Case–control studies show that mammographic density is a better risk factor when defined at higher than conventional pixel-brightness thresholds. We asked if this applied to interval and/or screen-detected cancers.Cumulus) and two increasingly higher thresholds . Measures were transformed and adjusted for age and body mass index (BMI). Using conditional logistic regression and adjusting for BMI by age at mammogram, we estimated risk discrimination by the odds ratio per adjusted standard deviation (OPERA), calculated the area under the receiver operating characteristic curve (AUC) and compared nested models using the likelihood ratio criterion and models with the same number of parameters using the difference in Bayesian information criterion (ΔBIC).We conducted a nested case–control study within the prospective Melbourne Collaborative Cohort Study including 168 women with interval and 422 with screen-detected breast cancers, and 498 and 1197 matched controls, respectively. We measured absolute and percent mammographic density using the Cumulus software at the conventional threshold  1.85–2.92); all ΔBIC > 14), and the association with BMI was independent of age at mammogram. After adjusting for percent Cumulus, no other measure was associated with risk . For screen-detected cancer, however, the associations were strongest for the absolute and percent Cirrocumulus measures , and after adjusting for Cirrocumulus, no other measure was associated with risk .For interval cancer, there was very strong evidence that the association was best predicted by The amount of brighter areas is the best mammogram-based measure of screen-detected breast cancer risk, while the percentage of the breast covered by white or bright areas is the best mammogram-based measure of interval breast cancer risk, irrespective of BMI. Therefore, there are different features of mammographic images that give clinically important information about different outcomes.The online version of this article (10.1186/s13058-018-1081-0) contains supplementary material, which is available to authorized users. Mammographic images can be used for more than identifying existing breast tumours – they contain information that predicts both 1) the risk of future breast cancers and 2) the likelihood of existing tumours being missed due to masking 0.5, where r is the correlation between X1 and X2, and then exponentiated it to obtain the appropriate OPERA. The inter-quartile risk ratio (IQQR) corresponding to a given OPERA is approximately OPERA2.5. We also used the area under the receiver operator curve (AUC) to measure the discriminatory ability of measures. All statistical analyses were conducted using the software Stata [P < 0.05 was considered to be statistically significant.As in our previous publications –15, we ure Stata , and fol2 distribution with degrees of freedom equal to the difference in number of parameters. The fits of models were also compared based on the differences in the Bayesian information criterion (ΔBIC), which for models with the same number of parameters is 2ΔLL. If ΔBIC is the BIC of model A minus the BIC score of model B, then exp (-ΔBIC) is approximately equal to the posterior odds in favor of model A; for example, ΔBIC = − 6 or − 14 means that model A is roughly 400 or 1,000,000 times, respectively, more likely to be the model that generated the data than model B. The strengths of evidence against the model with the poorest fit are conventionally interpreted as non-existent if < 2, positive if 2–6, strong if 6–10, and very strong if ≥ 10 [Parameter estimates were derived under asymptotic maximum likelihood theory. We compared the fits of nested models using the likelihood ratio criteria; under the null hypothesis, twice the absolute difference in the (maximum) log likelihood (ΔLL) has an approximately χ if ≥ 10 .P ≤ 0.001). Screen-detected cases differed from their matched controls in family history (P < 0.001) and BMI (P = 0.003).Table Cumulus, Altocumulus and Cirrocumulus measures of dense area were all greater for cases than for controls, for both interval and screen-detected breast cancer . Percent dense area measured by Cumulus, Altocumulus and Cirrocumulus was greater for cases with interval breast cancers compared with (1) their controls , and (2) cases with screen-detected breast cancers .Table P > 0.8). There was no association with BMI overall (see Table P < 0.02).For interval cancer, the association with BMI did not depend on age at mammogram (P < 0.001). The log (OPERA) was 0.61, 0.50 and 0.61 for Cumulus, Altocumulus and Cirrocumulus, respectively , There was very strong evidence that the Cumulus and Cirrocumulus measures gave a better fit than the Altocumulus measure (both ΔBIC ≥ 10).Table Cumulus where log (OPERA) was 0.85 compared with 0.65 and 0.72 for Altocumulus and Cirrocumulus, respectively . and that the Cumulus measure gave a better fit than the Cirrocumulus and Altocumulus measures (both ΔBIC ≥ 10). The risk gradient for Cirrocumulus was 30% and 17% higher than for the other two measures, respectively. Furthermore, there was very strong evidence that the Cumulus percent density measure gave a better fit than the Cumulus absolute density measure (ΔBIC = 28), with an estimated risk gradient 39% higher. Univariately, therefore, the Cumulus percent density measure gave a better fit for interval cancers, with an estimated risk gradient equivalent to an IQQR ~ 8-fold (95% CI 5–15).For percent density measures, there was very strong evidence that the OPERA estimates were all higher than for their corresponding absolute density measure , especially for P < 0.001). The log OPERA was 0.22, 0.22 and 0.28 for the transformed, normalized and standardized Cumulus, Altocumulus and Cirrocumulus measures, respectively . There was strong evidence that the Cirrocumulus measure gave a better fit than the Cumulus and Altocumulus measures (ΔBIC = 8). On the log odds scale, the risk gradient for Cirrocumulus was 24% higher than for the other two measures. Results were similar for the percent density measures adjusted for age and BMI.Table Cumulus as a percentage, using the likelihood ratio test and comparing with the log likelihood of 192.48 from Table P > 0.1). For example, when fitted together the OPERAs for the Cumulus attenuated but remained significant (P < 0.001) whereas the Altocumulus and Cirrocumulus estimates were reduced substantially and were no longer significant . In particular, adding the Cirrocumulus measure made no improvement to the fit (ΔLL = 0.7).Table Cirrocumulus that was a significant predictor  irrespective of which other measure(s) were in the model, and for both dense area and percent dense area measures. After adjusting for Cirrocumulus, using the likelihood ratio test and comparing with the log likelihoods of − 538.21 and − 536.75 from Table Cumulus measures no longer predicted risk in all multivariable models; their OPERAs were close to 1.0 and not significant whether considered as percent or absolute dense area.On the other hand, Table Cumulus measure dominates .Additional file Cirrocumulus measure was more than 3000 times more likely to be the measure that generated the data than either of the other two measures. Addition of the conventional measures did not add information. Also, in contrast to risk of interval disease, the risk of screen-detected breast cancer associated with BMI increased with age, similar to previous findings on the risk of breast cancer per se [We found that the risk predictors for breast cancer differ by mode of detection. First, there was very strong evidence that interval breast cancers are best predicted when mammographic density was defined conventionally as the white or bright areas, the more so when defined as a percentage. It was more than 20,000 times more likely to be the measure that generated the data than either of the other two measures. Addition of the other measures did not add information, and BMI did not appear to be a predictor of interval disease. On the other hand, we found very strong evidence that screen-detected breast cancers are best predicted by mammographic density when defined as the brighter areas on a mammogram, whether as an absolute or percentage measure. The r per se .Cumulus) was not predictive of screen-detected cancers once we fitted mammographic density defined at, in effect, a high pixel-brightness threshold. We have observed this before in case-control studies of breast cancer, for both Australian and Korean women, and when using screen-film and digital mammograms [Most importantly, the conventional conception of mammographic density . The consistency of our findings on interval cancers with our previous findings based on measurements by other investigators [It is not true that, because the three measures are correlated, they are equal proxies of the same underlying exposure. If this was true then the estimates of association would all move towards the null and the width of the confidence intervals would increase substantially when the measures were modelled together. But this did not happen. For screen-detected cancers, when absolute rt Study , a diffetigators , gives cCumulus as a percentage, this raises issues about whether the current thresholds for defining dense breasts for the purposes of recommending other screening modalities are appropriate. Moreover, the implications of having mammographically dense breasts depend on a woman’s underlying risk of breast cancer, and we have shown that the Cirrocumulus, rather than the Cumulus, measure is an important predictor of risk. Therefore, in order to deal more effectively with the issue of mammographically dense breasts protocols should be devised that take into account that there are multiple and different features of mammographic images that give clinically-important information about different outcomes.The major implication of our findings is that analyses of mammographic images can be used to predict both masking and risk, but that different aspects of the image need to be considered. To date, prediction of masking has been based on BI-RADS, which has in effect been defined in terms of percent density as a categorical variable. Given that we and others  have nowCirrocumulus, consistent with the literature on conventional measures of risk [Potential limitations of this study include the older age at baseline of the cohort and, hence, the diagnosis of breast cancer at older ages. It is interesting to note that the OPERA for our predictors of screen-detected cancers was about 1.4, even for  of risk , whereas of risk  and Kore of risk , 15 wome of risk ).Another limitation is that this study used screen-film images, whereas digital mammography is now the norm. Our previous case–control studies have shown that similar findings on risk arise from studies of digital and film mammograms, but it is nevertheless important to replicate our findings using digital mammography, and for diagnoses at different ages and with different time intervals in different populations. This requires new prospective studies, and we and others are working on developing such resources. Another limitation of this study is that we were not able to divide the period of 2 years used to define interval breast cancers occurring into shorter time periods, such as 12 months as in Boyd et al. [A potential limitation of the translation of our findings into clinical settings is that the measurements require person time and expertise. With respect to expertise, the investigators who performed the measurements are not radiologists but have achieved high repeatability within and between measurers, as aforementioned. We have been funded to train radiologists using the online, and therefore globally relevant, BreastScreen Reader Assessment Strategy initiative . We are Cumulus, Cirrocumulus and Altocumulus were measured in that order at the same time, un-blinded to the previous measure. Automated methods would allow multiple thresholds to be considered and, thus, could determine an optimal risk-predicting threshold.One strength of this study is the highly statistically significant and consistent results observed despite the fact that multiple measurers have been used and the definitions of the different density measurements involve subjective judgements. This is testament to the high repeatability of the average of risk measures across our trained measurers. It also suggests that there is the potential to derive even better predictors of risk, as random measurement error contributes to underestimation of risk gradients. For example, the measurers were blinded to their previous mammographic density measurements on the same mammogram, and better risk prediction might be possible if Another strength has been our use of the OPERA concept, which allows us to put risk factors into perspective in terms of their ability to differentiate cases from controls. OPERA relies on deriving the standard deviation of the risk factor after adjusting for other covariates and design variables. Not taking into account the need to adjust the standard deviation for covariates can make a substantial difference. For example, for unadjusted transformed percent mammographic density, the cross-sectional standard deviation was 0.63 