GHRL) and its receptor, the growth hormone secretagogue receptor (GHSR), play a role in cancer progression. Ghrelin gene and ghrelin receptor gene polymorphisms have been reported to have a range of effects in cancer, from increased risk, to protection from cancer, or having no association. In this study we aimed to clarify the role of ghrelin and ghrelin receptor polymorphisms in cancer by performing a meta-analysis of published case–control studies.There is growing evidence that the ghrelin axis, including ghrelin  and one ghrelin receptor  polymorphism in breast cancer, esophageal cancer, colorectal cancer and non-Hodgkins lymphoma.We conducted searches of the literature published up to January 2013 in MEDLINE using the PubMed search engine. Individual data on 8,430 cases and 14,008 controls from six case–control studies of an all Caucasian population were evaluated for three ghrelin gene (GHRL polymorphisms conferred reduced cancer risk (odds ratio [OR] 0.61-0.78). The risk was unchanged for breast cancer patients when analysed separately (OR 0.73-0.83). In contrast, the rs4684677 GHRL and the rs572169 GHSR polymorphisms conferred increased breast cancer risk . All dominant and co-dominant effects showed null effects (OR 0.96-1.05), except for the rs572169 co-dominant effect, with borderline increased risk .In the overall analysis, homozygous and recessive associations indicated that the minor alleles of rs696217 and rs2075356 GHRL) polymorphisms may protect carriers against breast cancer, and the rs4684677 GHRL and rs572169 GHSR polymorphisms may increase the risk among carriers. In addition, larger studies are required to confirm these findings.This study suggests that the rs696217 and rs2075356 ghrelin gene ( It is appreciated that ghrelin and its receptor (members of the ghrelin axis) play a role in the development and progression of cancer . GhrelinGHRL) or ghrelin receptor (GHSR) genes with cancer risk [GHSR gene polymorphisms with cancer risk to elucidate further the association between ghrelin axis gene polymorphisms and cancer.There is growing evidence that obesity and metabolic syndrome is associated with endocrine related cancers  and thatcer risk . Here, wGHRL) and ghrelin receptor (GHSR) genes. Previous studies reporting Caucasian genotypic data with case–control designs were chosen as eligible for this meta-analysis. In the first search, we used the terms, “ghrelin”, “polymorphism” and “cancer” which yielded 11 citations, five of which were excluded. From abstracts of the remaining six, one was excluded as it described an Asian population. Full texts of the remaining five studies were obtained, all of which complied with our inclusion criteria. In the second search, we entered the terms, “GHRL” and “cancer” in PubMed yielding 13 citations. A series of exclusions reduced the number to seven, full-texts of which were retrieved. We checked the reference lists of the full-text articles from both searches to minimize the possibility of missing relevant studies. Of the seven studies, six were either duplicated by the first search, or lacked genotype data, and therefore, only one further article was suitable for inclusion. Combining outcomes from the two searches gave a total of six articles which were included in our meta-analysis [Using PubMed, a literature search was performed for all association studies (available until January 2013) investigating links between cancer and the ghrelin  and the statistical power of each study. Assuming an odds ratio (OR) of 1.5 at a genotypic risk level of α = 0.05 (two-sided), power was considered to be adequate at ≥80%.var) and wild-type (wt) genotypes we estimated: (i) additive:  genotypes compared with the wt-wt, (ii) co-dominant: frequency of variant alleles, assuming the risk could differ across all three genotypes, (iii) recessive (var-var vs. wt-var + wt-wt) and (iv) dominant: (var-var + wt-var vs. wt-wt).The strength of association between the ghrelin polymorphisms and cancer risk was measured by odds ratios (ORs) with 95% confidence intervals (CIs). Pooled estimates of the OR were obtained by calculating a weighted average of OR from each study . For the2-based Q test [2-based Q test [2 statistic which measures degree of inconsistency among studies [To compare effects on the same baseline, we used raw data for genotype frequencies to calculate pooled ORs, which were obtained using either the fixed effects model , in the d Q test . Given td Q test , signifid Q test  and quan studies . Sensiti studies  and Sigm studies .GHRL) or ghrelin receptor (GHSR) single nucleotide polymorphisms (SNPs), the cancer type  and study sample sizes, are outlined in Table GHSR SNP (rs572169) showed effects other than null, and were examined further. The features of these four SNPs (in six different studies), which included cancer type , ethnicity, number of cases and controls, calculated statistical power, minor allele frequency (MAF) and HWE are summarised in Table A total of six genotyping studies –14,23 weGHRL polymorphisms  and the rs572169 GHSR polymorphism, and the effects observed in breast cancer studies alone are shown in Table GHRL polymorphism in breast, colorectal, esophageal and colorectal cancer were not altered when analyses were confined to breast cancer studies alone   was unaltered when confined to breast cancer studies   associated with breast and esophageal cancers was exacerbated when confined to breast cancer . Figure et al. [et al. [GHSR SNP rs572169 in breast and colorectal cancer  was also increased only when breast cancer was considered . While all of these effects of GHRL SNPs were obtained in zero heterogeneity (I2 = 0%), the effect of rs572169 was heterogeneous (I2 = 68-81%). Figure 2 = 68%) of the rs572169 increased risk pooled effect .The overall effects (odd ratios) for the three e et al. . On the  [et al.  is accomrs4684677 GHRL SNP  and the GHSR rs572169 SNP, both overall and in breast cancer (OR 1.08-1.10), with borderline significance (p = 0.05), all homogeneously obtained (I2 = 0-46%).Increased risks were also observed in the co-dominant model of breast cancer studies for the GHRL polymorphisms. Removal of the Dossus et al. [GHRL SNP rs696217 in the recessive model . The omission of the breast cancer study by Feigelson et al. [GHSR SNP rs572169 (from I2 = 68% to 0%), but left the pooled OR materially unchanged.Omitting the studies that deviated from HWE (including those at borderline level) did not materially alter the original summary effects for all four polymorphisms (data not shown). Sensitivity analysis did not alter the effects of the rs4684677 and rs2075356 s et al.  breast cn et al.  erased hGHRL SNP rs4684677 and a ~1.4-fold non-significant increased risk for the GHSR SNP rs572169. This GHSR polymorphism showed a ~1.1-fold increased risk, with borderline significance in the co-dominant model. In contrast, the rs696217 and rs2075356 GHRL polymorphisms were both protective (22% and 38%), suggesting linkage disequilibrium  between the two SNPs [GHRL SNPs have been linked with obesity [With a combined sample size of 22,438 , this meta-analysis provides evidence of overall homozygous and recessive associations, indicating a ~2-fold non-significant increase in cancer risk for the two SNPs . The str obesity ,26. TherGHRL rs2075356 (3056 T > C) and GHSR rs572169 (Gly57Gly) SNPs were found to be associated with 20% increased risk of breast cancer in a European study with 1,324 cases and 2,360 controls [GHRL SNP rs2075356 is present within the 3′ untranslated region of the recently discovered ghrelin transcript in2c-ghrelin, which is expressed in breast tumours, but not in normal breast tissue [The controls . These fcontrols ,28. Intet tissue , howevers2075356 56 T > C t tissue ,34.Each of the six component studies in our meta-analysis examined multiple polymorphisms of ghrelin and its receptors. The multiplicity of calculations involved necessitated statistical adjustment to avoid false-positive findings. All six studies were adjusted for multiple testing. Three used the conservative Bonferroni correction ,12,23, oet al. [et al. [These correction procedures, as well as the aforementioned features of the cases and controls in the component studies, reflect the overall strength of this meta-analysis. Other strengths of this study include: (i) ethnic homogeneity of the subjects given our focus on Caucasians only, resulting in minimal admixture and control for potential effects of population stratification; (ii) high sample sizes translating to robust statistical power of the component studies; (iii) statistical homogeneity in the comparisons, so that data in the included studies were similar enough to be pooled. Moreover, (iv) findings in the breast cancer subgroup were obtained in zero heterogeneity; (v) controls were either healthy or cancer-free and were matched to cases; (vi) tissue sources were blood; and (vii) all component studies were population-based which minimizes effects of selection bias, such that findings may be extrapolated to the general population. Nonetheless, limitations that need to be acknowledged are: (i) lack of representation in the various cancers (except breast cancer) disallowed further subgroup comparisons; and (ii) deviation from HWE among controls of Skibola et al.  and Wagn [et al.  in the rGHRL and GHSR SNPs may be involved in the pathophysiology of breast cancer. To our knowledge, this is the first meta-analysis to examine ghrelin polymorphisms and cancer risk. The demonstration of overall protective effects (of the rs696217 and rs2075356 SNPs) and increased susceptibility (for the rs4684677 and rs572169 SNPs) are derived from high-powered studies and are likely to increase the detection of low-penetrant effects. Further studies with larger and more well-defined sample populations are warranted to verify the role of GHRL and GHSR polymorphisms in cancer. This includes the analysis of additional metabolic, genetic and environmental contexts, which would be expected to influence the patient phenotype.In summary, our results indicate that


Evidence is lacking regarding the relationship between cigarette smoking and breast cancer in Japanese women. We examined the association between breast cancer incidence and active and passive smoking in the Japan Collaborative Cohort Study for Evaluation of Cancer Risk.Our study comprised 34,401 women aged 40-79 years who had not been diagnosed previously with breast cancer and who provided information on smoking status at baseline (1988-1990). The subjects were followed from enrollment until December 31, 2001. Cox proportional-hazards models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for the association between breast cancer incidence and tobacco smoke.During 271,412 person-years of follow-up, we identified 208 incident cases of breast cancer. Active smoking did not increase the risk of breast cancer, with a HR for current smokers of 0.67 (95% CI: 0.32-1.38). Furthermore, an increased risk of breast cancer was not observed in current smokers who smoked a greater number of cigarettes each day. Overall, passive smoking at home or in public spaces was also not associated with an increased risk of breast cancer among nonsmokers. Women who reported passive smoking during childhood had a statistically insignificant increase in risk , compared with those who had not been exposed during this time.Smoking may not be associated with an increased risk of breast cancer in this cohort of Japanese women. While the majority of studies have shown a weak positive or null association,4 the association appears to be strongest in premenopausal women5 or in women who started smoking at an early age or smoked before their first full-term pregnancy.6 A positive association with passive smoking has also been reported in some studies,7-10 but was not observed consistently in other studies.11-14 A recent review suggested that studies with detailed assessment of exposure to passive smoking were more likely to show a stronger positive association between passive smoking and breast cancer risk.4Breast cancer is a complex, multifactorial disease with a strong interaction between genetic and environmental factors.11,15-17 in which the incidence of breast cancer is generally lower than in Western countries. A recent systematic review, based on studies in Japanese women, concluded that smoking possibly increased the risk of breast cancer in the Japanese population.18 However, definitive evidence is still lacking as only one of the three cohort studies included in that review found a positive association in premenopausal women.Only a small number of epidemiologic studies have examined the relationship between smoking and breast cancer in Asian countries,19 Clarifying the relationship between smoking and breast cancer may provide insights into strategies aimed at preventing this malignancy. In order to better understand the association between active and passive smoking and breast cancer risk, we analyzed data from a large cohort study of mainly postmenopausal women in Japan.The sustained increase in breast cancer incidence in Japanese women over recent decades has become a major public health