their risk perception, the foregoing analysis suggests that they may have revealed only a small part of the whole picture. Risk perception was a layered concept for women in this study; their understandings of heredity, risk factors, genetics and popular discourses about cancer were overlaid with their sense of the social expectations about how they should interpret and manage their breast cancer risk; they felt they must justify thoughts and ideas that were inconsistent with their actions. In addition, even the interpretation of statistics was personal and varied from woman to woman. A woman may consider herself at a 'one in three' chance of getting breast cancer, but she may believe that she is not the 'one' who will get cancer in her family, while another woman may interpret a 'one in three' chance of getting cancer, to mean that she will therefore definitely die of breast cancer.While the tendency to see risk as a binary phenomenon (either it will or won't happen) has been reported by others ,34, hereWhile other qualitative research has found that women living at high risk tend to be either making lifestyle or health care adjustments to reduce risk ,35,36, wWhile there is agreement that understanding risk perception is an essential task if we are to assist women to manage risk, and make an informed decision about screening and prevention practices , there imiddle road' or 'one in three') provide only a portion of the information needed to understand their risk perception. Instead, risk perception, the emotional response to the risk perception and the practical response to risk perception are all interconnected and must be considered together.The analysis presented here is an attempt to answer the question; how do women perceive and manage unexplained familial breast cancer risk? We found no direct positive association between the number of family members diagnosed with breast cancer and perceived risk. We found that women's statements about their perceived risk (e.g. 'We recognised five 'risk management styles' expressed by women at high unexplained familial risk of breast cancer, and while this is unlikely to be an exhaustive list, it is a useful starting point. We argue that women's own way of making sense of their experience must continue to be considered legitimate and worthy of study.Given the main source of advice for many of these women was their general practitioner, this research also highlights the importance of GPs being adequately informed and resourced to manage risk assessment and the anxiety that will be associated for some women, and if not, for them to refer women to a more appropriate service and encourage them to attend. Women in this study who seemed best able to manage their risk were those who had a regular specialist, which may indicate that they were well informed and therefore able to negotiate the health care system effectively to arrange to see a specialist in the first place, or it may have been the interaction with the specialist that was facilitating and endorsing appropriate screening and management of risk.There are NO commercial associations that pose or create competing interests with the information presented in this manuscript.LAK conceived of the study, and participated in its design and coordination, conducted interviews, analysed the data and drafted the manuscript. BJM conducted interviews, contributed to the analysis and interpretation of the data, and commented on drafts of the manuscript, CA contributed to the study design, oversaw recruitment and commented on drafts of the manuscript, JLH contributed to study design, and interpretation of data analysis and commented on drafts of the manuscript. All authors read and approved the final manuscript.


The aim of the study is identification of correlations between the serum concentrations of iron and the risk of breast cancer among female BRCA1 mutations carriers and unselected breast cancer patients.The first group (99 triplet) selected for the trial were Polish women, positive for at least one of three founder mutations in BRCA1 gene dominating in Poland . Serum was collected at the time of breast cancer diagnosis. Persons with detected tumor were considered as cases and the others were considered as controls. One case and two controls were paired regarding many criteria  to achieve the maximum of similarity between them.The subjects of the second group (28 triplet) selected for the trial were Polish women, positive for at least one of three founder mutations in BRCA1 gene. Serum was collected 1-2 years before breast cancer diagnosis. One case and two controls were matched for year of birth, past history of cancer, adnexectomy status and cigarettes smoking to achieve the maximum of similarity between them.The subjects of the third group were unselected cancer for the trial were Polish women. Serum was collected during breast cancer diagnosis before treatment. One case and one control were matched for year of birth (+/- 3 years), number and location of cancer among Iº relatives, smoking-the number of pack years (+/- 10%), adnexectomy status, CHEK2 mutation.The proportion of cases and control in the first quartile was taken as a reference to calculate the odds ratio, confidence interval and p-value of the multivariate conditional logistic regression.The iron was quantitatively measured by ICP-MS (Inductively Coupled Plasma Mass Spectrometry), .This study shows that concentration levels of iron in blood serum are a strong factors associated with an additionally increased risk of breast cancer among BRCA1 mutation carriers and unselected breast cancer patients.For iron concentration in BRCA1 carriers (serum collected at the time of breast