for controls. However, after adjusting for age and body mass index, the standard deviation of the residuals became 0.34. Consequently, the log (OPERA) was 44% less than the log (OR) per cross-sectional standard deviation; not adjusting the standard deviation leads to an almost 50% overestimate of the risk-predicting ability of percent mammographic density.In summary, we have found that more risk-predicting information can be obtained from a mammogram than from the conventional concept of mammographic, or breast, density defined by the white or bright areas. We have also confirmed that the conventional measure of percent mammographic density applies to interval cancers and the masking phenomenon. When it comes to risk per se, however, we have confirmed our previous findings that the conventional measures are not the most informative mammography-based predictors, given that they are no longer significant after adjustment for our new measures based on higher pixel-brightness thresholds. Our newer measures could also be clinically useful given that we have shown that non-specialists can be easily trained and achieve high repeatability within and between measurers. For scientific accuracy, we have used the average of five measurements by five investigators, but reasonable accuracy was obtained by each individual investigator (data not shown); see Fig. Our finding that areas of high pixel brightness might better represent the breast tissue with a causal role in breast cancer is very important for multiple disciplines, such as biological research to identify specific tissue markers , geneticAdditional file 1:Table S1. For interval and screen-detected invasive breast cancer, marginal risk estimates for Cumulus, Altocumulus and Cirrocumulus measures of dense area and percent density adjusted for age and BMI. Table S2. For interval and screen-detected invasive breast cancer, multivariable risk estimates for Cumulus, Altocumulus and Cirrocumulus measures of dense area and percent density adjusted for age and BMI. Table S3. Combined ; total ; and -2Δ of log likelihood (LL) for Cumulus, Altocumulus and Cirrocumulus measures of dense area and percent density adjusted for age and BMI and P value for the differences. (DOCX 36 kb)


Serum lead, cadmium and arsenic were determined using atomic absorption spectrophotometry (AAS). Expression of ER, PR and HER2 were determined using immunohistochemistry. Data was analyzed using Mann-Whitney U-test and multiple regression, with p < 0.05 considered as being statistically significant. Estradiol and progesterone were significantly higher in breast cancer participants with ER− and PR− compared with those with ER+ and PR+ breast cancer (p < 0.05). Follicle stimulating hormone and LH levels were significantly higher in participants with ER+ and PR+ breast cancer compared with participants with ER− and PR− breast cancer (p < 0.05). Arsenic was inversely related with TSH in premenopausal participants with ER− and PR− . Sex hormones and gonadotropins appear to be involved in the pathogenesis of triple negative and luminal breast cancer, respectively.Breast cancer is broadly sub-divided into hormone responsive and non-hormone responsive subtypes. Estradiol has been associated with hormone responsive breast cancers. There is, however, a paucity of information on the role of sex hormones, gonadotropins, and thyroid hormone in non-hormone responsive breast cancer. This study aimed to determine differences in the serum levels of sex hormones, gonadotropins, thyroid hormones, and endocrine disruptors  in Nigerian women with hormone responsive and non-hormone responsive breast cancers. Seventy-nine non-pregnant women aged 28–80 years with histologically confirmed breast cancer were recruited, pre-therapy, into this cross-sectional study. They comprised 52 premenopausal women and 27 postmenopausal women recruited from the Surgical Oncology Clinic of the Department of Surgery, University College Hospital, Ibadan. Comparison of biochemical parameters were based on the positivity (+) and negativity (−) of estrogen receptor (ER), progesterone receptor (PR) and human epithelial receptor-2 (HER-2). Estradiol, progesterone, follicle stimulating hormone (FSH), luteinizing hormone (LH), free thyroxine (FT Breast cancer is a multifaceted disease with distinct biological subtypes. It presents with a varied spectrum of clinical, pathologic, and molecular features, with different prognostic and therapeutic implications . CliniciHormones are considered to be important in the etiology of breast cancer. High levels of estrogens have been associated with breast carcinogenesis . AlkylatThe role of progesterone in breast cancer is controversial. It is thought that it increases breast cancer risk in premenopausal women at the luteal phase. Breast mitotic rates are highest in the luteal phase of the menstrual cycle ,10. FollToxic metals, such as lead, cadmium, and arsenic, are a major source of oxidative stress, which is implicated in the development of breast cancer . The difThe study was a cross-sectional study. The study protocol was approved by the University of Ibadan and University College Hospital Health Review Committee (UI/EC/10/0193). Informed consent was obtained from the participants before their recruitment. Seventy-nine non-pregnant women with histologically confirmed breast cancer were recruited into this study, pre-therapy. Enrolment and basic characteristics of the study participants have previously been reported . Partici− versus 10 ER+; 71 PR− versus 8 PR+; 64 HER-2− versus 15 HER-2+; 17 postmenopausal ER− versus 10 postmenopausal ER+; 19 postmenopausal PR− versus 8 postmenopausal PR+; 46 premenopausal HER-2− versus 6 premenopausal HER 2+; and 18 postmenopausal HER-2− versus 9 postmenopausal HER-2+.The study participants were then grouped based on their immunohistochemistry results i.e., 69 ERAll the premenopausal participants in the study were ER- and PR-negative. Of the study participants, 83.5% presented at advanced stages of the disease (stages 3 and 4), while 16.5% of the study participants presented at stages 1 and 2 .Ten milliliters of venous blood were aseptically obtained by venipuncture from each participant and dispensed into a plain bottle. For premenopausal participants, blood samples were drawn between days five and nine of their menstrual cycle in the follicular phase (forward dating) and five to nine days before the anticipated start of their next menstrual cycle in the luteal phase (backward dating) . All sam2), luteinizing hormone (LH), FSH, free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH)were determined using enzyme immune assay (EIA) on TOSOH AIA System Analyzers . Serum arsenic, cadmium, and lead were determined using atomic absorption spectrophotometry .Serum progesterone, estradiol  software, version 18 . Mann Whitney − and ER+ breast cancer participants. Estradiol and progesterone were significantly higher in participants with ER− compared with participants with ER+. Moreover, estradiol was significantly higher in postmenopausal participants with ER− compared with postmenopausal participants with ER+. Luteinizing hormone and FSH were significantly higher in participants with ER+ compared with participants with ER−. Follicle stimulating hormone was also significantly higher in postmenopausal participants with ER+ compared with participants with ER−.− compared with women with PR+. Moreover, estradiol was significantly higher in postmenopausal participants with PR− compared with postmenopausal participants with PR+. Luteinizing hormone and FSH were significantly higher in participants with PR+ compared with participants with ER−. Follicle stimulating hormone was also significantly higher in postmenopausal participants with PR+ compared with participants with PR−.As shown in − compared with participants with HER-2+, while FSH was significantly higher in participants with ER+ compared with participants with HER-2− . In premenopausal women with ER− and PR−, estradiol was positively related with progesterone and TSH . Moreover, progesterone was inversely related with arsenic . Thyroid stimulating hormone was also inversely related with arsenic . In premenopausal women with ER−, FT4 was inversely related with arsenic (β = −0.330), while TSH was positively related with FSH (β = 0.281). In postmenopausal women with ER−, PR−, and HER-2−, LH was inversely related with lead , while LH was positively related with cadmium . In postmenopausal women with HER-2−, FSH was positively related with LH (β = 0.963), while progesterone was positively related with E2 (β = 0.896).+, and triple negative subtypes [+ breast cancers are responsive to endocrine and anti-HER-2 therapies, respectively. However, chemotherapy is effective in the management of triple negative breast cancer [Breast cancer is a heterogeneous disease with a wide spectrum of clinical, pathologic, and molecular features . It compsubtypes . Luminalt cancer .− and PR−. This is similar to the findings of Makanjuola et al. [−, PR− and HER-2−) in this study may benefit from chemotherapy as the first line of treatment. This is because they lack the appropriate hormone receptors. Participants with luminal breast cancer can, however, benefit from endocrine therapy.Premenopausal breast cancer is a challenge to patients, their family members, and the health care system. It is associated with adverse pathological factors, such as high-grade tumor, presentation at a later stage than their older counterparts, and hormone receptor negativity . The prea et al. . The adv− human mammary epithelial cells (HMLE-Ras) when injected into the mammary fat pad of laboratory animals. This effect was caused by the systemic induction of angiogenesis and stromal cell recruitment by estradiol. These observations, together with ours, suggest that estradiol can act as a potent promoter of metastasis in ER− tumors through mechanisms involving the host microenvironment.High levels of endogenous steroid hormones, particularly estrogens, are believed to increase breast cancer risk . In this−, PR−, and HER-2− (triple negative) breast cancer compared with participants with positive ER, PR, and HER-2 expressions. Primarily, progesterone may act via protooncogenes and growth factors to affect breast cell proliferation and breast cancer etiology [The role of estrogen in breast cancer as a potent breast mitogen is undisputed, however, the role of progesterone is grossly understudied . In thisetiology . The abs+ and PR+ compared with postmenopausal women with ER− and PR− in this study. Follicle stimulating hormone increases with age and correlates with a loss of ovarian reserve [Pituitary production of LH and FSH in premenopausal women is controlled by the secretion of gonadotropin releasing hormone (GnRH) from the hypothalamus. After menopause, the pulsatility in gonadotropin secretion is a consequence of a reduced release of hypothalamic GnRH and of a decreased sensitivity of the pituitary gonadotropin . Previou reserve . Our obs reserve  observed+ breast cancer compared with HER-2− breast cancer in this study. This aligns with the reports of Zhou et al. [+ breast cancer. This could be via mechanisms involving tyrosine kinase, which drives the proliferation of cells and evasion of apoptosis, genetic, and epigenetic modifications, as well as alterations in upstream regulators, such as the fox headbox p3 (Fox p3) and GATA4 [Follicle stimulating hormone levels were significantly higher in women with HER-2u et al. . Human eu et al. ,33. Obsend GATA4 .2 and TSH in premenopausal participants who were ER- and PR-negative. The biological activity of thyroid hormones and estradiol manifests in cells expressing their respective receptors, which belong to the nuclear receptor family. Moreover, estrogen-like effects of thyroid hormones have been reported [3, but inversely related with TSH in premenopausal participants with triple negative breast cancer. This relationship was not observed in postmenopausal participants. The reason for this observation is not clear, but suggests an interplay between progesterone and thyroid hormones in the pathogenesis of non-hormone responsive breast cancer.Changes in thyroid hormone levels have been associated with proliferative activity of breast cancer . In thisreported . Progest− and PR− breast cancer. Arsenic is a potent endocrine disruptor, which has been associated with malignancies. Davey et al. [deiodinase gene [Studies have suggested an association between exposure to heavy metals and carcinogenesis ,38. In ty et al.  observedase gene . In addi− and PR−, a positive relationship was observed between cadmium and LH. This buttresses the endocrine disrupting property of Cd, although, the mechanism through which this is carried out is poorly understood at present.Lead and cadmium can cross the blood-brain barrier and, thereby, disrupt the hypothalamic-pituitary axis . In postFindings from this study suggest that estradiol and progesterone may be involved in the pathogenesis of triple negative breast cancer, while gonadotropins may be involved in luminal breast carcinogenesisSmall sample size was a limitation in this study, therefore, studies with a large sample size are suggested to substantiate our findings.