concern in Japan.20,21 Briefly, the study was established in 1988-1990, with 110,792 people , aged 40 to 79 years, being enrolled from either the general population or from subjects who had municipal health check-ups in 45 areas throughout Japan. All the participants were followed up for all-cause mortality. In addition to mortality, the incidence of cancer was recorded in subjects living in 24 areas in which cancer registry systems were established.The Japan Collaborative Cohort Study for Evaluation of Cancer Risk (JACC) is a prospective cohort study designed to evaluate cancer risk associated with lifestyle factors in the Japanese population. A full description of the JACC Study is available elsewhere.Of the 64,327 women in the original cohort, 38,593 women lived in the 24 areas where data on incidence were available. We excluded women who reported a previous diagnosis of breast cancer (n=161) and women who gave no information on smoking status in the baseline questionnaire (n=4031), leaving 34,401 women eligible for the present analysis. The average age at enrollment was 58.0 years.We obtained informed consent by requesting the subjects to sign the cover page of the questionnaire. In some areas, informed consent was obtained at a group level, after the purpose of the study and confidentiality of the data had been explained to community leaders. The Ethics Board at Nagoya University School of Medicine approved the study in 2000.At baseline, we used a self-administered questionnaire to obtain information on demographic characteristics, tobacco and alcohol use, physical activity and other lifestyle factors. Questions on active cigarette smoking comprised smoking status , age at which smoking started, the number of cigarettes smoked per day, years of smoking, and smoking cessation. Information on passive smoking was collected in nonsmokers by recording the response to the following three questions. Firstly, “In the past, were you exposed to tobacco smoke at home?” Women who responded that they had been exposed to environmental tobacco smoke (ETS) were also asked to report the frequency of this passive exposure as either sometimes, 1-2 days/week, 3-4 days/week, or almost every day. Secondly, “In the past, were you exposed to tobacco smoke in public spaces?” Women who answered ‘yes’ to this question also reported the frequency of this passive exposure. Thirdly, “Were you exposed to tobacco smoke from family members in your childhood?” The subjects were categorized as having been exposed to passive smoking if they reported ever being exposed to tobacco smoke at home or in public spaces.Information on other potential risk factors for breast cancer, such as alcohol drinking, age at menarche, parity, age at the birth of her first child, and age at menopause, was also collected in the baseline questionnaire.Follow-up was conducted from enrollment until December 31, 2001. During this period, population registries in the municipalities were used to ascertain the residential and vital status of the participants. In Japan, registration of death is required by Family Registration Law and theoretically provides complete mortality data. Breast cancer incidence was confirmed mainly through linkage of records to the population-based cancer registry in each area. To complete the incidence data, we also conducted a systematic review of death certificates and reviewed medical records in local major hospitals in some areas.22During the study period, 2.7 percent of the subjects were lost to follow-up due to having left the study areas. The proportion of cancer cases with death certificate only was 5.3 percent (11 of 208 cases). The mortality to incidence ratio for breast cancer was 0.15 in the cohort covered by cancer registries. This value was lower than that available from population-based cancer registries in Japan (between 0.20 and 0.30).2), alcohol consumption , daily walking , parity , age at the birth of her first child , menopausal status , age at menarche , use of sex hormones (yes/no) and family history of breast cancer in a first-degree relative (yes/no). These variables were selected as covariates as they are known to, or alternatively have been suspected of modifying the risk of breast cancer. We also conducted analyses limited to postmenopausal women only, as the mean age of the study cohort was 58 years and 66 percent of the women reported their age at menopause in the baseline questionnaire.For each participant in the cohort, the person-years of follow-up were counted as either the time from enrollment to the diagnosis of breast cancer, death from any cause, or the end of follow-up , whichever occurred first. For breast cancer cases ascertained only by death certificates, the person-years of follow-up were calculated from enrollment to death from breast cancer. Women who died of causes other than breast cancer or moved out of the study areas were treated as censored cases. We used Cox proportional-hazards models to estimate the hazard ratio (HR) and 95% confidence interval (CI) for the association between breast cancer incidence and tobacco smoke. The analyses on the association between passive smoking and breast cancer risk were limited to nonsmokers. Potential confounding factors included in the multivariable models were age (continuous), study area , body mass index .All During 271,412 person-years of follow-up, we identified 208 incident cases of breast cancer. Overall, passive smoking at home or in public spaces was not associated with an increased risk of breast cancer in nonsmokers . PassiveNo significant increase in breast cancer incidence in relation to active smoking was observed in the analyses limited to post-menopausal women only, with the HR being 1.20 (95% CI: 0.52-2.80) for current smokers.We also conducted an analysis using nonsmokers who had not been exposed to passive smoking either at home or in public spaces as a reference group. The risk estimates for current and past smoking in this group were essentially unchanged (data not shown).We examined the relationship between cigarette smoking and breast cancer in a large Japanese cohort comprised mainly of postmenopausal women. Our findings indicated that neither active nor passive smoking were associated with an increased risk of breast cancer in our study cohort.2,3 The Nurses’ Health Study concluded that smoking did not increase the risk of breast cancer.14 When adjusted for alcohol drinking, no association was observed between cigarette smoking and breast cancer risk in a collaborative reanalysis of individual data from 53 epidemiologic studies.3 In contrast, a pooled analysis including both case-control and cohort studies published before December 2004 reported an approximately 40 percent increase in the risk of breast cancer in active tobacco smokers.4 However, cohort studies are more likely to show no association, or to yield modest risk estimates compared with case-control studies. This suggests that recall bias or selection bias inherent in case-control studies may influence the association between breast cancer and active smoking.We found no indication of an increased risk for breast cancer in current smokers. Previous studies have provided conflicting results on the association between active smoking and breast cancer risk, with the majority of studies showing no significant association, or only a modest, positive association.23 Breast cancer can be classified according to estrogen receptor and/or progesterone receptor expression, with each type having different clinical, pathological and molecular features.24 The positive association between breast cancer and smoking may be diluted or masked in studies that treat breast cancer as a single outcome, as we did in our analyses. Secondly, given that the majority of the women in our cohort were nonsmokers at baseline and only the small number of current smokers developed breast cancer during follow-up, it was difficult to detect a statistically significant relationship between smoking and breast cancer risk. Thirdly, concern has been raised previously that studies showing no significant positive associations included many women in the reference group who had been exposed to passive smoking but who had never smoked.4 This may explain, in part, the lack of association we observed in our study. However, even when we included women who had never been exposed to either active or passive smoking as the reference group, we observed no increased risk of breast cancer in current smokers. Fourthly, the majority of the women in our cohort were postmenopausal. We therefore conducted an analysis limited to postmenopausal women only and found no significant associations. Accordingly, we consider that our finding of a lack of a significant association between active smoking and breast cancer risk is applicable to postmenopausal Japanese women. However, the lack of information on menopausal status at diagnosis of breast cancer did not allow us to carry out a detailed analysis. Our result is consistent with that of another large cohort study conducted in Japan,16 in which no significant association was obtained between smoking and breast cancer incidence in postmenopausal women. However, the possibility remains that smoking may be associated with an increased risk of breast cancer in premenopausal women, as that cohort study showed a 3.9-fold increase in breast cancer risk for premenopausal Japanese women.16 In contrast to the inconsistent results for premenopausal women, the majority of studies have shown that cigarette smoking was not associated with an increased risk of breast cancer in postmenopausal women.3,4We have interpreted our finding of a lack of association between active smoking and breast cancer risk from both a biological and methodological perspective. Firstly, it has been suggested that considerable heterogeneity exists in the etiology of breast cancer.4 However, three large cohort studies conducted in the United States did not confirm the positive findings of these case-control studies.12-14 In the Nurses’ Health Study, passive smoking was unrelated to breast cancer risk.14 Similarly, a large, prospective study reported no association between ETS from a smoking spouse or from other sources and the risk of death from breast cancer.12 In contrast, a recent Japanese cohort study reported a significant 2.6-fold increased risk of breast cancer for passive smoking in premenopausal women.16 Moreover, a review by the California Environmental Protection Agency concluded that regular ETS exposure was related to breast cancer diagnosed in younger women who were primarily premenopausal.25 The interpretation of these contradictory results is difficult, given the heterogeneity of breast cancer etiology, variation in study design and the precision of ETS measurement. However, active smoking is not an established risk factor for breast cancer, and the amount of exposure is lower from ETS than from active smoking. In addition, previous studies that examined this association were of small sample size and retrospective. On the basis of these facts, we consider it unlikely that passive smoking plays a major role in the development of breast cancer, although it may be related to breast cancer in certain high-risk populations.In the present study, passive smoking at home or in public places was not associated with an increased risk of breast cancer in nonsmokers. Evidence supporting a positive association between passive smoking and breast cancer risk has been derived mainly from case-control studies.The strength of our study was its prospective design, which avoided recall bias inherent in case-control studies. Information on other risk factors for breast cancer was available and potential confounding factors were controlled for in the analyses examining the association between smoking and breast cancer.26 Another limitation of our study was that we did not collect information on menopausal status at diagnosis of breast cancer, hormonal receptor status or genetic polymorphisms, all of which can be used to define breast cancer risk more accurately.27,28 Finally, the validity of our findings on passive smoking may be a concern given the relatively high percentage of missing data (24.8%) regarding this exposure. Random errors are more likely in this situation and therefore the real association may have been underestimated. Further improvements in the measurement of passive smoking are therefore needed in order to provide more accurate risk estimates for passive smoking and breast cancer.The limitations of our study merit consideration. As mentioned earlier, due to the small number of breast cancer cases who were current smokers, we were unable to conduct a detailed analysis examining the association between breast cancer and factors such as age when smoking was started, frequency, and duration. Previous studies suggested that early childhood may be a critical period of risk, and that there may be an increased risk with starting smoking at an earlier age and long duration of smoking.In conclusion, our results suggest that smoking is not associated with the risk of breast cancer in this cohort of Japanese women.


