CTLA-4) polymorphisms and breast cancer susceptibility, but the results remained inconsistent. Therefore, we evaluated the relationship between four common CTLA-4 polymorphisms and breast cancer risk by a meta-analysis, aiming to derive a comprehensive and precise conclusion. We searched EMBASE, Pubmed, Web of Science, CNKI, and Wanfang databases until July 18th, 2016. Finally, ten eligible studies involving 4,544 breast cancer patients and 4,515 cancer-free controls were included; all these studies were from Asia. Odds ratio (OR) and 95% confidence interval (CI) were used to evaluate the breast cancer risk in five genetic models. The results indicated that the CTLA-4 +49A>G (rs231775) polymorphism had a significant association with decreased breast cancer risk in allelic, homozygous, dominant and recessive models. Also, the +6230G>A (rs3087243) polymorphism reduced breast cancer risk especially in the Chinese population under homozygous and recessive models. In contrast, the −1661A>G (rs4553808) polymorphism increased breast cancer risk in allelic, heterozygous and dominant models, whereas −1722 T>C (rs733618) did not relate to breast cancer risk. In conclusion, CTLA-4 polymorphisms significantly associate with breast cancer susceptibility in Asian populations, and different gene loci may have different effects on breast cancer development. Further large-scale studies including multi-racial populations are required to confirm our findings.Previous studies have investigated the association between cytotoxic T-lymphocyte antigen-4 ( Breast cancer has been the most common type of cancer and the main cause of cancer death among women in the world, which was estimated to have 1.7 million new cases in 2012 . Breast CTLA-4 gene, which is located in human chromosome 2q33, is one of the most important genes involved in immune responses to a variety of antigens  in exon 1 (rs3087243) in 3′-untranslated region (rs4553808) and −1722 T>C (rs733618) in the promoter region  guidelines .rs231775 or rs308724 or rs4553808 or rs733618,” and “breast cancer.” The eligible article must be published in English or Chinese. References in retrieved articles were also searched manually.We searched the databases of EMBASE, PubMed, Web of Science, Wanfang, as well as Chinese National Knowledge Infrastructure (CNKI) to identify all the relevant articles up to July 18th, 2016. Keywords for search were: “CTLA-4 or Cytotoxic T-lymphocyte antigen 4 or CD152,” “polymorphism or variation or SNP or CTLA-4 with breast cancer susceptibility; (2) All the breast cancer patients were diagnosed by pathology or histology; (3) detailed data of the allele and genotype distributions are available; (4) the controls were cancer-free individuals. In addition, articles meet the following criteria were excluded: (1) articles that were reviews, conference abstracts, or repeat publications; (2) study design were based on family; (3) studies with no control groups. The quality of each included study was assessed by the Newcastle-Ottawa Scale for case-control studies  case-control study conducted in human and investigated the association of SNPs in  studies .P value of HWE in control. Any discrepancy was discussed between authors and refereed by Zhijun Dai to reach a consensus.According to the selection criteria, two authors (Zhiming Dai and Tian Tian) reviewed the literature independently and extracted the raw data and information from each eligible study including: first author, publication year, country of origin, racial ancestry, source of control, genotype method, total number of case and control, allele frequency and genotype distribution in case and control, and CTLA-4 polymorphisms. Pooled ORs were calculated under the following genetic models: allele comparison of B vs. A, homozygote of BB vs. AA, heterozygote of AB vs. AA, dominant model of (BB + AB) vs. AA and recessive model of BB vs. (AA + AB). Heterogeneity among studies were estimated by I2 test and chi2-based Q statistic and significance was considered at I2>50%  and/or +6230G>A (rs3087243) and/or −1722 T>C (rs733618) and/or −1661A/G (rs4553808) polymorphisms were identified for further analysis (P > 0.05) except for one study for one SNP . In subgroup analyses, rs231775 was also found to significantly reduce the breast cancer risk in Chinese and subgroup based on population under allelic, homozygous and recessive models.Seven studies containing 3,613 cases and 3,608 controls focused on breast cancer risk with CTLA-4rs3087243 polymorphism. The results presented a significantly lower breast cancer risk in homozygous and recessive genetic models in Chinese women .There were four studies all of which were from China with 1,402 cases and 1,407 controls investigating the relationship between and breast cancer susceptibility and CTLA-4rs733618 polymorphism, we aseessed 4 studies containing 1,560 cases and 1,489 controls. Overall, our analysis did not suggest any association between rs733618 and breast cancer susceptibility. However, when stratifying by source of control, rs733618 was observed to increase breast cancer risk based on population in three genetic models .For  CTLA-4rs4553808 polymorphism. We observed a higher risk in overall analysis under three models , random-effects model was applied.As presented in Each study was sequentially removed to assess the impact of single study on the combined ORs. The result showed that the omission of any study didn’t alter the overall estimations substantially, indicating that our meta-analysis results were robust .CTLA-4 gene and breast cancer risk