No prior study to our knowledge has examined the joint contribution of a polygenic risk score (PRS), mammographic density (MD), and postmenopausal endogenous hormone levels—all well-confirmed risk factors for invasive breast cancer—to existing breast cancer risk prediction models.p-values < 0.001) from 55.9 to 64.1 (8.2 units) in premenopausal women (Gail + PRS + MD), from 55.5 to 66.0 (10.5 units) in postmenopausal women not using hormone therapy (HT) , and from 58.0 to 64.9 (6.9 units) in postmenopausal women using HT (Gail + PRS + MD + prolactin). For the Rosner–Colditz model, the corresponding AUCs improved  by 5.7, 6.2, and 6.5 units. For estrogen-receptor-positive tumors, among postmenopausal women not using HT, the AUCs improved  by 14.3 units for the Gail model and 7.3 units for the Rosner–Colditz model. Additionally, the percentage of 50-year-old women predicted to be at more than twice 5-year average risk (≥2.27%) was 0.2% for the Gail model alone and 6.6% for the Gail + PRS + MD + all hormones model. Limitations of our study included the limited racial/ethnic diversity of our cohort, and that general population exposure distributions were unavailable for some risk factors.We conducted a nested case–control study within the prospective Nurses’ Health Study and Nurses’ Health Study II including 4,006 cases and 7,874 controls ages 34–70 years up to 1 June 2010. We added a breast cancer PRS using 67 single nucleotide polymorphisms, MD, and circulating testosterone, estrone sulfate, and prolactin levels to existing risk models. We calculated area under the curve (AUC), controlling for age and stratified by menopausal status, for the 5-year absolute risk of invasive breast cancer. We estimated the population distribution of 5-year predicted risks for models with and without biomarkers. For the Gail model, the AUC improved , mammographic density (MD), and postmenopausal endogenous hormone levels are all well-confirmed breast cancer risk factors.No prior study to our knowledge has comprehensively examined the joint contribution of these biological factors to improving existing breast cancer risk prediction models .We conducted a nested case–control study within the prospective Nurses’ Health Study and Nurses’ Health Study II that included 4,006 cases and 7,874 controls ages 34–70 years.We calculated the area under the curve (AUC), controlling for age and stratified by menopausal status, for the 5-year absolute risk of invasive breast cancer.We found that for both the Gail and Rosner–Colditz models, the AUC was significantly improved for both invasive and estrogen-receptor-positive breast cancers in postmenopausal women not using hormone therapy.Additionally, the percentage of 50-year-old women predicted to be at more than twice 5-year average risk (≥2.27%) was 0.2% for the Gail model alone and 6.6% for the Gail + PRS + MD + all hormones model.In this study, the addition of PRS, MD, and endogenous hormones substantially improved existing breast cancer risk prediction models.If confirmed, these findings may help identify women at higher risk who would most benefit from chemoprevention or other risk-reducing strategies. Breast cancer is the most commonly diagnosed cancer in women. Risk prediction models have been developed to estimate an individual woman’s breast cancer risk, and have been used to both set clinical trial entry criteria  and provMultiple common genetic risk variants  and breaThe NHS was established in 1976 and included 121,700 female registered nurses aged 30–55 years , and theWe identified incident breast cancer cases up to 1 June 2010 through biennial questionnaires, confirmed the diagnoses with the participants (or next of kin), and obtained permission to collect relevant medical or pathology reports. We restricted this analysis to invasive breast cancer. We used tumor tissue microarrays (TMAs) ,29 as thIn each cohort, we assessed 5-year breast cancer risk using the Gail and Rosner–Colditz risk scores. The Gail score includes number of first-degree relatives with a history of breast cancer, age at menarche, age at first birth, number of previous breast biopsies by age, and information on atypical hyperplasia at biopsy ,3. We usThe original factors included in the Rosner–Colditz model were age at menarche, age at first birth, birth index (a combination of number of children and birth spacing), family history of breast cancer, history of benign breast disease, premenopausal duration, type of menopause, postmenopausal duration, duration of postmenopausal HT use by type and timing, BMI, height, and alcohol intake . Recentln = 1,309) to improve statistical power. No women were identified more than once in this study. Sixty-one women initially identified as controls who subsequently became breast cancer cases were excluded from the analysis.The biospecimen collections for each cohort have been described in detail elsewhere ,33–36. BAs previously reported , we usedWe used unconditional logistic regression models to assess the relative risks (95% CIs) of invasive breast cancer with both continuous measures and quartile categories (based on control distributions) of PRS, MD, and circulating hormone levels, adjusting for matching factors. To evaluate improvement in risk prediction, we calculated the age-adjusted area under the curve (AUC)  as a meaSince endogenous hormone–breast cancer associations differ by menopausal status and HT use , we evalBesides primary analyses stratified by menopausal status and HT use, we further evaluated the overall contribution of adding PRS, MD, and hormones among all invasive cases. Because the PRS and hormones are particularly strongly associated with ER+ breast cancer ,39, we ahttp://seer.cancer.gov/) data in white women for the years 2000–2008 (SEER17). We decided a priori to not conduct a similar analysis for the Rosner–Colditz model. Because we used the exposure distribution in our controls to estimate the population distribution, the greater the number of risk factors involved , the greater the chance our controls would not provide a sufficiently accurate reflection of the population distribution.For the Gail model among postmenopausal women not using HT , we also calculated the population distribution of predicted 5-year risks. To do this, we used the following data: (1) the relative risks from the nested case–control study ,43, (2) p-value < 0.05 indicating statistical significance. The analyses employed were all planned a priori. Additional study methods are provided in To assess potential model over-fitting, we used 10-fold cross-validation . Lastly,Compared with controls, cases were more likely to have benign breast disease, have breast cancer family history, and consume alcohol. Also, the PRS, MD, and circulating hormone levels were higher among cases than controls  to 66.0  for the Gail model  when including PRS, MD, and all hormones for postmenopausal women not using HT . We selected a minimal set of hormones that have been shown to provide the largest prediction improvement for invasive breast cancer . CirculaNotably, in our study population, only approximately 45% of postmenopausal women were not using HT, as the blood collections occurred during a period of time when HT was used more frequently than in the US today. In contrast, based on 1999–2010 data from the US National Health and Nutrition Examination Survey (NHANES), about 95% of postmenopausal women are not current HT users . This suMultiple issues important to the potential clinical use of these biomarkers for risk prediction still need to be addressed. Our prior work found that circulating hormone levels may only need to be measured every 10 years , althougLimitations of this study deserve comment. Although this study represents one of the largest to date to evaluate the contribution of measured MD or hormone levels to risk prediction, we did not have such data on all women. However, the baseline AUCs were similar among women with measured and imputed data, and results were similar when using measured data. Because of our nested case–control design with age matching, we were not able to assess the contribution of age to the AUC, and our absolute AUC values are as a result lower than those including age would be. Also, we only included 67 SNPs, although a larger set of SNPs (at least 94) has been identified , which mIn summary, our findings indicate that the incorporation of multiple biomarkers improves the current Gail and Rosner–Colditz models for both total invasive breast cancer and ER+ breast cancer. If validated in independent populations, our findings could help identify women at higher risk who would most benefit from chemoprevention, screening, and other risk-reducing strategies.S1 Methods(DOCX)Click here for additional data file.S1 STROBE Statement(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S5 Table(DOCX)Click here for additional data file.S6 Table(DOCX)Click here for additional data file.S7 Table(DOCX)Click here for additional data file.S8 Table(DOCX)Click here for additional data file.S9 Table(DOCX)Click here for additional data file.S10 Table(DOCX)Click here for additional data file.S11 Table(DOCX)Click here for additional data file.