Prolonged estrogen exposure is believed to be the major cause of endometrial cancer. As possible markers of estrogen exposure, various menstrual and reproductive features, e.g., ages at menarche and menopause, are found to be associated with endometrial cancer risk. In order to assess their combined effects on endometrial cancer, we created the total number of menstrual cycles (TNMC) that a woman experienced during her life or up to the time of study and two genetic risk scores, GRS1 for age at menarche and GRS2 for age at menopause. Comparing 482 endometrial cancer patients with 571 population controls, we found TNMC was associated with endometrial cancer risk and that the association remained statistically significant after adjustment for obesity and other potential confounders. Risk increased by about 2.5% for every additional 10 menstrual-cycles. The study also showed that high GRS1 was associated with increased risk. This relationship, however, was attenuated after adjustment for obesity. Our study further indicated women with high TNMC and GRS1 had twice the risk of endometrial cancer compared to those low in both indices. Our results provided additional support to the involvement of estrogen exposure in endometrial cancer risk with regard to genetic background and lifestyle features. Endometrial cancer is the most frequently diagnosed gynecological cancer in the developed countries, and the fourth-most common female malignancy after breast, lung and colorectal cancer3Reproductive characteristics, such as parity and ages at menarche, menopause, and first live parturition, reflect, to a certain extent, exposure to endogenous estrogens and progesterone6789101113HNFIB), has been identified by genome-wide association study (GWAS)16181920212223232425Common genetic variations have been suspected to be involved in endometrial cancer risk, but to date only one single nucleotide polymorphism (SNP), rs4430796 at 17q12 close to HNF1 homeoboxB (−4.2), were slightly younger (p = 0.053), more obese (p = 10−26.8), had a greater proportion whose BMI changed more than 35% (p = 10−8.4), were more likely to have had induced menopause (p = 10−7.4), were younger at menarche (p = 0.005), and were less likely to have used oral contraceptives (p = 0.010). Cases also experienced more menstrual cycles than controls, 422.9 versus 396.1 TNMC (p = 10−4.3), and had higher genetic risk scores for menarche, either non-weighted GRS1 (p = 0.021) or weighted GRS1 (p = 0.011). No difference was found in genetic risk score for menopause, either non-weighted GRS2 (p = 0.97) or weighted GRS2 (p = 0.92), nor was age at natural menopause significantly different between cases and controls (p = 0.68). In addition, cases and controls were not different in having a family history of cancer (p = 0.24) or use of estrogen (p = 0.074).From several GWAS reports, we identified for GRS calculations 26 menarche-associated and 22 menopause-associated SNPs that matched our selection criteria. The associations of endometrial cancer risk with TNMC and GRS are shown in To assess whether TNMC and GRS1 have joint effects on endometrial cancer, we created a combined TNMC-GRS1 variable with four levels. Level one included those with low TNMC and low GRS1 (both less than their medians); level two was those with high GRS1 and low TNMC; level three with low GRS1 and high TNMC; and level four with high GRS1 and high TNMC (both higher than their medians). Prolonged unopposed estrogen exposure is believed to be a key risk factor contributing to the development of endometrial cancer. Previous studies have investigated in endometrial cancer the roles of several major reproductive and menstrual features that are partially or potentially involved in estrogen exposure, such as age at menarche, age at first live parturition, parity number, age at last live parturition, and age at menopause. Individually, all of these factors have been found to be associated with risk of endometrial cancer67891011As a composite measure, the total number of menstrual cycles combines both reproductive and menstrual features. One of the most important hormonal changes during each menstrual cycle is the substantial rise and fall of estradiol levels13th and 5th) of the genetic risk score on age at menarche had odds ratios of 1.14  and 1.13 , respectively, for breast cancerIn addition to the use of a composite measure to assess the inferred phenotype of endogenous estrogen exposure, we also created two genetic measures, using genetic polymorphisms discovered by GWAS. Genetic risk scores were developed for their associations with endometrial cancer risk, one for age at menarche (GRS1) and one for age at menopause (GRS2). The method we used to construct genetic risk scores is well-established and widely employed by researchers in the genetic field272729In addition to TNMC, we also calculated total months of menstrual cycles (TMMC) during life or to the time of study, and analyzed its association with endometrial cancer risk. Like TNMC, TMMC was also significantly associated with endometrial cancer risk (data not shown). Given that TMMC was quite similar to TNMC and that average length of menstrual cycle was not associated with the disease, we did not present the results of TMMC analysis in this report. Although an estrogen effect is the major underlying mechanism explaining the findings of our analysis, estrogen levels and the balance between estrogen and progesterone may not be constant in each menstrual cycle, especially when the cycles are anovulatory. Secondary amenorrhea, which was not considered in our TNMC calculation, may also be a potential factor influencing our assessment of estrogen effect. Furthermore, the reproductive and menstrual parameters used for calculation of the composite variables may have other biological effects which are not estrogenic or have additional effects which are independent from their contributions to the composite variables. Thus, caution should be exercised when one interprets our results.Obesity is a strong risk factor for endometrial cancer. Obese women have been reported to have 4 to 6-fold increases in endometrial cancer risk compared to women with normal weight31534353639Finally, the results of our study should be interpreted with caution because there are a number of inherited methodological limitations. First, the study results were established on the basis of single-site investigation with a moderate sample size and inherited possibility for selection bias. Second, some of the exposure variables in the study were subject to possible recall bias, though the likelihood and impact appeared to be small. Third, these observations need to be confirmed by independent studies. Fourth, in calculation of TNMC, we did not consider the potential impact of secondary amenorrhea that some women might experience occasionally.In conclusion, our study suggests that high frequency of menstrual cycles, resulting from long reproductive life, fewer pregnancies and other factors, may play a role in the etiology of endometrial cancer. Furthermore, this composite measure appears to have synergistic interactions with common genetic polymorphisms that determine early age at menarche, and the synergy is independent of obesity, a strong risk factor for endometrial cancer. If our findings can be confirmed by other epidemiologic studies, we may consider including the composite measure in risk prediction models for endometrial cancer.A population-based case-control study was conducted in Connecticut between December 2004 and March 2009. The study was approved by the Institutional Review Boards at Yale University (IRB number: HIC 0305025270), Connecticut State Department of Health and 28 Connecticut hospitals involved. The methods were carried out in accordance with the approved guidelines. Eligibility of the study subjects has been described elsewhereTo evaluate the collective effect of reproductive factors, we constructed a total number of menstrual cycles variable (TNMC), which estimated the total number of menstrual cycles experienced during life or up to the time of our investigation. This composite measure was computed from age at menarche, age at menopause, average length of menstrual cycles, total months of all pregnancies, and total months of breastfeeding. TNMC was calculated based on the following formula: [(age at menopause − age at menarche) × 12 − total months of all pregnancies − number of live births × 1.5 − /2 − total months of oral contraceptive use] × 30/average length of menstrual cycles (days). Menstrual cycles were assumed to resume at 1.5 months post parturition if no breastfeeding was performedGenomic DNA was isolated from peripheral blood using a commercial DNA extraction kit. SNP genotyping was performed using the HumanOmniExpress BeadChips . The BeadChips results were run on an Illumina iScan system using the Infinium HD Assay Super Automated Protocol. The GenomeStudio Genotyping (GT) Module  was used for data normalization and genotype calling. After filtering out SNPs with completion rates <90%, minor allele frequencies <1%, and not in Hardy–Weinberg equilibrium (P < 0.0001) among the controls, 1053 subjects including 482 cases and 571 controls with genotype information on 649,351 SNPs were included in a previous genome-wide association study (GWAS) of endometrial cancer2 < 0.5); (b) number of failed genotypes for each SNP was fewer than five study subjects; and (c) associations between SNPs and menarche or menopause age had the same direction between our study and the GWAS. The few study subjects that had missing SNP genotype information were assigned mean risks that were calculated separately in 482 cases and 571 controls, rounded to the nearest whole unit. For the 26 SNPs that were not genotyped in our data, highly linked proxy SNPs were selected using the 1000 Genome Pilot1 for the CEU population, which is primarily of Northern/Western European ancestry ( https://www.broadinstitute.org/mpg/snap/ldsearch.php).Several GWAS have been published reporting SNPs associated with age at menarche and age at natural menopause. We selected 26 menarche-associated181920212324252) was calculated based on self-reported weight and height 5 years before interview. BMI was classified into three groups: normal weight (<25 kg/m2), overweight (25 < 30 kg/m2), and obese (≥30 kg/m2). In addition to the cross-sectional evaluation, we also calculated BMI change over time. BMI change was defined as [(BMI 5 years before interview − BMI at 20 s)/BMI at 20 s] × 100, and the values were grouped into four categories: BMI change less than or equal to 5%, BMI change greater than 5% but less than or equal to 20%, BMI change greater than 20% but less than or equal to 35%, and BMI change greater than 35%.Body mass index . All other statistical tests were performed with Statistical Analysis System (SAS) software . All P-values were two-sided.Both continuous and categorical variables were used for data analysis of total numbers of menstrual cycles and genetic risk scores. For categorical data, TNMC was classified into four groups according to the quartile distribution among control subjects. GRS was divided into three groups based on tertile distributions in the controls. Attained age, age at menarche, and age at natural menopause were considered as continuous variables. Education was grouped into 4 levels, including less than 12 years, 12 years to 3 years of college, completion of college or university, and graduate school. Menopausal status was categorized as pre-menopause, natural post-menopause and induced post-menopause. Linear regression was used to analyze the associations of GRS with age at menarche and age at natural menopause, with adjustment for age and race. Differences of continuous variables between cases and controls were evaluated by Student t statistic. Associations of endometrial cancer risk with TNMC and GRS were analyzed using the unconditional logistic regression that yielded odds ratios and 95% confidence intervals. Both unadjusted and adjusted models were developed in the analysis, and various multivariable models were created to adjust as appropriate for sets of variables that included age, race, years of education, BMI, BMI change, estrogen hormone use, family history of cancer and OC use. Trends were examined by considering odds ratios for continuous variables. Associations between SNPs and endometrial cancer risk were evaluated by log-additive logistic regression using PLINK .