either (P > 0.05).We implemened Begg’s funnel plot and Egger’s test to asesess the publication bias. As shown in CTLA-4 gene resulted in quantitative reduction of CTLA-4 expression and led to a severe immunoregulatory disorder  genotypes. Previous studies also found that rs3087243 was associated with breast cancer susceptibility as a subgroup of several cancer sites , these results need to be taken with caution. One previous study found a positive signal of rs733618 polymorphism with breast cancer (We didn’t find any relationship between t cancer  while ott cancer . So furtCTLA-4rs4553808 polymorphism was realated to an increased breast cancer risk in both overall and Chinese population in allelic, heterozygous and dominant models. This suggested that CTLA-4 −1661G allele is more likely to be a risk factor of breast cancer than A allele. Previous meta-analysis also found rs4553808 may increase cancer risk especially for breast cancer (P-value of HWE in control of one study was less than 0.05 (In contrast, t cancer . But thehan 0.05 , suggestrs3087243, rs733618 and rs4553808 polymorphisms. Secondly, our results need to be interpreted with caution since we did not find any studies from Europe, Africa or America and most of the included studies were from China. Therefore, more studies with large population and more ethnic groups are needed to provide sufficient statistical power. Thirdly, other factors such as environmental variants, age, and living habit are generally considered to contribute to cancer susceptibility. Lacking data of these factors for adjustment may impact the estimation of breast cancer risk. Lastly, bias may still exist because we failed to find any studies of other races and we did not have access to gray literature.Several limitations of our research should be noticed. Firstly, the sample size in this meta-analysis was relatively small, especially for rs231775, rs3087243 and rs4553808 polymorphisms in human CTLA-4 gene significantly associated with breast cancer susceptibility in Asians, particularly in the Chinese population. In consideration of the limitations of our work, further large-scale studies including multi-racial populations are required to confirm our findings.In summary, our meta-analysis suggests that 10.7717/peerj.2815/supp-1Table S1Click here for additional data file.10.7717/peerj.2815/supp-2Supplemental Information 1Click here for additional data file.


Approximately 100 common breast cancer susceptibility alleles have been identified in genome-wide association studies (GWAS). The utility of these variants in breast cancer risk prediction models has not been evaluated adequately in women of Asian ancestry.We evaluated 88 breast cancer risk variants that were identified previously by GWAS in 11,760 cases and 11,612 controls of Asian ancestry. SNPs confirmed to be associated with breast cancer risk in Asian women were used to construct a polygenic risk score (PRS). The relative and absolute risks of breast cancer by the PRS percentiles were estimated based on the PRS distribution, and were used to stratify women into different levels of breast cancer risk.P < 0.05. Compared with women in the middle quintile of the PRS, women in the top 1% group had a 2.70-fold elevated risk of breast cancer (95% CI: 2.15–3.40). The risk prediction model with the PRS had an area under the receiver operating characteristic curve of 0.606. The lifetime risk of breast cancer for Shanghai Chinese women in the lowest and highest 1% of the PRS was 1.35% and 10.06%, respectively.We confirmed significant associations with breast cancer risk for SNPs in 44 of the 78 previously reported loci at Approximately one-half of GWAS-identified breast cancer risk variants can be directly replicated in East Asian women. Collectively, common genetic variants are important predictors for breast cancer risk. Using common genetic variants for breast cancer could help identify women at high risk of breast cancer.The online version of this article (doi:10.1186/s13058-016-0786-1) contains supplementary material, which is available to authorized users. Genome-wide association studies (GWAS) to date have identified approximately 100 genetic loci associated with breast cancer risk . ApproxiWe have recently identified several new genetic variants associated with breast cancer risk among women of Asian ancestry –12. As mThis study gathered data from 11 participating case–control studies from three sources: 12,893 women (6269 cases and 6624 controls) of East Asian origin participating in nine studies in the Breast Cancer Association Consortium (BCAC) that were conducted in China, Japan, South Korea, Thailand, and Malaysia; 5152 Chinese women (2867 cases and 2285 controls) from the Shanghai Genome-Wide Association Studies (SGWAS) who were participants in the Shanghai Breast Cancer Study (SBCS), the Shanghai Breast Cancer Survival Study (SBCSS), and the Shanghai Women’s Health Study (SWHS) ; and 5522 Chinese women (2769 cases and 2753 controls) who were participants in Stage 2 of the Shanghai breast cancer Genome-Wide Association Studies (SGWAS-stage2) [P < 10−7, or had genotype discrepancies in >2% of duplicate samples were excluded across all Collaborative Oncological Gene–environment Study (COGS) consortia.Samples from the nine studies in the BCAC were genotyped using a custom Illumina iSelect array (iCOGS) comprising 211,155 SNPs, as part of a large collaboration for replication and fine-mapping of promising associations selected from GWAS of multiple cancers. Detailed information about the quality control (QC) has been