To assess the most recent high-quality evidence for endometrial cancer prevention strategies.Obesity is an established risk factor for endometrial cancer.Weight cycling and weight gain in middle age are risk factors for endometrial cancer.Bariatric surgery reduces the risk of endometrial cancer by up to 81% in obese women who attain and maintain a normal weight.Combined oral contraceptives provide durable protection against endometrial cancer for 30 years or more.Ever use of the levonorgestrel intrauterine system (LNG-IUS) and inert intrauterine devices reduce endometrial cancer risk.The first oestrogen-based non-progestin HRT for non-hysterectomised women that contains estradiol and bazedoxifene has an effective protective effect on endometrium.Bisphosphonates reduce endometrial cancer risk.Weight loss and LNG-IUS would seem to be an effective strategy for preventing the development of obesity-driven endometrial cancer in the highest risk women. Future research may identify other safe and effective chemoprevention interventions, such as aspirin, bisphosphonates or metformin. The incidence of endometrial cancer continues to rise unabated. Over the past 20 years, the incidence has risen by more than 50%. In the UK alone, more than 9000 new cases are diagnosed each year and it is responsible for the deaths of more than 2000 women. The incidence in women under 50 increased by 2% every year between 1992 and 2012 [An ageing population, changing patterns of hysterectomy use and tamoxifen therapy may all contribute to these trends, but the overwhelming culprit is undoubtedly the obesity epidemic. Across Europe, it has been estimated that 60% of endometrial cancer cases may be due to excess weight.Most endometrial cancers are what Bokhman termed type 1 endometrial cancers, where low-grade cancer develops in a hyperplastic endometrium, often on a background of obesity or diabetes . The bio2) has doubled in the last three decades; each year, 2.8 million people around the world die as a result of being overweight or obese. Obesity accounts for 44% of the disease burden of diabetes and 23% of that of ischaemic heart disease [Worldwide, the prevalence of obesity , and disproportionate treatment-related morbidity [Whilst the majority of endometrial cancer is sporadic, at least 3–5% of new diagnoses are made in women with a familial predisposition. The most common cause of this is Lynch syndrome , which is a highly penetrant autosomal dominant inherited predisposition to cancers of the endometrium, bowel, ovary and prostate, amongst others. In women with Lynch syndrome, the lifetime risk of endometrial cancer may be as high as 70%, compared with a lifetime risk of 2–3% in the general population, and often precedes a colorectal cancer diagnosis by approximately 10 years . IdentifRisk-reducing surgery, in the form of hysterectomy and bilateral salpingo-oophorectomy when family complete, is well established in the primary prevention of Lynch syndrome–associated endometrial and ovarian cancers (women with Lynch syndrome have a 10–12% lifetime risk of ovarian cancer) , 9. No eBiomarker studies have shown that combined oral contraceptives and synthetic progestin reduce endometrial proliferation, in women with Lynch syndrome. However, it is unknown whether hormonal contraceptives are as effective for chemoprevention in Lynch syndrome as they are in the general population .Tamoxifen is a selective oestrogen receptor modulator (SERM) used for the prevention and adjuvant treatment of breast cancer. It has been associated with increased endometrial polyps and hyperplasia, and an increased relative risk of endometrial cancer in postmenopausal women of 4.01 (95% CI 1.7–10.9). There is no endometrial surveillance programme in place for tamoxifen users, but women and clinicians should be aware of the risks , and invPCOS affects 6–8% of women of reproductive age. Women with PCOS are overrepresented in young endometrial cancer patients, and a meta-analysis has estimated the lifetime risk of endometrial cancer in women with PCOS to be in the region of 9% (odds ratio (OR) 2.89), the increase likely driven by a toxic combination of insulin resistance and anovulatory cycles leading to oligo or amenorrhoea. For this reason, a crucial aspect of PCOS management is induction of regular withdrawal bleeds, in an attempt to reduce the risk of developing endometrial hyperplasia and cancer.Whilst diet and weight reduction have been shown to improve the clinical manifestations of PCOS such as insulin resistance and reproductive manifestations, there is no evidence it reduces the risk of developing endometrial cancer . Based o2 increase in BMI increases the relative risk (RR) by 1.59, and at a BMI > 42 kg/m2, RR 9.11 (95% CI 7.26–11.51). Risk is higher in women who have never used hormone replacement therapy (HRT)  [The World Cancer Research Fund has concluded that the risk of endometrial cancer is reduced by moderate physical activity and maintaining a healthy weight . Whilst 8–51.84) .Lifestyle modification can result in 4–6% weight reduction over 2 to 4 years, and anti-obesity drugs can lead to 7–10% weight reduction; however, only bariatric surgery produces significant and, crucially, durable results , 23. Barp = 0.014) in over 2800 women who underwent surgical or conventional weight management treatment. Other cancers were also reduced after bariatric surgery and the number needed to treat (NNT) to prevent one cancer over 10 years with bariatric surgery was 31 [Over 18-year median follow-up, the prospective, non-randomised SOS Study has demonstrated that bariatric surgery significantly reduces the risk of endometrial cancer (hazard ratio (HR) 0.56, 95% CI 0.35–0.89, y was 31 •.Studies continue to show that as well as excess body weight being a risk factor for endometrial cancer, so too is adult weight gain, weight cycling, the duration of overweight/obesity and possibly being overweight in childhood/at age 18 •, 28–30.There is now convincing evidence that women with higher physical activity levels have a lower risk of endometrial cancer than women with the lowest activity levels, in particular overweight or obese women with high activity levels  , 32•. StArthur et al. modelled a Healthy Lifestyle Index (HLI) in 3185 women and reported that for every unit increase in HLI, there was a 5% reduction in endometrial cancer risk. When they directly compared the low vs. high HLI groups, there was a 46% reduction in risk •.Diabetes may increase the risk of endometrial cancer; however, meta-analyses are frequently plagued by the confounders of inactivity and obesity, as alternative or additional endometrial cancer risk factors. After multivariate adjustment, studies have estimated the increase in relative risk to be in the region of 1.42 to 4.1 .An umbrella review in 2015 supported an association between type 2 diabetes and endometrial cancer. It examined 8174 cases, found no significant bias within the studies, and reported Summary Random Effects estimates of 1.97 (95% CI 1.71–2.27), and 95% prediction intervals of 1.23 to 3.16 . Sacerdop = 0.7), but may improve risk of recurrence or overall survival [It has not been proven that modulation of insulin resistance is an effective mechanism for preventing EC , 37. Mansurvival .2, the risks of COC are likely to outweigh the benefits (UKMEC 3 recommendation), which precludes its use as chemoprevention in the most obese women [Long-term follow-up data provides convincing evidence that use of combined oral contraceptives (COC) is associated with a significant and enduring reduction in the lifetime risk of endometrial cancer. Iversen et al. demonstrate that the protective effects of COC persist for at least 30 years, in this updated follow-up study of users who were recruited between 1968 and 1969 •. The fase women .Oral, injectable and intrauterine progestin use has been shown to reduce the risk of endometrial cancer. Data from the Finnish Cancer Registry showed a standardised incidence ratio of 0.46 for endometrial cancer in users of the LNG-IUS. The NOWAC study was a Norwegian population-based prospective cohort study. Median follow-up was 12.5 years; 9% of the cohort reported LNG-IUS use during or prior to 1998–2007. After adjusting for BMI, activity, age at start of follow-up, combined oral contraceptive use, menopausal status and parity ever-users of LNG-IUS had RR of endometrial cancer of 0.34 (95% CI 0.18–0.65) compared with never-users •.Almost 25 years ago, the harmful effects of unopposed oestrogen HRT in women with a uterus were apparent. Sequential HRT has also been shown to increase the risk of endometrial cancer, with risk being inversely proportional to the number of days progestin is given for. Continuous combination has not been shown to increase endometrial cancer risk and may even reduce it, presumably because of the protective effects of progesterone on the endometrium .Recent years have seen the emergence of the first oestrogen-based, progestin-free oral menopausal HRT for non-hysterectomised women. Conjugated oestrogens with the SERM bazedoxifene (CE/BZA) minimise estrogenic effects on endometrium and breast whilst effectively addressing menopausal symptoms and protecting against osteoporosis. A similar randomised, double-blind study of 17β-estradiol/raloxifene did not provide adequate endometrial protection. CE/BZA has been studied in five RCTs involving more than 7500 women and no increase in endometrial hyperplasia was found. It may be an option for women who poorly tolerate the side effects of progestins •.Preclinical and animal model studies have shown that bisphosphonates have anti-tumour effects, in part through induction of apoptosis and inhibition of proliferation and angiogenesis. They have been shown to affect the growth and metastasis of gynaecological cancers in cell lines and animal models. A meta-analysis of cohort and case control studies demonstrated a statistically significant endometrial cancer risk reduction with 1–3 years of bisphosphonate use in 6499 endometrial cancer cases from 226,560 participants. With 3 or more years of bisphosphonate use, a 56% reduction in endometrial cancer risk was seen  •.p = 0.14) [In their 2005 randomised controlled primary prevention trial of 39,876 women in the Women’s Health Study, Cook et al. found no association between low-dose aspirin use  and endometrial cancer risk  . A 2016  = 0.14) . The res = 0.14) .Continued efforts to promote breastfeeding may help to reduce endometrial cancer risk in the general population. In their meta-analysis, Jordan et al. demonstrated an 11% reduction in endometrial cancer risk in women who had breastfed  comparing 8981 endometrial cancer cases with 17,241 controls from cohort and case control studies .Felix et al. presented a pooled analysis of individual level data from 18 epidemiological studies, which was the largest investigation of IUD use and EC risk to date . Pooled OR for ever-use of IUD was 0.81 (95% CI 0.74 to 0.9) compared with never-use with the inverse association being strongest in users of inert IUDs, and weaker in users of copper, hormonal or a combination of types of IUDs. Nulliparous IUD users gained more benefit than parous IUD users. Proposed mechanisms of action by which IUDs reduce endometrial cancer risk are increased decidual loss, alterations in hormone receptor expression and stimulation of an inflammatory microenvironment in the uterus .A meta-analysis of 13 studies (no RCTs) demonstrated a weak inverse relationship between high isoflavone (soy) consumption and endometrial cancer risk . NovasoyThe largest meta-analysis in the literature, including 1.4 million participants and 10,100 cases of endometrial cancer, with follow-up of 11 to 20 years concluded there was a dose-dependent reduction in endometrial cancer risk with coffee intake, stronger but not limited to caffeinated coffee. One cup of caffeinated coffee per day was associated with a 7% reduction in endometrial cancer risk , compared with a 4% risk reduction with one cup of decaffeinated coffee/day  •.Merritt et al. conducted a nutrient-wide association study (NWAS) on data from 1303 endometrial cancer cases from the EPIC study and 1531 endometrial cancer cases from the Nurses