The breast cancer incidence in Asia is rising. To explore whether the etiology of breast cancer is different from the known risk factors from studies in Western countries, we conducted a nested case-control study using data from the Taiwan National Health Insurance Research Database (NHIRD).All medical conditions based on the first three digits of the ICD-9 and a list of medical conditions based on literature review were retrieved for each case and control. The odds ratios (OR) and 95% confidence intervals (CI) of the associations between medical conditions and breast cancer risks were estimated using conditional logistic regression and adjusted for occupation, number of breast cancer screening, and the average number of outpatient visits prior the diagnosis. The associations were also estimated for younger (<50 years old) and older subjects separately.The analyses included 4,884 breast cancer cases and 19,536 age-matched controls. Prior breast diseases , obesity , endometriosis , uterine leiomyoma , hypertensive diseases , and disorders in lipid metabolism  were associated with increased breast cancer risk. No heterogeneity was observed between age groups (<50 and ≥50 years old).In addition to benign breast diseases, obesity, endometriosis, uterine leiomyoma, hypertensive diseases, and disorders of lipid metabolism were associated with a subsequent breast cancer risk.Our results suggest that estrogen related factors may play an important role in breast cancer risks in the Taiwanese female population. Worldwide, breast cancer was the most common cancer and the most important cause of deaths from cancer in women in 2012 .Although breast cancer incidence is increasing globally, the pattern differs between Asia and Western countries. The peak age at diagnosis was around 60–70 years in the Western countries, whereas the peak age at diagnosis was about 40–50 years in the Asian populations . It is gIt has been suggested that cluster of diseases may imply similar etiologies between diseases, common risk factors, or effects of treatment for the prior disease . A priorThe aim of the study was to investigate the etiology of breast cancer by exploring the associations between prior chronic diseases and breast cancer risks using NHIRD.The NHI program has been described previously . BrieflyDisease and breast cancer status (yes or no) were defined as if a subject ever received care for that specific disease or cancer from any outpatient clinic at least twice or ever been hospitalized due to the specific disease or cancer (based on the major diagnostic code). The earlier date of the visits of the outpatient clinic or the hospitalization was assigned as the date of diagnosis.I2 statistics which represents the percentage of total variation contributed by between-study variance [The breast cancer incidence was calculated from the whole LHID2000 and LHID2005, respectively. Medical histories based on the first three digits of the ICD-9 and the corresponding A-code and aggregated medical conditions based on literature review were retrieved for each case and control . The prevariance . SensitiAnalyses were performed using SAS 9.3. All tests were two sided and statistical significance was assessed at the level of 0.05.Among the 5,233 newly diagnosed breast cancer cases, 2,526 were identified from the LHID2000 and the other 2,707 were identified from the LHID2005 . Among tMedical conditions that presented in at least five cases and were statistically significant associated with breast cancer (p<0.05) in LHID2005 were validated in the LHID2000 and the dataset that combining LHID2000 and LHID2005. Diseases may be presented in aggregated forms and the codings may depend on the physicians’ practice. heterogeneity = 0.47 for obesity, pheterogeneity = 0.20 leiomyoma, pheterogeneity = 0.54 for hypertensive diseases and pheterogeneity = 0.39 for disorders of lipid metabolism).In addition to benign breast diseases, which have been recognized as a marker of enhanced risk or a precursor of breast cancer , endometEstrogen has been implicated in numerous diseases, including cancers of the breast, ovary, colorectal, and endometrial cancers, cardiovascular diseases, osteoporosis, neurodegenerative diseases, insulin resistance, endometriosis, uterine leiomyoma, and obesity ,22. A prThe association between endometriosis and breast cancer had been reported previously, but the results were inconsistent . HoweverWe identified three publications ,27,28 onAlthough ovarian diseases share risk factors with breast cancer in endogenous estrogen and reproductive characteristics, most studies failed to observe an association, except one study . HoweverMetabolic disorders have been associated with several types of cancer, including the breast cancer ,32. Meta131I treatment [We did not observe an association between thyroid diseases and breast cancer risk. An elevated breast cancer risk is well documented in thyroid cancer patients ,35,36, preatment ; howeverreatment . Recent reatment ,41.Most studies on polyps or cholelithiasis and breast cancer were based on the common risk factor theory, e.g. diet. However, except for a few studies ,43, mostOther associations, such as gingival and periodontal diseases or unspecified disorders of back are difficult to explain. We cannot rule out the possibility of false findings, although the strengths of associations were similar in both LHID2000 and LHID2005. Nevertheless, it is reasonable that general medical examination (ICD9: V70) was inversely associated with breast cancer risks. It is likely that the use of general medical examination results in early detection of pre-malignant lesions, thus the patient could receive proper treatments before the lesion progresses to a malignant tumor. On the other hand, increased medical surveillance may increase the possibility of detecting a cancer.Other limitations of the present analyses include that we did not consider the treatment, duration, and the severity of the preceding diseases, as well as the behavior risk factors, in the current analyses. The increased or decreased breast cancer risk could be a result of the treatment of the previous disease or the shared risk factors; therefore, the associations do not imply causality in etiology. Secondly, chance findings could be resulted from multiple comparisons; these results have to be interpreted with causation. Thirdly, having some diseases, e.g. metabolic syndrome, might imply an increased medical surveillance, thus may increase the probability of detecting a breast cancer, and vice versa. These were evident in higher number of screening tests and average ambulatory visit per year in In general, the use of claim data reduces the possibility of recall bias and assures a relatively completed medical history. Both hypotheses- and data-driven analyses reached similar conclusions. The results from the data-driven analyses may worth for further investigation.In conclusion, our results suggest that estrogen-related factors may play an important role in breast cancer risks in the Taiwanese female population. It may be worthy of an investigation on the effects of endocrine-disrupting chemicals on estrogen-related diseases, such as endometriosis, uterine leiomyoma, and the related cancers.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.