described previously . BrieflyThe SGWAS samples were genotyped using Affymetrix 6.0, comprising 906,602 SNPs, and Affymetrix 500 K array, comprising approximately 500,000 SNPs . GeneticThe SGWAS-stage2 samples were genotyped using an exome chip comprising approximately 50,000 SNPs with minor allele frequency over 1%, which included most of the GWAS-identified breast cancer variants .Most SNPs included in this analysis were genotyped directly, and some SNPs were imputed using IMPUTE and the 1000 Genomes data as a reference panel.P < 0.05 (one-sided) was considered statistically significant. Tests for pairwise SNP by SNP interactions were also evaluated using logistic regression under the log-additive genetic model with the same adjustments already stated.A total of 88 SNPs at 78 breast cancer loci identified to date were included in this analysis. First, we evaluated associations between each SNP and breast cancer risk using logistic regression, assuming a log-additive genetic model with adjustment for age, population structure , and study sites, when applicable. We analyzed the association between each SNP and breast cancer risk separately for each data source. The final associations, combining the three sources, were derived using fixed-effect meta-analysis with inverse-variance weights. Any SNP with an association βi is the per-allele log odds ratio (OR) for breast cancer associated with the risk allele for SNPi, which is the number of risk alleles  for the SNP, and n is the total number of significant SNPs. Thus, the PRS summarizes the combined effect of SNPs having significant association with breast cancer risk.Second, to investigate the association between breast cancer risk and the combined effects of all significant SNPs, a PRS was derived for each study participant using the formula:F = N), with mean value μ and variance σ2 [pi is the effect allele frequency of the SNPi, qi = 1 − pi, and βi is the log OR.Under the multiplicative polygenic model, and given a large number of unlinked loci, each conferring a small effect, the population distribution of the PRS is normal ), with the parameters μ' = μ + σ2 and σ'2 = σ2 [The distribution of the PRS in breast cancer cases is also normal  are known:Third, the discriminative accuracy of using the PRS to predict breast cancer risk was evaluated with the AUC, which was calculated theoretically , 18 giveq of the population at highest risk. The proportion q is the complementary measure, the proportion needed to follow-up (PNF) [F, G):Additionally, the AUC was also evaluated using logistic regression models and a nonparametric approach . The AUCup (PNF) , 18. Givj as:h1(t) is the baseline hazard rate of developing breast cancer at age t in the reference group, h1(t) = h*(t)(1 – PAR), where PAR is the population attributable risk (PAR) related to the PRS and the theoretical prediction of the ORj for individuals in the PRS interval j between two percentiles  versus the 40th–60th percentiles:h*(t) is the age-specific breast cancer incidence rate in a composite population, in urban Shanghai during 2002 and 2003 [h2(t) is the mortality rate at age t from all causes of death, except breast cancer, in the population, estimated using age-specific nonbreast cancer mortality in Shanghai in 2002 and 2003 [Finally, we used an approach similar to that described previously for the Gail model  to estimand 2003  or in Koand 2003 ; and h2and 2003  or in Koand 2003 .P < 0.05  and the number of risk alleles of a SNP carried by a woman. Some loci had multiple SNPs. In three of these loci , the most significant SNPs in Asian women  were different from the most significant SNPs in European women . Only the SNP with the most significant association with breast cancer risk in each locus was selected for the PRS. The PRS for Asian women therefore included 44 SNPs.The PRS was derived based on the effect  of 0.38 for the PRS distribution in East Asian women (Eq.  and the p) which are included in the proportion q of individuals in the population at highest risk, while PNF assesses the proportion of the general population at highest risk (q) that one needs to follow in order that a proportion p of those destined to become cases will be followed. Given the SD of 0.38 for the PRS distribution, we estimated that approximately 2.6% of breast cancer cases in the general population would be found among those who were in the top 1% of PRS (PCF = 2.6% when PNF = 1%)  of the SNP–breast cancer association by breast cancer estrogen receptor (ER) status in multiple loci (Additional file As reported previously , we obseFinally, we evaluated the interaction between the PRS and age and pairwise multiplicative SNP by SNP interaction; no significant results were observed.In this study, we demonstrated the value of using common breast cancer variants, summarized as a 44-SNP PRS, to discriminate the breast cancer risk for women of East Asian ancestry. Compared with the recent report for women of European ancestry , we founWe reported previously the contribution of a genetic risk score derived from eight breast cancer-related SNPs in the prediction of breast cancer risk . The 44-A limitation of this study is that this analysis included original studies that identified several new genetic variants among women of Asian ancestry –12, whicWe have shown that known common genetic variants are important predictors for breast cancer risk, and using a 44-SNP PRS could help discriminate breast cancer risk in women of East Asian ancestry, although the discriminatory ability is not sufficient for clinical application.