Health Studies and confirmed an inverse association between coffee intake and endometrial cancer risk .Several factors are thought to contribute to the protective effect of coffee. Caffeine is associated with levels of sex hormone-binding globulin (SHBG) and, as a consequence, levels of bioavailable oestrogen and testosterone. Coffee contains antioxidants and chlorogenic acid, which may inhibit glucose absorption. Coffee has been shown to have an inverse relationship with plasma C peptide levels and the risk of diabetes mellitus .A meta-analysis by Zhou et al., which included six case control or cohort studies, not all of which were controlled for physical activity, found a reduced risk of endometrial cancer with higher intake of green tea. One cup per day was associated with an 11% risk reduction in a dose–response analysis . No protective effect was seen with black tea. Green tea has higher levels of catechins than black tea, such as epigallocatechin gallate, which has been found to induce apoptosis and cell cycle arrest, and inhibit oestrogen-induced activation of endometrial cells.The main focus of our research is the prevention and early detection of endometrial cancer. These themes ranked as the most important endometrial cancer research priorities for patients, carers and healthcare professionals in our award-winning James Lind Alliance Priority Setting Partnership . We founOur aim is to identify a high-risk endometrial tissue signature that predicts those women at greatest risk of developing endometrial cancer to target for prevention measures . Our theoretical risk prediction model will facilitate the identification of women for stratified prevention interventions and ongoing work seeks to validate our model in large UK populations . Such inFuture research must target the gaps in our knowledge. Can we identify those at highest risk of developing endometrial cancer and how best can we prevent it? Well-designed observational and interventional studies may address the questions of aspirin, NSAID and other potential chemoprevention agents. The degree of benefit will need to be weighed against the potential adverse effects of such drugs.For now, it would seem that prevention strategies should focus on minimising risk through weight reduction and/or stability, improving access to bariatric surgery, and by educating women and healthcare professionals about the importance of weight and activity levels on their risk of type 1 endometrial cancer. The LNG-IUS is an effective tool for women at highest risk.Future research may provide us with the justification to use aspirin, metformin or bisphosphonates for chemoprevention but at present the evidence for either their efficacy or their long-term safety in high-risk women is lacking.Use of the Healthy Lifestyle Index may help women take control of minimising their personal risk and help healthcare professionals quantify risks for patients. Work must continue in identifying a high-risk molecular/phenotypic signature for targeted prevention, and efforts to identify women with Lynch syndrome must continue.


Lobular carcinoma in situ (LCIS) of the breast is a risk factor of developing invasive breast cancer. We evaluated the racial differences in the risks of subsequent invasive breast cancer following LCIS.We utilized data from the Surveillance, Epidemiology, and End Results registries to identify 18,835 women diagnosed with LCIS from 1990 to 2015. Cox proportional hazards regression was used to estimate race/ethnicity-associated hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) of subsequent invasive breast cancer.P = 0.046). Compared to white women, black women had significantly elevated risks of subsequent invasive breast cancer , and invasive cancer in the ipsilateral breast  and in the contralateral breast . Black women had significantly higher risks of invasive subtypes negative for both estrogen receptor and progesterone receptor  and invasive subtypes positive for one or both of receptors . The risk of subsequent invasive breast cancer was comparable in Asian women and Hispanic women compared with white women.During a median follow-up of 90 months, 1567 patients developed invasive breast cancer. The 10-year incidence was 7.9% for Asians, 8.2% for Hispanics, 9.3% for whites, and 11.2% for blacks (Black women had a significantly higher risk of developing invasive breast cancer, including both hormone receptor-positive and hormone receptor-negative subtypes, after LCIS compared with white counterparts. It provides an opportunity to address health disparities. Lobular carcinoma in situ (LCIS) is a pre-malignant breast lesion that increases a woman’s long-term risk of developing invasive carcinoma –5. CompaAlthough considered as low-risk pre-invasive or benign lesions, controversy persists regarding whether to classify LCIS as a precursor of subsequent invasive carcinoma or just as a lesion that increases the risk of breast cancer in a woman’s lifetime , 9, 11. Pathological models of breast cancer progression have proposed distinct ductal and lobular pathways from normal breast tissue to invasive breast cancer . Ductal n = 20,021). Patients who underwent bilateral mastectomy were excluded (n = 716). Race/ethnicity was determined as mutually exclusive categories of non-Hispanic white (hereafter acknowledged as white), non-Hispanic black (black), non-Hispanic Asian (Asian), and Hispanic. The analysis excluded Pacific Islanders and other racial classifications (n = 470). Thus, 18,835 women with LCIS were included in the analysis.The cases included in this study were from the SEER database. The data were derived from 17 SEER registries which represent approximately 28% of the US population. De-identified SEER data were utilized thus exempting the study from review by our Institutional Review Board. The analysis included women diagnosed with primary unilateral LCIS (no concurrent DCIS) between January 1990 and June 2015 who had no prior cancer history, were aged 20 or older, and were followed for at least 6 months , death, or December 2015. The Kaplan-Meier estimates of 10-year probabilities of subsequent invasive breast cancer were computed for each of the four race/ethnic groups, and log-rank tests were performed to test for significant differences. We utilized the Lunn-McNeil competing risk models, an extension of the Cox proportional hazards regression models [To compare categorical and continuous variables across racial/ethnic groups, we used the n models , to estiP < 0.05 was used to indicate statistical significance.Each statistical model was adjusted for age , year of LCIS diagnosis , treatment of LCIS , and registries. The analyses were stratified by age at the diagnosis of LCIS (< 50 years vs ≥ 50 years). The interaction between race/ethnicity and age at the diagnosis of LCIS was assessed by including a cross-product term in multivariable-adjusted models. The statistical significance of an interaction term was evaluated by the likelihood ratio test. All statistical analyses were conducted with SAS (9.4 version). A two-sided Among 18,835 women with LCIS, 78.6% were white, 8.2% were black, 4.6% were Asian, and 8.6% were Hispanic. Mean age was 54.1 (a range of 20–95). They were followed for 90 months on average. While 9.9% of patients did not receive surgery, 83.0% had breast-conserving surgery alone, 1.4% were treated with breast-conserving surgery and radiation therapy, and 4.2% had a unilateral mastectomy.Table n = 1536) or other body parts  during the 90-month follow-up. Of these subsequent invasive tumors, 801 (51.1%) were ductal, 408 (26.0%) were lobular, and 242 (15.4%) had both lobular and other types of histology. We observed a significant racial/ethnic difference (P = 0.046) in the cumulative incidence of subsequent invasive breast cancer  subsequently developed invasive breast cancer in either breast  patients were diagnosed with contralateral invasive breast cancer during a median follow-up of 91 months (range 6–311 months). There was no significant difference in the cumulative incidence of contralateral invasive breast cancer by race/ethnicity  (Table Heterogeneity = 0.15).An analysis of hormone receptor status in subsequent invasive breast cancer was performed in white women and black women n = 16,47  [We assessed receptor expression in subsequent invasive breast cancer following LCIS between black women and white women, identifying that black women had a significantly higher risk for ER−PR− invasive subtypes. This correlated with other studies that have identified higher risks of these receptor statuses in black women . The obs 0.0004) . Thus, t 0.0004) . These fWithin this study, differing treatment options were noted to be favored among patients of various races. Breast-conserving surgery alone was chosen by 83.0% of patients, 9.9% did not receive surgery, 4.2% had a unilateral mastectomy, and 1.4% were treated with both breast-conserving surgery and radiation therapy. Among the patients who chose mastectomies, white women were more likely to do so than women of racial minorities, and among the patients who chose no surgical interventions, black women were more likely to do so than women in the other racial groups. These racial variations in choices may be due to healthcare disparities, due to greater preferences of a certain type of treatment based on concomitant cultural norms, or due to the absence of a standardized treatment for LCIS based on the uncertainty regarding the lesion’s malignancy potential , 27. TheOverall, NCCN guidelines recommend counseling patients on lifestyle modifications and follow-up surveillance appointments that include annual mammography, physical examinations, and interval history every 6 to 12 months . As a stAdjuvant therapy such as chemoprevention is an effective method to reduce patient’s risk of developing breast cancer, specifically ER+ invasive breast cancer , 31. TheThis study has limitations. SEER registries did not provide information regarding endocrine therapy utilization, family cancer history, comorbidities, obesity, alcohol consumption, breast cancer screening after LCIS, and socioeconomic status, which may influence the risk of second breast tumors. Although an adequate analysis was conducted from the LCIS patient data, receptor status in LCIS lesions, tumor grade, and tumor size information were unavailable for more than half of patients and thus were not accounted for in the analysis. Treatment status was missing in less than 2% of patients. Missing indicators were documented for this analysis. This approach has been demonstrated to have no significant impacts on the estimated associations between exposures and cancer outcomes when missing is less than 50% .Our study provides the largest population-based analysis on the association between race/ethnicity and the development of subsequent invasive breast cancer after LCIS and for the first time addresses the risk of hormone receptor-negative breast cancer following LCIS. Black women with LCIS had an elevated risk of subsequent invasive breast cancer, including both ER+/PR+ and ER−PR− tumors. Asian and Hispanic women did not have a higher risk of developing these lesions when compared to white women. Further research may refine post-treatment surveillance strategies and might better understand racial preferences for and provider-patient communications about LCIS treatment. In addition, studies to identify which gene expression and molecular alterations in LCIS are associated with the risk of developing invasive carcinoma may open new pathways for chemoprevention and improve patient care to reduce the disproportionate burden of breast cancer in black women. These results also highlight the importance of understanding genetic background, early-life environmental/behavioral exposures, and their interactions as contributors to racial differences in risk of developing invasive breast cancer following LCIS.Additional file 1: Table S1. The race-associated hazards ratios of subsequently developing invasive breast cancer in women with LCIS during three time intervals.Additional file 2: Table S2. The race-associated hazard ratios of subsequent invasive breast cancer in women with LCIS by age at the diagnosis of LCIS.