Specific coffee subtypes and tea may impact risk of pre- and post-menopausal breast cancer differently. We investigated the association between coffee  and tea intake and risk of breast cancer.A total of 335,060 women participating in the European Prospective Investigation into Nutrition and Cancer (EPIC) Study, completed a dietary questionnaire from 1992 to 2000, and were followed-up until 2010 for incidence of breast cancer. Hazard ratios (HR) of breast cancer by country-specific, as well as cohort-wide categories of beverage intake were estimated.Ptrend = 0.029. While there was no significant effect modification by hormone receptor status (P = 0.711), linear trend for lower risk of breast cancer with increasing caffeinated coffee intake was clearest for estrogen and progesterone receptor negative (ER-PR-), postmenopausal breast cancer (P = 0.008). For every 100 ml increase in caffeinated coffee intake, the risk of ER-PR- breast cancer was lower by 4% . Non-consumers of decaffeinated coffee had lower risk of postmenopausal breast cancer  compared to low consumers, without evidence of dose–response relationship (Ptrend = 0.128). Exclusive decaffeinated coffee consumption was not related to postmenopausal breast cancer risk, compared to any decaffeinated-low caffeinated intake , or to no intake of any coffee . Caffeinated and decaffeinated coffee were not associated with premenopausal breast cancer. Tea intake was neither associated with pre- nor post-menopausal breast cancer.During an average follow-up of 11 years, 1064 premenopausal, and 9134 postmenopausal breast cancers were diagnosed. Caffeinated coffee intake was associated with lower risk of postmenopausal breast cancer: adjusted HR = 0.90, 95% confidence interval (CI): 0.82 to 0.98, for high versus low consumption; Higher caffeinated coffee intake may be associated with lower risk of postmenopausal breast cancer. Decaffeinated coffee intake does not seem to be associated with breast cancer.The online version of this article (doi:10.1186/s13058-015-0521-3) contains supplementary material, which is available to authorized users. Coffee and tea are the most popular beverages consumed worldwide, rendering them as relevant dietary exposures . Coffee A major systematic review by the World Cancer Research Fund and American Institute for Cancer Research had concluded that for the association between coffee and tea intake and pre- and postmenopausal breast cancer, evidence did not allow for definite conclusions . A minorPremenopausal and postmenopausal breast cancers have been argued for some time to be diseases with somewhat different etiologies ,15, and We determined the association between coffee  and tea consumption with risk of pre- and postmenopausal breast cancer within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort . DistincThe EPIC study is an on-going multi-center prospective cohort study aimed at investigating the association between diet, lifestyle, genetic and environmental factors and the development of cancer and other chronic diseases. It consists of 521,448 men and women, followed-up for cancer incidence and cause-specific mortality for several decades. There are 23 EPIC centers in 10 European countries, that is, Denmark, France, Germany, Greece, Italy, Netherlands, Norway, Spain, Sweden, and United Kingdom. Details have been described elsewhere [This study pertains to female participants of the EPIC cohort between 25- and 70-years old at recruitment. We excluded participants with prior history of cancer, incomplete dietary/non-dietary information, and poorly completed questionnaires based on their ratio of energy intake versus energy expenditure (bottom 1% or top 1% of the cohort), leaving 335,060 women.All participants provided written informed consent. The study was approved by the International Agency for Research on Cancer (IARC)’s ethical review committee and by the respective local ethical committees.Diet was assessed using country-specific questionnaires , namely As the exact structure of the questions varied by center and questionnaire, complete information on caffeinated and decaffeinated coffee intake was available only in Germany, Greece, Italy (except Ragusa and Naples), the Netherlands, Norway, Spain, Sweden (except Umea), and the United Kingdom. Analyses of caffeinated and decaffeinated coffee consumption only included women with complete information on type of coffee intake, that is, those whose different types of coffee intakes added up to their total coffee intake. For caffeinated coffee consumption, 226,368 participants were included. Since none of the participants in Norway and Sweden consumed decaffeinated coffee, they were excluded from analysis for decaffeinated coffee consumption, leaving 176,373 participants. Information on tea intake was not available in Norway, leaving 299,890 participants.As the cohort consists of multiple populations with a wide range of variation in terms of volume and concentration of coffee and tea intake, country specific quartiles for these beverages were estimated based on distribution of intake within each country, after excluding the non-consumers. This yielded the following intake categories for total coffee, caffeinated coffee and tea: none, low, moderately low, moderately high, and high. As decaffeinated coffee intake was less common, we used tertiles of intake for the consumers and intake categories were: none, low, medium, and high.The outcome of interest was first incident of primary invasive breast cancer . As data on menopausal status at diagnosis was lacking, breast cancers occurring before the median menopausal age of 50 years were considered premenopausal, whereas those diagnosed at 50 years or older were considered postmenopausal. Information on hormone receptor status was provided by each center based on pathology reports. This information was routinely available for tumors diagnosed after 1997 to 2006, depending on the center.Follow-up was based on linkage with population cancer registries in Denmark, Italy, Netherlands, Norway, Spain, Sweden and the United Kingdom. In France, Germany and Greece, combined methods including health insurance records, cancer and pathology registries, and active follow-up were used. Censoring dates for most centers depended on the dates at which cancer registries were considered complete . In Germany, Greece and France where active follow-up was undertaken, dates of censoring were up to March 2010, December 2009, and July 2005, respectively. Loss to follow-up was less than 4%.Multivariable Cox regression was used to examine the association between coffee or tea consumption and risk of breast cancer. Time at entry was age at recruitment, and exit time was age at diagnosis with breast cancer as first tumor, death, emigration, loss to follow-up, or end of follow-up. The non-zero slope of the scaled Schoenfeld residuals on the time function suggested that the proportional hazard assumption was met. All analyses were stratified by age at recruitment in one-year categories and by centers to control for differences in recruitment or follow-up procedures and questionnaire design. We studied consumption of beverages both as categorical and continuous (increment of 100 ml/day) variables. Non-consumers of coffee comprised a relatively small group (<10%) and seemed to have some unique health behaviors: they were less likely to have ever smoked, consume alcohol, or to have ever used oral contraceptives, and they were more likely to be physically inactive compared to the rest of the study population. We, therefore, used the low coffee consumers as the reference group in the categorical data analysis. To test for linear trends, the categories were entered as a continuous term  in the Cox model. Since most coffee consumers tend to consume caffeinated as well as decaffeinated coffee, we additionally cross-classified coffee intakes in relation to breast cancer. This yielded eight categories, of which (any) decaffeinated coffee consumers with low caffeinated coffee intake comprised the largest group and was hence chosen as the reference for reasons of statistical robustness.Two separate Cox models were fitted for pre- and postmenopausal breast cancers  and only about half of the premenopausal cases (58.6%). Hormone-receptor defined analyses were, hence, only done among postmenopausal breast cancers and were not possible within premenopausal breast cancers.As a form of sensitivity analysis, we also analyzed beverage intake using categories based on the overall cohort instead of country specific intake.To improve comparability across centers, dietary intake was calibrated by a 24-hour dietary recall method common to all centers, in a random sub-sample of 8% of the cohort at baseline  for hazard ratios (HRs) not including 1 were considered statistically significant. All analyses were performed using SAS version 9.1 .Two-tailed A great majority of the study participants consumed coffee, with a median total coffee intake ranging from 93 ml/day in Italy to 900 ml/day in Denmark (not shown). Decaffeinated coffee was consumed by about 50% of the study population. Median decaffeinated coffee intake ranged from 2 ml/day in Spain and United Kingdom to 140 ml/day in France. Tea was consumed by approximately 66% of the total cohort resulting in a median intake ranging from close to 0 ml/day in Greece to up to 475 ml/day in United Kingdom.The mean age at recruitment was 51 years with 43% of the participants being postmenopausal. Based on body mass index (BMI) classification by the World Health Organization, 58% of participants were of normal weight, 29% overweight and 13% obese.Compared to the low coffee consumers, those with high coffee consumption were more likely to have ever smoked, used oral contraceptives, be physically active, and consumed more alcohol but less tea Table . They weDuring an average 11 years of follow-up, 10,198 first incidences of primary invasive breast cancer were observed among 335,060 women. Of these, 1,064 were premenopausal breast cancers. Hormone receptor status was available in approximately 70%  of total breast cancer cases, out of which 50% were double hormone receptor positive tumors (ER+ PR+), followed by 33% of single hormone receptor positive tumors (ER+ or PR+), whereas 17% were double negative tumors (ER- PR-).Tables Ptrend = 0.272 .While moderately low intake of total coffee consumption seemed to be associated with higher risk of premenopausal breast cancer , no dose response relationship was observed; Ptrend = 0.029 (Table P = 0.711), a linear trend for lower risk of breast cancer with increasing caffeinated coffee intake was clearest for ER- PR- breast cancer (P = 0.008). For every 100 ml higher caffeinated coffee consumption, the risk of ER- PR- breast cancer was lower by 4% . The risk of ER+ PR+ breast cancer was lowered by 2% per 100 ml . However, the P value for trend test of categorical analyses was not significant  showed a modest decrease in risk of postmenopausal breast cancer; adjusted HR: 0.90, 95% CI: 0.82 to 0.98. There was no dose response relationship (Ptrend = 0.128).No association was observed between decaffeinated coffee intake and premenopausal breast cancer Table . Non-conP = 0.716).Compared to low decaffeinated coffee consumers, it seemed that the non-consumers of decaffeinated coffee had a lower risk of developing ER- PR- breast cancer , than ER+ PR+ breast cancer . However, test for interaction with hormone receptor status was not statistically significant .As compared to decaffeinated coffee consumers with low caffeinated coffee intake, non-consumers of decaffeinated coffee with higher intakes of caffeinated coffee had significantly lower risk of postmenopausal breast cancer. Within consumers of decaffeinated coffee, no such association with higher intakes of caffeinated coffee was observed. Exclusive decaffeinated coffee consumption was also not associated with risk of postmenopausal breast cancer compared to decaffeinated coffee consumption with low caffeinated coffee intake Table . Post-hoTea consumption was neither statistically significantly associated with risk of premenopausal nor postmenopausal breast cancer Table . The adjOur sensitivity analyses showed that results remain essentially unchanged when analysis of beverage intake was conducted using cohort wide categories of intake instead of country specific categories Tables , 4 and 6In this study, high versus low caffeinated coffee intake was associated with a modest but statistically significantly lower risk of postmenopausal breast cancer. This association was only detected in women not consuming decaffeinated coffee. Although abstinence of decaffeinated coffee  seemed to be associated with lower risk for postmenopausal breast cancer, exclusive decaffeinated coffee intake was not associated with increased risk. Tea intake was not associated with risk of postmenopausal breast cancer. Neither caffeinated coffee, decaffeinated coffee, nor tea intake impacted the risk of premenopausal breast cancer.Our null finding for the association between total coffee intake and risk of postmenopausal breast cancer corroborates the findings of most previous large-scale prospective studies and meta-analyses ,28. The et al. in Canada (odds ratio comparing highest versus no consumption: 0.63 (95% CI: 0.43 to 0.94) [per se does not impact breast cancer risk [The observation that caffeinated coffee was significantly associated with lower risk of postmenopausal breast cancer seems to be in agreement with the finding of a recent population based case–control study by Lowcock to 0.94) . This stto 0.94) , had furto 0.94) . Other rto 0.94) -35. Whilcer risk ,32-34,36cer risk . This exPost-hoc analyses also showed that exclusive decaffeinated coffee consumption was not associated with increased risk of postmenopausal breast cancer compared to no intake of any coffee. Taken together, these findings seem to suggest that decaffeinated coffee intake is not associated with postmenopausal breast cancer. The apparent decrease in risk among non-consumers of decaffeinated coffee may be explained by findings of previous studies, which have suggested that decaffeinated coffee consumers may be unique in terms of lifestyle or medical history [In this study, those who reported not to consume decaffeinated coffee seemed to have a significantly lower risk of breast cancer. However, we did not observe a dose–response relationship. Cross-classified coffee intake analysis further showed that exclusive decaffeinated coffee consumption was not associated with risk of postmenopausal breast cancer compared to decaffeinated coffee and low caffeinated coffee consumption.  history ,38. Deca history . This isA meta-analysis on the association of tea intake with breast cancer risk had found no overall protective effect of black tea  . This coBesides having a sufficiently large number of premenopausal breast cancers, we also had a relatively high number of breast cancer cases whose hormone receptor statuses were available (approximately 70%) to allow analysis by ER and PR status. Our findings further support the view that pooling of pre- and postmenopausal breast cancers as a homogenous entity is not recommended. We do, however, acknowledge that data on menopausal status at diagnosis was not available, and we had to use age at breast cancer diagnosis as a proxy. Although coffee and tea intakes were measured only at baseline, analyses of participants in the EPIC sub-cohort of Umea in Sweden , as wellWithin a very large cohort of women, our findings show that higher caffeinated coffee intake is associated with a modest lowering in risk of postmenopausal breast cancer. Decaffeinated coffee intake does not seem to be associated with risk of breast cancer. The mechanism by which caffeinated coffee impacts breast cancer risk warrants further investigation.