cancer diagnosis) all quartiles above the first one had a decreased risk of breast cancer. The results are shown in Table For iron concentration in BRCA1 carriers (serum collected 1-2 years before breast cancer diagnosis) the last quartile had a decreased risk of breast cancer. The results are shown in Table Individuals classified in the III and IV quartile had lower risk of breast cancer however results were statistically insignificant.The strongest result and lowest cancer risk was for Fe > 1350 μg/l For iron concentration in unselected breast cancer patients (serum was collected during breast cancer diagnosis before treatment) all quartiles were statistically insignificant. The results are shown in Table Individuals classified in the III quartile had lower risk of breast cancer however results were statistically insignificant.The strongest result and lowest cancer risk was for Fe > 1000 μg/l .For iron concentration in unselected breast cancer patients (serum was collected during breast cancer diagnosis before treatment) before 55 years old, third quartile had a decreased risk of breast cancer. The results are shown in Table Individuals classified in the III quartile had lower risk of breast cancer ;The strongest result and lowest cancer risk was for Fe concentration higher than 987 μg/l (III quartile) ; max 1285 μg/l (III quartile)


Tallness has consistently been associated with an increased risk of breast cancer. We investigated the association further by decomposing height into leg length and sitting height.From the prospective Danish cohort ‘Diet, Cancer and Health’, 23 864 postmenopausal women enrolled during 1993–1997 were followed for a diagnosis of breast cancer in the Danish Cancer Registry through 2009.P=0.47).The incidence rate ratios for breast cancer were 1.11 (95% CI=1.06–1.16) for each 5 cm increase in total height and 1.09 (95% CI=1.01–1.17) and 1.14 (95% CI=1.04–1.25) for each 5 cm increase in leg length and sitting height, respectively. There was no statistical significant difference between the associations for leg length and sitting height (Leg length does not seem to be more strongly associated with breast cancer among postmenopausal women than sitting height. Adult height has consistently been found to be positively associated with breast cancer   and women who had menstruated within the past 12 months and were current users of HRT (N=4125)).Women included in the present study were postmenopausal at baseline  were based on Cox regression models, with age as the time axis. Adjustments were made for parity , age at birth of first child (continuous), age at menarche (continuous), use of HRT (current/past/never), duration of HRT (continuous), alcohol intake (continuous), length of schooling (low: ⩽7 years/medium: 8–10 years/high: >10 years) and BMI at baseline (continuous). Women with missing information on these covariates (except age at menarche) were excluded from the analyses, thus, 23 864 women remained in the study cohort.To investigate whether the positive association between adult height and breast cancer is primarily due to an association with leg length, we tested whether the associations with leg length and sitting height were similar in a model including leg length and sitting height as well as covariates . We also calculated IRRs for ER-positive and ER-negative breast cancer as well as IRRs for ductal and lobular breast cancer, respectively . A heterogeneity test was performed for IRRs by histological subtype and by ER status. Tests were based on the likelihood ratio test statistics calculated from Cox’s partial likelihood. Confidence intervals were based on Wald’s test of the corresponding regression parameters, that is, on the log scale for the IRRs. The SAS procedure PHREG was used for statistical analyses .P=0.47).A total of 1209 breast cancer cases were identified during a mean follow-up period of 11.8 years (range 0.0–15.1 years) among the 23 864 postmenopausal women. The IRR for breast cancer was 1.13 (95% CI=1.08–1.19) times higher for each 5 cm increment in height after adjustment for age . There wHeight was positively associated with ER-positive breast cancer but not with ER-negative breast cancer, although there was no statistically significant heterogeneity in the risk estimates . PositivIn our large prospective study, we found that both components of height – leg length and sitting height were positively associated with risk of breast cancer among postmenopausal women. Height was positively associated with ER-positive breast cancer and with both ductal and lobular breast cancer.Our study had the advantage of utilising data from a large prospective cohort that included standardised measurements of heights performed by a trained technician and information on a variety of potential confounders. Also, we had reliable follow-up and breast cancer data. However, we lacked information on childhood growth and birth size that potentially could help elucidate the underlying mechanisms for the association between height and breast cancer.A positive association between adult height and breast cancer has been found in a large number of studies (in utero and childhood growth. Birth weight and length (Adult height may represent a proxy for Previous studies have generally not shown any clear differences for overall height associations by ER/PR status of the breast cancer cases  in line Our findings do not support that leg length is the component of height most strongly associated with breast cancer among postmenopausal women, thus decomposing height into leg length and sitting height did not add further information to explain why tall women are at greater risk of breast cancer than short women.