An increased prevalence of allergies and an increased incidence of breast cancer have been observed. The hypothesis that atopy may have a protective effect against the risk of different types of breast cancer was evaluated.In this study, 11,101 patients  with different types of breast cancer were tested for allergies. Allergies were confirmed based on the retrospective analysis of allergy diagnostic procedures in patients who had been previously diagnosed with breast cancer. The retrospective prevalence rates of active allergic diseases, including allergic rhinitis, bronchial asthma and atopic dermatitis, were assessed. All patients were also analyzed for bronchial asthma and allergic rhinitis according to the relevant guidelines. A group of healthy control patients was used for the comparisons.The women with breast cancer had a significantly lower incidence of IgE-mediated allergic diseases than the controls. The odds ratios (ORs) for allergic rhinitis, atopic dermatitis, and bronchial asthma were 0.61 (95% CI: 0.57–0.73), 0.17 (95% CI: 0.11–0.44), and 0.73 (95% CI: 0.65–0.83), respectively. The mean serum concentrations of total IgE were significantly lower in the study population of women with breast cancer than in the patients of the control group .Our results suggest that the overall incidence of allergies, especially allergic rhinitis, is lower in patients with certain types of cancer than in individuals who did not have cancer. Further studies are needed to confirm our findings. Breast cancer is also the most commonly occurring cancer among women (approximately 12% of women worldwide). There are many risk factors for developing breast cancer, for example, the occurrence of mutations in the BRCA1 and BRCA2 genes, hormone therapy during t cancer ,4. Amongt cancer ,6,7,8.The possible relation between atopy and the induction of neoplasms such as breast cancer is still being investigated; however, few studies have focused on this topic. Some studies have reported allergies in patients with different types of neoplasms; however, the determination of a possible causal relationship was ambiguous ,10,11. KIn a meta-analysis of available data by Wang et al. that analyzed the relationship between atopy and cancer, the authors also present some studies on breast cancer . There wThe aim of this study was to test the hypothesis that there is a relationship between atopy and breast cancer in women.A retrospective method was used to assess the relationships between certain medical events, the occurrence of allergies and breast cancer in this case. This is the first step before for a planned prospective study that could indicate a possible link between breast cancer and atopy.The methods were similar to those of the study by Kozlowska et al. . This reThe medical data from patients’ charts were obtained from 3 oncological centers, 15 GP centers and a regional allergology clinic, which cooperated together in southern Poland. The study was based on a cooperative program, which was carried out as part of a multicenter study on the monitoring of atopic diseases and acceded to the consent requirements of the bioethics committee at the Medical University of Silesia (KNW/0022/KB1/18/14).The epidemiological structure and socioeconomic distribution of the respondents were matched to the Poland 2017 statistical data. The study population was selected using stratified sampling and included women over 30 years of age. The study population sampling method was designed to provide a population that was representative of the typical age and sex of those with breast cancer in Poland in 2017.The patient databases from each site were analyzed simultaneously. In total, 52,308 of a possible 95,186 medical charts were randomly selected and checked. The number of participants that were assessed for eligibility and completed the study is presented in the diagram in The inclusion criteria for the study group were as follows:Patients were over 30 years of age;Patients had a confirmed breast cancer diagnosis; andPatients underwent basic oncological treatment .Based on these criteria, 28,800 patients were enrolled.The exclusion criteria were a lack of detailed documentation and a lack of patient consent. Finally, a group of 11,101 patients comprised of women aged 30 to 84 years was analyzed. The mean time of breast cancer disease duration was 6.5±4.1 years, and the mean time after basic treatment was 2.1±1.4 years at the time of data collection (March-July 2018).The control group included 18,910 patients (women) who were selected from GP centers and allergological clinics . The incWomen over 30 years of age;Individuals without a diagnosis or clinical suspicion of breast cancer.The distribution of age and sex was similar to that of the study group.The control group was formed by screening medical records from the medical databases of GPs and regional allergological clinics in the same region of Poland as the main study group.The same exclusion criteria that were used in the study group were used for the control group.Allergic rhinitis was confirmed based on medical documentation, including laryngological examinations and a history of clinical symptoms according to the ARIA guidelines . BronchiD. pteronyssinus, D. farinae, Aspergillus fumigatus, Alternaria tennis, Cladosporium herbarium, dog, cat, grass mix, birch, alder, hazel, and mugwort. IgE values above 0.35 IU/ml were considered positive.The measurement of the concentration of total IgE and allergen-specific IgE (sIgE) was performed using a Pharmacia CAP system . The following specific IgE allergens were analyzed: Skin-prick tests  to the inhalant allergens mentioned above were performed according to previously published guidelines .All types of cancer were previously diagnosed based on clinical symptoms, imaging tests , biopsies, serum measurements, cancer markers and the ICD-10 code. The study involved only patients who had received oncological treatment and were undergoing follow-up.The data were analyzed with a statistical software package . The parametric descriptive data were compared using Student’s t test or the Mann-Whitney U test. To explore the association between the presence of breast cancer and reports of allergy, asthma, allergic rhinitis, and atopic dermatitis, a multiple logistic regression model was estimated, and the results are presented as the odds ratios (ORs) and 95% confidence intervals (95% CIs).Cluster analysis was used to reveal hidden structures by grouping patients with similar characteristics into homogenous groups while maximizing the heterogeneity across groups. Such a tool increases the reliability of the observations obtained in a retrospective study, especially when data are from different sources. Moreover, this method is recommended when we expect a rare medical event .In the present study, the program STATISTICA was used to analyze important variables that are described below, and it self-formed models based on the mutual relations of the examined variables. The k-means method, as the most widely used centroid-based clustering algorithm, was performed. It is a statistical tool for searching for dependencies of examined features that were not established for example in retrospective cross-sectional studies. Based on these analyses, 5 different clusters (models) were obtained.The following patients’ features were tested as variables: low (<30 kU/L), medium (30–100 kU/L) or high (>100 kU/L) concentration of total serum IgE; all of the comorbidities mentioned in This was done to see the possible relationship between the clusters (endotypes) of patients studied and the occurrence of breast cancer. ANOVA or Pearson’s chi square test were used to compare differences between variables in the obtained cluster models.These endotypes were supposed to show the possible relationship between the various clinical features of the occurrence of allergy, the results of tests, patient lifestyle and the occurrence of breast cancer.The study was approved by the local ethics committees of the Medical University of Silesia in Poland (KNW/0034/2011). All patients signed an informed consent form.The obtained results revealed a significantly lower prevalence of atopic disease in women with breast cancer compared to controls. However, the mean time of allergy duration and the distribution of the type of atopic diseases were similar between the two groups. The population details are presented in D. pteronyssinus , D. farinae  and grass pollen .The OR of a clinical manifestation of any active allergy  in women from the study group who were diagnosed with different types of breast cancer was 0.53 (95% CI: 0.43–0.72). The OR for each type of allergy was as follows: allergic rhinitis, 0.61 (95% CI: 0.57–0.73); atopic dermatitis, 0.17 (95% CI: 0.11–0.44); and bronchial asthma, 0.73 (95% CI: 0.65–0.83). The presence of pre- or postmenopausal breast carcinoma did not influence the frequency of allergy. There were no significant differences in the allergen profiles of the analyzed allergic patients in the cancer and control groups. Allergy to mites and grass pollen were predominant in both groups as follows: The mean serum concentration of total IgE was significantly lower in the study population than in the control group . An inverse correlation between the total IgE concentration and the presence of breast cancer was observed . Total serum IgE was independent of the type of breast cancer, except for metaplastic carcinoma, where a correlation was observed. The details are presented in Cluster analysisThe cluster analysis revealed five models as follows.Model 1: a low concentration of total IgE, urban area, a high incidence of comorbidities, a low risk of active allergy, and a low risk of atopic dermatitis.Model 2: a moderate concentration of total IgE, nonsmoking, rural area, and a low risk of allergy.Model 3: a moderate concentration of IgE, smoking, a high risk of bronchial asthma symptoms, and atopy in family.Model 4: a low concentration of IgE, a low risk of allergic rhinitis and asthma symptoms, and comorbidities.Model 5: a low concentration of IgE, nonsmoking, urban area, and an allergy to house dust mites.The detailed characteristics of the clusters are presented in These results confirmed the possible relation between breast cancer diagnoses and some evidence of allergies. Models 2 and 5 show the inverse association between IgE concentration and the presence of breast cancer diagnosis. On the other hand, in models 1 and 4 with a high prevalence of women with breast cancer, the mean concentrations of IgE were relatively lower in comparison to others. However, the other analyzed allergic features, for example, type diseases, did not have a strong association with the occurrence of breast cancer. These results are consistent with those of a previous study from the Kozlowska group . The resThe possible mechanism that could explain the inverse correlation between atopy and breast cancer is the lack of hyperreactivity of the immune system in women with this cancer, as observed in allergic subjects. The immune system can recognize and remove neoplastic cells; and sometimes, this role could be organ specific .On the other hand, the results showed a lower risk of IgE allergic diseases in the study population with breast cancer than in the general population. This risk was significantly lower than that observed by some other authors. However, the analyzed population was significantly smaller, and the criteria for an atopic diagnosis were imprecise ,21,22,23The protective role of IgE against carcinogenesis was confirmed by Van Hemelrick et al. . This stThe cluster analysis revealed that patients with breast cancer dominated clusters 1 and 4, where a low concentration of IgE and a low risk of allergic diseases were found. This finding is consistent with other results showing an inverse correlation between active symptoms of allergic disease and the presence of breast cancer.This study was limited by some procedural limitations. The assessment of the allergies in patients with cancer diagnoses was complicated and affected by a number of factors. Patients and physicians were typically focused on addressing the underlying disease, i.e., cancer.The influence of oncologic therapies, such as chemotherapy and radiation therapy, could not be excluded from influencing the results of the allergy tests . There were no analyses for IgE-mediated food allergies in this study because of the relative rarity of these conditions in adults.Finally, the fact that the control group was obtained from GP sites and the study patients from outpatient oncology clinics, despite having similar ages and being the same sex, could have been an important confounder .The authors are aware of the study restrictions. Despite the use of restrictive statistical tools recommended in such studies, the obtained observations should be treated as preliminary. Basing data only on the analysis of documentation results is necessary to eliminate a large group of data that could significantly affect the final results. This study is the starting point for a future prospective study with a similar purpose and assumptions.The observed results may indicate that there is an inverse association between the incidence of breast cancer and the low frequency of IgE-mediated allergic diseases. A protective role of IgE in breast cancer is possible. Further studies are needed to confirm our findings.