OR = 0.723, 95% CI = 0.541–0.965, p = 0.028 and OR = 1.500, 95% CI = 1.078–2.087, p = 0.016, respectively). Subgroup comparisons revealed that rs2446405 and rs17268974 were related to ER status, and rs130021 was associated with PR status. Our findings suggest that rs700519 and rs2069522 are associated with susceptibility to breast cancer among the Han Chinese population and have a cumulative effect with three other identified SNPs. Further genetic and functional studies are needed to identify additional SNPs, and to elucidate the underlying molecular mechanisms.Exposure to high levels of estrogen is considered an important risk factor for susceptibility to breast cancer. Common polymorphisms in genes that affect estrogen levels may be associated with breast cancer risk, but no comprehensive study has been performed among Han Chinese women. In the present study, 32 single-nucleotide polymorphisms (SNPs) in estrogen-related genes were genotyped using the MassARRAY IPLEX platform in 1076 Han Chinese women. Genotypic and allelic frequencies were compared between case and control groups. Unconditional logistic regression was used to assess the effects of SNPs on breast cancer risk. Associations were also evaluated for breast cancer subtypes stratified by estrogen receptor (ER) and progesterone receptor (PR) status. Case-control analysis showed a significant relation between heterozygous genotypes of rs700519 and rs2069522 and breast cancer risk ( Breast cancer is one of the most common malignancies in women, and it causes serious health issues in women worldwide . AlthougO-methyltransferase (COMT), as well as many other estrogen-signaling regulatory enzymes, is involved in the catabolism of cholesterol into estrogens and their subsequent degradation [The normal growth and function of breast epithelial cells are under hormonal control. Estrogen acts as a key driver for breast cancer because it can increase the frequency of mitotic activity, thereby stimulating cell divisions and increasing the potential of cells to accumulate mutations ,7. It isradation . To exerradation . Thus, aCYP17, CYP19, CYP1A1, CYP1B1, COMT, GSTP1, and ERα/β, and the risk of breast cancer, especially in postmenopausal women [Single-nucleotide polymorphisms (SNPs) are the most frequent type of variation in the human genome, and are also valuable in tests of association with common diseases and pharmacogenetic traits ,13. Manyal women ,19,20,21al women . Althougal women . Except al women ,15. ChinCYP11A1, and three variants  were identified as associated with susceptibility to breast cancer [CYP17A1, HSD17B1, CYP19A1, and STS), seven in metabolism genes , six in estrogen receptors (ERα and ERβ), and five in estrogen-signaling regulatory enzymes . The study was performed on Guangdong Han Chinese women.In a previous study, we genotyped six SNPs in the estrogen biosynthesis gene t cancer . In the p < 0.05); therefore, statistical analysis based on case-control comparisons was adjusted for age. The most common tumor histopathological type was invasive ductal carcinoma (IDC), accounting for 83.96% (445) compared to 4.91% (26) of other tumor types including invasive lobular carcinoma (ILC), mucin-producing carcinomas (Muc), and medullary carcinoma (Medul) and 11.13% (59) of unknown types. Only five patients (0.94%) presented with stage 0 (carcinoma in situ), and stages 1–4 accounted for 23.77%, 24.34%, 30.94%, and 8.87% of patients, respectively. The cases consisted of 270 (50.94%) ER-positive tumors, 190 (35.85%) ER-negative tumors, 237 (44.72%) PR-positive tumors, and 223 (42.08%) PR-negative tumors, whereas the remaining 70 tumors (13.21%) were untested.The baseline characteristics of the 1076 subjects (546 controls and 530 cases) are shown in p > 0.05 in healthy controls, a genotyping rate ≥ 85%, and a minor allele frequency (MAF) > 0.01 was conducted. Five SNPs  that deviated from HWE were omitted from further case-control analysis.Quality control of all of the SNPs, consisting of a Hardy-Weinberg equilibrium (HWE) CYP19A1 was significantly associated with breast cancer risk. The frequency of the heterozygous genotype C/T was lower in the breast cancer group than in the control group (20.9% vs. 26.2%). Women who carried the C/T genotype and T allele could be protected against breast cancer . The results are shown in We compared the genotypic and allelic frequencies of 11 SNPs in estrogen biosynthesis genes based on the case-control study and observed that rs700519 in CYP1A2 rs2069522 was significantly different between cases and controls. In contrast to rs700519, the heterozygote T/C of rs2069522 increased the risk of breast cancer  [ptrend = 0.030). Women with five high-risk genotypes had a statistically significant 1.286 times higher risk of developing breast cancer than controls .= 0.045) . To invep = 0.02, 0.02, 0.03, and 0.04) after adjusting for age based on the trend test for association. The other SNP (rs700519) failed to reach this threshold (p = 0.08).The admixture maximum likelihood (AML) method was employed to evaluate the cumulative effect from multiple variants. As expected, four SNPs  were significant at the 5% level . Dividing into four functional sub-pathways for the global test revealed strong associations with the estrogen biosynthesis  and metabolism  sub-pathways. However, the other two sub-pathways showed no association with breast cancer.The global test yielded a marginally significant association for the whole estrogen-related pathway ; however, for rs17268974, A/A was associated with ER(−) tumors . A/G carriers of rs130021 also showed a tendency toward PR(+) tumors . The complete results for the different inheritance models are shown in Given the significance of hormone receptors in breast cancer progression and clinical diagnosis, stratified analysis, based on ER and PR status and genetic polymorphisms, was performed. Finally, three SNPs  were found to be distributed differently among breast cancer subgroups. Genotype A/A and allele A of rs2446405 showed a stronger association with ER(+) tumors than ER(−)  is located in exon 7 of e tissue . The up-t cancer . Individ4Cys is lt cancer ,28,29,30t cancer , polycyst cancer , and surt cancer . In the t cancer . Howevert cancer ,35,36. Aactivity ,38,39. SA2 genes . DespiteA2 genes ,42. HoweA2 genes ,43. FurtCYP1B1 (rs1056836), COMT (rs4680), and ERα (rs9340799) were significantly related to breast cancer susceptibility among Caucasian women [Genetic polymorphisms in estrogen-related genes have been intensively investigated in many studies. However, these studies produced inconsistent results ,31,44,45an women ,21, but CYP11A1 and found that rs2279357, rs2959003, and rs2959008 were related to breast cancer risk [Polymorphisms in genes could affect the levels of transcription, translation, and activity of enzymes and result in wide inter-individual variability of responses to carcinogenic substances. Although the effect of a single polymorphism on tumorigenesis is weak, multiple loci could combine to generate a cumulative risk that cooperates with environmental exposure . We havecer risk . CombineIt is necessary for all hormones to combine with their corresponding receptors to exert their biological functions. The expression of receptors, such as ER, PR, and human epidermal growth factor receptor-2 (HER2), is included in routine clinical classification and evaluation of breast cancer . Their eCYP1A1 T3801C, CYP1A1 A2455G, and COMT Val158Met, were identified as susceptibility loci in breast cancer development according to recent meta-analysis reports [Our study had some limitations. First, menopausal status can modify a woman’s risk of developing breast cancer, and the incidence rate differs between premenopausal and postmenopausal women. In the current study, we did not evaluate the associations for postmenopausal and premenopausal women separately because information on menopausal status was not obtained from most of the participants. Second, the statistical power for all of the 1076 subjects was larger than 83% to detect a log-additive genotype relative risk of 1.30 . It was  reports ,50,51. HThe present study was reviewed and approved by the regional ethical committee of Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China (IRB No: 2009-SCBCGS-GZ-01) on 12 January 2009. Written informed consent was obtained from all of the participants in the trial.A total of 1076 Han Chinese women were included in the current study; 530 were cases with breast cancer and 546 were controls. All of the patients were recruited from Nanfang Hospital after a pathological diagnosis was ascertained. Clinical information was obtained from the patients’ medical records, including demographic characteristics, age at diagnosis, menopausal status, ER status, PR status, HER2 status, clinical stage, degree of differentiation, size of tumor, and lymph node involvement. The healthy controls were derived randomly and simultaneously from the same hospital, and were matched by ethnicity and geographic location. All of the controls were checked by a physician for the absence of cancer, and family history of their first-degree relatives was self-ascertained.Peripheral blood samples were collected from the participants and stored at −70 °C until DNA extraction. Genomic DNA was extracted from EDTA-containing blood using the EZNA blood DNA kit  according to the manufacturer’s instructions. The DNA was stored at −70 °C.The rationale for SNP selection has been described in detail elsewhere ,52. BrieFor each SNP, a pair of amplification primers and an extension primer were designed using Assay Design 4.0 software. Genotyping was performed using the high-throughput MassARRAY iPLEX platform (Sequenom) through multiplex reactions. The genotyping rate of DNA samples was set to ≥85%.http://hydra.usc.edu/gxe). We conducted a case-control study for all of the subjects, and then the patients were stratified by ER and PR status. Association analysis based on unconditional logistic regression was carried out by estimating OR and 95% CI with multiple inheritance models  for each SNP. HWE was assessed using Fisher’s exact test and the χ2 test. The statistical tests were implemented using SPSS 13.0 software combined with the Web-based tool SNPstats (http://bioinfo.iconcologia.net/SNPstats). We also performed the AML-based global test of association for the whole estrogen-related pathway as well as for four sub-pathways after adjusting for age using software provided by the authors of Tyrer et al. [p value of 0.05.The statistical power of the case-control study was calculated using QUANTO software version 1.2.4 (University of Southern California, Los Angeles, CA, USA; r et al. . All of In conclusion, we have presented an integrated analysis of the relationship between common variants in estrogen-related genes and breast cancer risk. Our study provides molecular genetic evidence suggesting that the independent and combined effects of these polymorphisms potentially reflect exposure to estrogen and as a consequence, an increase in breast cancer susceptibility. Our data suggest that this association could be specific to ER status. These findings may contribute to obtaining a more conclusive understanding about the underlying etiology of breast cancer and provide new strategies for breast cancer prevention, early detection, and specific treatment.


EDCs). This study reviews the current state of the science associating one such means of exposure, hair products containing EDCs, with breast cancer risk in African American women. We found a growing body of evidence linking: (1) environmental estrogen and EDC exposures to breast cancer risk, (2) the presence of such chemicals in personal care products, including hair products, and (3) the use of certain hair products with potential breast cancer risk in African Americans. At the same time, there is also increasing concern in the lay community about this risk. These results indicate the need for additional research, and the opportunity to benefit from strategic partnerships in community‐collaborative approaches in order to better understand the potential “cost of beauty.”The incidence rate of breast cancer for African American women has recently converged with that of non‐Hispanic White women in the United States, although African Americans have a higher mortality rate due to this disease. Although most research exploring health disparities associated with this phenomenon has focused on differences between women based on biology and behavior, both the academic and lay communities have begun to explore the potential role of environmental exposure to estrogen and endocrine disrupting chemicals ( Breast cancer is the most common cancer among African American women While race is a social construct, the concept is sometimes conflated with biological differences between people, and it can be difficult to separate the two within the literature. Danforth argues that four breast cancer disparities between African Americans and Whites—early age of onset, more advanced stage of the disease at presentation, more aggressive histologic changes, and worse survival—are the result of biological properties influenced by nonbiological features Endocrine disrupting chemicals (EDCs) are chemicals, or chemical mixtures, that interfere with the normal activity of the endocrine system, which is made up of many tissues and hormones in the body that are responsible for human growth, development, and reproduction EDCs that mimic the effects of estrogen in the body may contribute to disease risk because exposure to estrogen, endogenously and exogenously, is associated with breast cancer However, the specific mechanisms by which EDCs may affect breast cancer etiology are still under investigation. Normal mammary gland development is regulated in part by hormones and occurs in stages during gestation, puberty, and pregnancy. EDCs may alter mammary gland development in ways that increase the risk of breast cancer, as exposure to EDCs during development may cause chemical alterations that make tissue more susceptible to a second exposure of a carcinogen Both dose levels and timing of exposure affect the reaction of the mammary gland to EDCs. Although EDCs pose a risk throughout one's life span, individuals are especially vulnerable when exposed in utero, and even when the exposure to EDCs is removed, women can still be impacted over generations as they inherit a particular type of gene regulation. Arguably, this is what occurred when the daughters of some women who took one type of EDC As environmental estrogen and EDC exposures have been associated with breast cancer risk, and the presence of such chemicals are found in personal care products, including hair products, this review assesses associations between hair products known or suspected to contain such ingredients, and breast cancer risk in African American women.Peer‐reviewed studies were identified through searching EBSCO, PubMed, and Google Scholar using multiple combinations the following terms: African American/Black, breast cancer, hair, hair products, personal care products/PCPs, endocrine disrupting chemicals/EDCs/endocrine disruptors, and estrogen(s). The abstracts of search results were read for relevancy to the review; studies appearing to relate to the topic were then read and assessed for inclusion. To be included in the review, studies must have met the following criteria: (1) focus on African American girls or women; (2) consider exposure to hair products with known or potential hormonally active ingredients; and (3) engage in analyses related to breast cancer risk. Studies associated with breast cancer survivor behavior or breast cancer education were not included. References from articles found were also examined and considered for inclusion. Given that this is still a new area of research, abstracts found during the search were not excluded. In all, six articles and one abstract were included in the review, reflecting a small but growing body of research linking the use of certain hair products to breast cancer risk in African American women.A number of different hair products were assessed in the studies reviewed, including hair preparation, relaxer, perm, cream, root stimulator, oil, lotion, and conditioner. These products are applied to the scalp and/or hair in different ways, are in contact with the scalp for different periods of time, contain different chemicals, and enter the body through different mechanisms. In addition, the use of some products, such as relaxers, can result in scalp lesions and burns, whereas the use of other products will not. These variations in exposure should be taken into account when considering the findings described below  and anti‐estrogenic activity (AEA) of eight hair and skin products commonly used among African Americans, using a cell proliferation assay with an MCF‐7 cell line derived from human breast cancer Although only a small number of studies have been conducted specifically exploring the role of hair products containing EDCs on breast cancer risk in African American women, they indicate a connection exists, making this an actively growing area of research (Studies reviewed are summarized in Table This review was initiated in response to community concern about African American women's risk of breast cancer and the use of hair products. We found that there is indeed a growing body of evidence that warrants further investigation. Although additional scientific research is clearly needed, the topic is already a source of concern in the lay community. With a number of advocacy groups calling for increased investigation, regulation, and communication around the issue, the academy has begun to respond with additional studies and collaborations. One such organization that serves as a bridge between the academic and lay communities is The Silent Spring Institute, whose researchers partner with community advocates to engage in research and outreach focusing on the impact of environmental factors on women's health, particularly breast cancer In fact, bills have recently been introduced in Congress to increase consumer protection: the Safe Cosmetics and Personal Care Products Act of 2013 One of the limitations of this review on the potential relationship between hair products and breast cancer risk in African American women is that it addresses a new topic for which there is still very little research that has been published, and thus, few studies were available to include in this review. As a result, a statistical meta‐analysis of findings could not be conducted, and instead, a mix of clinical, laboratory, and epidemiological studies were presented. While this is a limitation and can make interpretation of findings more difficult, it is also a strength in that it points to the concern that researchers from multiple disciplines have for the issue, and their varied approaches to discovering more about potential risk. Further, as reflected in the lay literature, there is clear concern from the community about this topic, although it can be difficult to bridge the lay and academic communities. As such, writing a review that both is accessible to multiple audiences and draws upon a varied set of literature, requires including quite a bit of background information, which may be considered a limitation. While one of the strengths of this study is that it describes the concern of the lay community on this topic, future research must also seek to better understand and address the challenges in communicating evolving findings to the African American public for which hair is more than just an afterthought or a potential area of risk. Hair is a complex issue in the African American community, often viewed as representing identity, race, class, heritage, and other factors There are many ways in which future research on breast cancer risk and hair product use should proceed and is indeed proceeding, including more sophisticated epidemiological investigations and increasing work in laboratory studies with hair products and breast cancer cells. Such work could benefit from policies that require full disclosure of ingredients and chemicals in hair products, so that researchers can describe risks more completely. In addition, while exposure to a single EDC can cause harm, contact with multiple EDCs may have a damaging additive effect, and it is important for researchers to assess “the environmental reality of long‐term low‐dose exposure to complex mixtures” Through strategic partnerships, the academic, lay, and policy‐making communities have the opportunity to work together to not only better understand the role of EDCs found in hair products and breast cancer health disparities in African American women, but also to engage in a thoughtful debate about the potential “cost of beauty,” and how we can transition to safer alternatives that would allow us to move toward the elimination of these inequities.There are no conflict of interest disclosures from any authors.