We assessed the long-term risk of screen-detected and interval breast cancer in women with a first or second false-positive screening result.Joint analysis had been performed using individual-level data from three population-based screening programs in Europe . Overall, 75,513 screened women aged 50–69 years from Denmark (1991–2010), 556,640 from Norway (1996–2008), and 517,314 from Spain (1994–2010) were included. We used partly conditional Cox hazards models to assess the association between false-positive results and the risk of subsequent screen-detected and interval cancer.During follow-up, 1,149,467 women underwent 3,510,450 screening exams, and 10,623 screen-detected and 5700 interval cancers were diagnosed. Compared to women with negative tests, those with false-positive results had a two-fold risk of screen-detected  and interval cancer . Women with a second false-positive result had over a four-fold risk of screen-detected and interval cancer . Women remained at an elevated risk for 12 years after the false-positive result.Women with prior false-positive results had an increased risk of screen-detected and interval cancer for over a decade. This information should be considered to design personalised screening strategies based on individual risk. If no breast cancer is diagnosed, the screening result is considered as false-positive, which may cause distress and anxiety to the women.13 i.e., women recalled for further assessments were declared negative, when they should actually have been declared as having cancer. Misclassified cancers would emerge mostly in a short time interval after the screening-negative result, either as an interval breast cancer during the following 24 months, or as a screen-detected cancer at 2 years. However, there is limited evidence regarding the long-term risk of interval breast cancer and screen-detected cancer after a false-positive result. We hypothesise that if the long-term increase in risk is similar for screen-detected cancer and for interval breast cancer in women with false-positive results, it suggests that false-positives may be risk markers for breast cancer development later in life rather than precursors of malignancy.Further assessments that turn out negative might represent misclassification and missed cancers,Given that false-positive results are the most common adverse effect of screening mammography, the risk attributable to false-positive results examinations could be substantial if the association with breast cancer is strong. Women with false-positive screening results represent a group of women with potential for stratification based on their individual breast cancer risk. Although few women experience a false-positive screening result more than once during their lifespan, on the longitudinal perspective of sequential biennial screening examinations for each woman, their risk of breast cancer should be assessed. No previous study has examined whether a second false-positive screening result influences the risk of breast cancer to a greater extent, or its impact on the risk of an interval breast cancer.Using individual level data from long standing mammography programs in Copenhagen in Denmark, Norway, and Spain, we conducted a joint study to evaluate the association between a first and second false-positive screening result and the long-term risk of interval breast cancer and screen-detected cancer.14 The programs have been described in detail elsewhere.19We performed a joint analysis using individual level data from the population-based screening programs in the Copenhagen Mammography Register in Denmark, BreastScreen Norway, and the Spanish Breast Cancer Screening Program. All three screening programs target women aged 50–69 years, perform biennial screening, and are run according to the European Guidelines for Quality Assurance in Breast Cancer Screening.Briefly, the organised and population-based screening program in the municipality of Copenhagen started in 1991, and there was a national roll-out of the program in 2008–2010. Two trained breast radiologists independently interpret the screening mammograms and classify the women as negative or positive. In case of disagreement a third radiologist is consulted, until consensus is reached. Women classified as positive are recalled for additional assessment. Ninety-five percent of recall examinations take place within 10 working days after mammographic reading. Women with no breast cancer diagnosed after additional assessment are referred back to routine screening, while women diagnosed with breast cancer are referred for treatment.17 Two trained breast radiologists read the screening mammograms independently and give a score 1–5 for each breast. Cases with a score of 2 or higher by one or both radiologists are discussed at a consensus meeting where the final decision about recall is taken. Recall examinations take place 1–2 weeks after the screening examination. If no malignancy is stated, the women are referred back to screening. All women diagnosed with breast cancer are referred to treatment.BreastScreen Norway started as a pilot in 1996 and became nationwide in 2005.16 We included data from eight centres of the mammography screening program in Spain. The screening mammograms are interpreted and classified according to the BI-RADS scale or equivalent15 by two trained breast radiologists. Women with abnormal mammographic findings are recalled for further assessments within 3 weeks after mammographic reading. If no malignancy is stated, women are referred back to screening, while women diagnosed with breast cancer are referred for treatment.Population-based screening in Spain started in one setting in 1990 and became nationwide in 2006.Our study included information about 75,513 women screened in Denmark, (1991–2010), 556,640 screened in Norway (1996–2008), and 517,314 screened in Spain (1994–2010) . A screen-detected cancer was defined as a breast cancer  diagnosed at further assessment due to abnormal findings of screening mammography interpretation.An interval breast cancer was defined as a breast cancer diagnosed after a negative screening or after false-positive screening, either before the next screening (2 years) or within 2 years after the final screening among women who reach the upper age limit. A woman was considered an irregular attendee if she re-attended screening after having missed at least one biennial screening invitation. In addition, information was collected on whether the screening examination was performed with screen film mammography (SFM) or full field digital mammography (FFDM).For each woman, person-years at risk were calculated from the date of first screen. Women contributed person-years at risk to the screened negative group from the date of first screen until the date of first false-positive result, if any. Contribution to the first false-positive group started at the date of first false-positive result until the date of second false-positive result, if any, whereupon they started contributing to the second false-positive group. Censoring times during follow-up were calculated differently for the analyses of screen-detected and interval breast cancers. To calculate the risk of screen-detected cancer, women were censored at the date of last screening examination in the study period, or at the date of breast cancer diagnosis following last screening participation. Since interval breast cancers can show up at any time in the two-year period after a negative screening examination, to calculate the risk of interval breast cancer women were censored at 24 months after last recorded screening date in the study period, or at the date of interval cancer diagnosis, whichever came first. Women with a screen-detected cancer diagnosed at first screen were not included in the analyses because they could not have a previous negative or false-positive result.We compared characteristics of the study population in the three countries. We examined the crude rates of screen-detected and interval breast cancers overall and stratified by country. Rates were calculated as the number of screen-detected cancers and number of interval cancers, divided by the number of women-years at risk in each group. Confidence intervals for rates were calculated using exact Poisson distribution.20 By using a partly conditional Cox model, we included all screening mammograms received by an individual woman accounting for within woman correlation. Since the information is included at a mammogram level, the covariates in the models were analyzed as time-changing variables. Separate models were used to estimate the risk of screen-detected and interval breast cancer. To account for possible confounders, all models were adjusted for age at screen (continuous), type of attendance (regular or irregular), and mammography type (SFM or FFDM). The individual effect of the adjusting variables in the estimates is presented in Supplementary materials, section We used a partly conditional frailty Cox proportional hazard model to assess the association between a false-positive screening result  and the risk of breast cancer.We analyzed data from 1,149,467 women aged 50–69 years at screen. The average follow-up for screen-detected cancers was 5.6 years, while for interval breast cancers it was 6.3 years. During follow-up, 10,623 women were diagnosed with a screen-detected breast cancer, 5700 women with interval breast cancer, 113,634 women had a first false-positive screening result, and 8149 had a second false-positive screening result .25 The study aimed at comparing tumour characteristics between interval breast cancers diagnosed in women with and without prior false-positive results. The authors did not include time as an adjusting variable in their analyses and the unit of analysis was the screening mammogram rather than the women. Consequently, their results are not comparable with our study.Our findings are consistent with previous studies that analyzed long-term breast cancer risk after a false-positive result.10 An increased risk of breast cancer has also been reported in opportunistic screening in the US, where Barlow et al.7 found a higher risk of breast cancer (OR = 1.69) within 1 year after a false-positive result.Several studies have estimated the short-term risk of breast cancer in the screen subsequent to a prevalent false-positive screening result. In the context of population-based screening programs in Europe, a study from the United Kingdom found and increased risk of interval breast cancer and of screen-detected cancer at second screen in women with a false-positive result.13 Besides, the study also found that the average time from false-positive result to breast cancer diagnosis was significantly shorter among misclassified cases than among those non-misclassified (4.0 vs 7.8 years). The differences in average time are due to the fact that the cancer was already present at the time of false-positive result in misclassified cases. Another European study argued that three fourths of breast cancers diagnosed in women with false-positive result were already present at the baseline referral.12 They also showed that 63% of misclassified cases turned out to have breast cancer within 2 years after the false-positive result, while the proportion was 37% for cases in the reference group. It is thus likely that short-term studies are overestimated due to misclassification and lack of thorough follow-up time. Sensitivity analyses showed consistent results in our study population when breast cancers diagnosed in the first 26 months of follow-up were excluded from the analyses (Supplementary material, section Misclassification is an unavoidable part of studies assessing the risk of breast cancer after a false-positive result. A