Breast cancer risk assessment including genetic testing can be used to classify people into different risk groups with screening and preventive interventions tailored to the needs of each group, yet the implementation of risk-stratified breast cancer prevention in primary care settings is complex.To address barriers to breast cancer risk assessment, risk communication, and prevention strategies in primary care settings, we developed a Web-based decision aid, RealRisks, that aims to improve preference-based decision-making for breast cancer prevention, particularly in low-numerate women.RealRisks incorporates experience-based dynamic interfaces to communicate risk aimed at reducing inaccurate risk perceptions, with modules on breast cancer risk, genetic testing, and chemoprevention that are tailored. To begin, participants learn about risk by interacting with two games of experience-based risk interfaces, demonstrating average 5-year and lifetime breast cancer risk. We conducted four focus groups in English-speaking women (age ≥18 years), a questionnaire completed before and after interacting with the decision aid, and a semistructured group discussion. We employed a mixed-methods approach to assess accuracy of perceived breast cancer risk and acceptability of RealRisks. The qualitative analysis of the semistructured discussions assessed understanding of risk, risk models, and risk appropriate prevention strategies.P=.008). In the qualitative analysis, we identified potential barriers to adopting risk-appropriate breast cancer prevention strategies, including uncertainty about breast cancer risk and risk models, distrust toward the health care system, and perception that risk assessment to pre-screen women for eligibility for genetic testing may be viewed as rationing access to care.Among 34 participants, mean age was 53.4 years, 62% (21/34) were Hispanic, and 41% (14/34) demonstrated low numeracy. According to the Gail breast cancer risk assessment tool (BCRAT), the mean 5-year and lifetime breast cancer risk were 1.11% (SD 0.77) and 7.46% (SD 2.87), respectively. After interacting with RealRisks, the difference in perceived and estimated breast cancer risk according to BCRAT improved for 5-year risk (In a multi-ethnic population, we demonstrated a significant improvement in accuracy of perceived breast cancer risk after exposure to RealRisks. However, we identified potential barriers that suggest that accurate risk perceptions will not suffice as the sole basis to support informed decision making and the acceptance of risk-appropriate prevention strategies. Findings will inform the iterative design of the RealRisks decision aid. Breast cancer confers significant morbidity and mortality on women in the United States, and the primary prevention of this disease is a major public health issue. In 2014, an estimated 232,670 women in the United States will be diagnosed with breast cancer and 40,000 women will die from this disease . Many wo, the effective use of quantitative information to guide health behavior and make health decisions) affects up to 93 million Americans and constrains counseling about cancer risk and prevention strategies . But I think because of external effects, it is hard for us to determine what percentage we might be more susceptible to.”“I have no idea what the percentage is. No one in my family had breast cancer. They had cysts in their breasts. I have no idea. Nobody smokes in my home. But walking around here, I’m exposed to it.”“You can’t do catch-up. If it’s in you, you are going to get it [breast cancer].”“I think the risk [for breast cancer] for everybody is 100%...because anyone can get it.”“I have 50% chance. My mother died from breast cancer and I had a breast surgery. My daughter had a big lump in her chest at 12. My father had prostate cancer. It’s a horrible death. I still hear my mother screaming.”“I would like to know if I have the gene mutation. So for me to say that being my mom had it [breast cancer] and take a pill and prevent it and not knowing if I have the gene doesn’t make sense to me.”Distrust toward the health care system:“No, because we don’t have the knowledge and don’t ask, and the doctor won’t up and give it to you.”“If you ask your doctor in the clinic, he’s going to look at you how do you know that? With that look. The condescending attitude. Where did you hear about that?”“I would look for several doctors. I wouldn’t believe in one doctor’s result I swear because they are all human. The way medicine is going today, it’s not as humanistic as it was. They are not talking to you in the face. They are staring at a bloody computer screen. Dentists are the same. The whole way of practicing medicine today is so highly technical. I would have to seek out a second, third, or maybe even a fourth doctor before I make a decision. I don’t base my decision strictly on what the doctor says. They’ve been wrong at times.”“Unfortunately we all need to be very proactive and never accept no for an answer. Simply because one or two people said no, they are not going to do the [genetic] test...I think you have to keep going and if it’s something deep down in your heart that is someone should get the test, then they should receive that test.”“Medical establishment has certain guidelines and recently there is some conflict about mammograms. There is a group, it’s like a renegade group and say you don’t need a mammogram every year, you just need it every 3 or 4 years. Don’t listen to them, because they are rebels. These groups also said you don’t need to do it in your 40s, you just need to do it in your 50s or 60s. These groups always pop up.”Access to care:“Why would the health insurance pay for the chemoprevention pill but not for the genetic test to see if you have the gene? I would have an issue with my insurance.”“The [genetic] test that Angelina Jolie took was $3000, so right now how can everybody find out if they can’t afford it...or if they don’t have insurance?”“My feeling is that the only deterrent [to genetic testing] would be the cost. If it’s just a blood test, not invasive, what could possibly stop me? For me, personally, it would be the $3000. That’s a biggie...it’s the only thing that would be stopping me.”“The ones with money can get all this testing done. For people that don’t have money, they are out there.”A consistent theme in our analysis was uncertainty among participants that all factors were accounted for in determining their breast cancer risk. The most commonly expressed concern was the potential for the risk assessment tool to miss something that was unknown and outside their control.Similar to several prior studies on risk communication, participants referred to quantitative risk with many misconceptions. Having a close family member with cancer appeared to influence a participant’s feeling of risk. Women that relayed their experience with a close friend or family member often used the proverbial “50% chance” to express the idea that anyone can get breast cancer.Participants viewed any risk, even a low risk, with a degree of uncertainty and therefore not acceptable as the basis for their eligibility to get genetic testing. The perceptions among participants was the “test might uncover the unexpected”. According to one participant who stated her breast cancer risk is 2%: “I would still want to know. There’s always that possibility. There is always that chance and I may not be in the high-risk group and that might be the key to finding out if I carry it [genetic mutation]”. These comments highlight the need for educating patients about when genetic test results are informative or uninformative for estimating cancer risk.None of the participants recalled discussing breast cancer risk with their physician. Notably, they expressed their own lack of knowledge as a reason for not initiating a discussion and doubted that their physician would engage. Participants expressed a degree of responsibility to seek out the information they needed to inform their decisions and the need to be proactive because providers won’t “give it up”.The recent debate about mammographic screening guidelines was discussed in the context of suspicion and distrust. Participants speculated about possible ulterior motives, such as the lack of funding for diseases that concerned women and these perceptions led to reduced credibility of the information they received. These passages highlight how source credibility  may extend perceived uncertainty in breast cancer risk assessment tools.In responding to barriers to genetic testing, not having money was discussed as primary. The financial constraints expressed by women led to many concerns that lack of money or insurance would limit their access. Removing the financial barrier, many of the women expressed the desire to receive genetic testing. As stated by one participant: “If it’s free, I’ll go every 6 months”. Stated by another women: “The ones with money can get all this testing done. For people that don’t have money, they are out there”. Only one woman voiced concern that a woman might regret a decision to “cut their breasts off” based upon their genetic testing results, stating that genetic testing is far too soon to be necessary because “some people will panic”. These comments highlight our participants’ view that use of risk assessment to pre-screen women for eligibly for genetic testing may be perceived as service rationing.In this community of largely Hispanic women from Upper Manhattan, we demonstrated a significant improvement in accuracy of breast cancer risk perception after interacting with the experience-based dynamic interfaces to communicate risk embedded in the RealRisks decision aid. This improvement was found in high numeracy women and also in low numeracy women who systematically have been shown to overestimate their breast cancer risk ,26.However, consistent with previous research ,28, our , the 35-year-old woman diagnosed with breast cancer without clear risk factors).First, there is a great deal of uncertainty regarding breast cancer risk and the utility of the risk prediction models. There may be misconceptions about testing for breast cancer susceptibility genes—for example, as previously shown, some may incorrectly believe that the BRCA test can diagnose cancer . Prior sProminent in our analysis was the perception that health care itself was the source of distrust, which contributes to the uncertainty of the breast cancer risk prediction models. It is well understood that one of the most important determinants of responses to risk information is likely to be whether the information source is perceived to be credible and trustworthy. Eagley, Wood, and Chaiken have identified two types of communicator bias that message recipients might infer . The firAnother novel finding was the perception of using risk models to guide breast cancer risk management options as a barrier to access to care. Some of the women in our focus groups viewed not being eligible for genetic testing as service rationing. As one woman stated “only the ones with money can get all this testing done”. The well-known Angelina Jolie effect resulted in demand for BRCA testing to almost double . AlthougWhile underutilized in the United States, breast cancer risk assessment including genetic testing can be used to classify people into different risk groups with screening and preventive interventions tailored to the needs of each group . By riskOur urban-dwelling female participants, who were largely minorities with a high proportion of low numeracy, may not be representative of the general population in other geographic areas. However, given that this is an understudied and underserved population, this is also a unique strength of our study. There may have also been selection bias, where women with a greater interest in expressing their opinions about breast cancer may have been more likely to participate, which affects the generalizability of our results.We conducted this study to inform the iterative design of the RealRisks decision aid. While the experience-based interface resulted in improved accuracy of breast cancer risk perceptions, our qualitative findings identified additional barriers to risk-based health care delivery, which need to be addressed . For exa