study from Denmark showed that one out of every four women who later developed breast cancer after a false-positive result were misclassified at baseline assessment.28 In a previous study that used data partially included in this study, we found that women with a non-proliferative breast disease had a two-fold risk of breast cancer, whereas women with a proliferative breast disease had a three-fold risk, and women with a proliferative disease with atypia had over a four-fold risk.26 Interestingly, we also found that between 40 and 45% of breast cancer cases were contralateral to the prior benign breast lesion, which has been shown in other previous studies.27 The findings suggest that a large percentage of benign lesions, particularly those with a lower risk such as non-proliferative lesions and proliferative lesions without atypia, are a marker of future breast cancer risk rather than a pre-malignant lesion that will develop into a breast cancer.The sustained long-term increased risk strengthens the idea of a biological susceptibility for developing future breast cancer in women with mammographic abnormalities. The results suggest that the mammographic abnormalities might be risk markers rather than precursors of subsequent breast cancer. This is consistent with the excess breast cancer risk found in women with a benign breast disease.31 Nevertheless, the sensitivity analyses to test the impact of the heterogeneity across countries showed little impact on the overall estimates (Supplementary material, section In our study population, the screening programs share very similar standards and management policies. However, the number of women analyzed differed across countries, as well as the rates of screen-detected cancer, interval breast cancer, and false-positive results (Supplementary material, section 25 Secondly, we had no information on breast density which would have enriched our analyses. High mammographic density is a major risk factor for breast cancer,34 and has been also associated with an increased risk of false-positive results.35 Nevertheless, a previous study showed that mammographic density and prior false-positive results were independent risk factors for breast cancer, which minimises the possible bias introduced by this lack of information. Finally, we had no information on laterality of the mammographic finding that caused the recall for further assessments and thus, we are unable to assess how many cancers developed at the site of the initial mammographic lesion.We analyzed the risk of screen-detected cancer and interval breast cancer in women with false-positive result using individual level data from three population-based screening programs in Europe. The analyses are based on long-term follow-up data, which includes information from the start of each screening program, with a follow-up of more than 15 years. The availability of thorough data of each woman enabled us to map exposure and outcome on an individual level, with no loss to follow-up. However, the study has some limitations. Firstly, we lacked information on which recalls for further assessments lead to a biopsy recommendation, which would have added interesting information to estimate the risk associated with false-positive results including an invasive procedure with benign outcome. Previous studies have shown that the breast cancer risk increased after a biopsy recommendation compared to those with only additional imaging procedures.No prior studies have assessed differences in the long-term risk of screen-detected cancer and interval breast cancer after a first and second false-positive result in population-based mammography screening. We observed a similarly increased risk of screen-detected and interval breast cancer among women with a false-positive result. Consistently, the risk similarly increased four-fold after a second false-positive result. Interval breast cancers are a major detriment of mammography screening. Women with an interval breast cancer diagnosis do not have a substantial benefit from routine screening participation. Based on our findings it might be advisable to inform women with false-positive results about their specific increased risk for screen-detected and interval breast cancer. The highly increased risk reveals a sub-group of women that may be eligible for more intensive screening strategies. Since false-positive results affect a large number of screened women, the outcome of previous screening participations should be considered in risk prediction models aimed at personalizing breast cancer screening strategies based on women’s individual breast cancer risk.In conclusion, we found that women with false-positive results had a two-fold risk of having a later screen-detected and interval breast cancer. The risk increased to a four-fold after a second false-positive screening result and remained elevated for 12 years after experiencing the false-positive result.The datasets generated and analysed during the current study are not publicly available, but are available from the authors on reasonable request.Supplementary Material


Objective: To investigate the correlation between periodontal disease and breast cancer.Materials and Methods: PubMed and China National Knowledge Infrastructure (CNKI) databases were searched up to February 8, 2018 for observational studies examining the association between periodontal disease and breast cancer. Study selection was conducted according to predesigned eligibility criteria, and two authors independently extracted data from included studies. Meta-analysis was performed using the Comprehensive Meta-Analysis v2 software and risk estimates were calculated as relative risks (RRs) with corresponding 95% confidence intervals (CIs).Results: A total of 11 study were included. Meta-analysis indicated that periodontal disease significantly increased the risk of breast cancer by 1.22-fold . Amongst participants with periodontal patients and a history of periodontal therapy, the risk of developing breast cancer was not significant . The association results between periodontal diseases and breast cancer were found to be robust, as evident in the leave-one-out sensitivity analysis.Conclusions: Periodontal disease may be a potential risk factor for the development of breast cancer among women, and thus effective periodontal therapy may present as a valuable preventive measure against breast cancer. Periodontal disease, a complex polymicrobial inflammatory disease, is a public health burden and is partially responsible for tooth loss. Existing epidemiological studies have linked periodontal disease to numerous systemic conditions, such as cardiovascular disease , pretermCancer is a leading cause of mortality worldwide. Among the female-specific malignancies, breast cancer remains the most common cancer type in developed countries, accounting for one-third of newly diagnosed cancers . AvailabOur study was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement .Studies were eligible for inclusion if they met the following criteria: (1) adopting a cohort or case-control design; (2) study participants with periodontal disease, as the exposure of interest; (3) female-specific breast cancer, as the outcome of interest; (4) providing relative risks (RRs), HRs or odds ratios (ORs) and corresponding 95% CIs, or data for their calculation; (5) published in full in English-language or Chinese-language peer reviewed journals. For multiple study reports with the same study population, data from the longest follow-up duration were extracted and analyzed.PubMed and China National Knowledge Infrastructure (CNKI) databases were searched up to February 8, 2018 for case-control and cohort studies examining the association between periodontal disease and breast cancer. The following key words and subject terms were used: “periodontitis,” “periodontal disease,” “oral status,” “dental health,” “breast cancer,” “cancer,” and “carcinoma.”Two authors independently extract the following data extraction from all eligible studies: the first author's name, year of publication, country, study design, follow-up period, age, sample size, periodontal disease, and breast cancer ascertainment, type of periodontal therapy, reference of control, dental and smoking status, risk estimates with corresponding 95%CIs, and corresponding adjustments. Any disagreements over the extracted data were resolved by consensus or by consulting a third author.P0) + (P0 × OR)], in which P0 is the incidence of the outcome of interest in the non-exposed group  and corresponding 95%CIs across the included studies. HRs and incidence density ratios (IDRs) were directly considered to be equivalent to RRs. Where ORs were reported they were transformed into RRs using this this formula: RR = OR/[. Visual inspection of a funnel plot revealed a degree of publication bias  (n = 2)  , 32, 34, (n = 2) , 31 and  (n = 2) , and the (n = 2) , 18, 32  (n = 2) , 29–34 w (n = 2) , 31, 34, (n = 2) , 32, 33 I2 = 51.40 %, P = 0.04;sensitivity analysis: I2 = < 0.01, P = 0.48) although the pooled estimates  remained consistent between the overall results.We conducted sensitivity analysis by removing one study at a time from the overall met-analysis Figure , OmissioI2 = 51.40 %, P = 0.04)to low one  upon removing the study by Söder et al. (The leave-one-out sensitivity analysis led to a decline of the level of statistical heterogeneity declined from moderate (r et al. , indicatThis meta-analysis of 11 observational studies suggested that periodontal disease might be a risk factor for female-specific breast cancer. Finding from sensitivity analyses confirmed the robustness of our association results. According to the findings from subgroup analyses, a number of confounding factors might be influencing the results of the overall analysis, including study design, follow-up period, and history of periodontal therapy.Periodontal disease is a complex infectious diseases , and itsIt is worth highlighting that a similar meta-analysis by Shi et al.  was publDespite our efforts, however, there are some limitations of our meta-analysis. First, although we were able to identify one  contribuBased on currently available evidence, we urge healthcare professionals and the general public to be further aware of the potential association between periodontal disease and breast cancer. The current meta-analysis provided useful insights on the potential effect of periodontal disease on the risk of developing breast cancer, however, further research establishing the precise mechanisms underlying such effect, such as the relationship between altered oral flora, inflammatory marker influx and hormonal levels is warranted. Furthermore, the influences of potential confounding factors, such as smoking status, dietary history, use of contraceptives, marriage, and childbirth status, stress, types of breast cancer, severity of periodontal disease should also be explored.This meta-analysis indicated that periodontal disease might be a potential risk factor for the development of breast cancer in women, and effective periodontal therapy could pose as a viable preventive measure against breast cancer. However, the association between different severity of periodontal disease and sub-types of breast cancer remain to be ascertained. Nonetheless, we are confident that the findings of the current meta-analysis could be helpful in increasing awareness and importance of oral health maintenance, which may led to a reduced risk of developing breast cancer.JS, LW, and X-TZ designed this study. CF and Y-HJ performed search and collected data. Y-JZ re-checked data. LW, CF, and Y-HJ performed analysis. JS and LW wrote the manuscript. X-TZ reviewed the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.