In order to activate women to participate in breast cancer screening programs, a good understanding is needed of the personal characteristics that influence how women can be activated to search for more information, consult friends and doctors, and participate in breast cancer screening programs. In the current study, we investigate the effect of six personal characteristics that have in previous research been identified as important triggers of health behavior on breast cancer screening activation: Health awareness, Need for Cognition, Affect Intensity, Breast cancer knowledge, Topic involvement, and the Perceived breast cancer risk. We test the effect of these factors on four activation variables: intention of future information seeking, forwarding the message to a friend, talking to a doctor, and actual breast cancer screening attendance. Additionally, we try to unravel the process by means of which the antecedents  lead to activation. To that end, we test the mediating role of perceived breast cancer threat, perceived efficacy of screening, and the evoked breast cancer anxiety as mediators in this process. The data were collected by means of a cross-sectional survey in a sample of 700 Flemish (Belgium) women who were invited to the free-of-charge breast cancer population screening. Screening attendance of this sample was provided by the government agency in charge of the organisation of the screening. Health awareness, affects intensity, topic involvement, and perceived risk have the strongest influence on activation. Breast cancer anxiety and perceived breast cancer threat have a substantial mediation effect on these effects. Efficacy perceptions are less important in the activation process. Increased health awareness and a higher level of perceived risk lead to less participation in the free of charge population based breast screening program. Implications for theory and practice are offered. The limitation of the study is that only a standard invitation message was used. In future research, other types of awareness and activation messages should be tested. Additionally, the analysis could be refined by investigating the potentially different activation process in different subgroups of women.  One in seven women are confronted with breast cancer over their lifespan . Early dOne specific strategy to motivate cancer prevention and early detection behaviors is to tailor health messages to the characteristics of the target group. Latimer et al.  and WillPrior research has identified a number of personal characteristics of the target group that can have an impact on health behavior and decisions ,3. ThreeMost previous studies have focused on behavioral outcomes such as actual screening attendance. However, the actual attendance is only one aspect of activation and it may be the end result of other, intermediary, forms of activation, such as being triggered to look up more information, forward a message to friends, or visit a doctor. These types of activation may be important because they may eventually lead to more awareness and actual screening behavior. An important theoretical contribution of our work is that it explicitly takes these other activation behaviors (or intentions thereto) into account, something that has not received much attention in previous studies.Another important knowledge gap we try to fill, and for which there is only scant previous research, is to unravel the mechanism behind the effects of personal characteristics on breast cancer screening activation. Testing the mental processes through which personal characteristics have an activation effect, is an essential contribution to insight into the mechanism of activation. Based on the protection motivation and the extended parallel processing model, we explore to what extent evoked threat, anxiety, and perceived efficacy mediate the effect of personal characteristics on activation. In summary, in the current study, we investigate the effect of six intrinsic and topic-specific personal characteristics on breast cancer screening participation activation: health awareness, need for cognition, affect intensity, prior breast cancer knowledge, topic involvement, and perceived risk of breast cancer. A mediation model is proposed and tested of the effects of personal characteristics on perceived threat and efficacy and breast cancer anxiety (mediators), and to what extent the latter processing variables have an effect on breast cancer screening activation. The conceptual framework of the study is shown in Six personal characteristics are studied in the current study, based on their potential relevance for breast cancer screening attendance as well as on other activation variables: intention to seek breast cancer information in the future, forward the message to a friend, talk to a doctor, and to participate in the population based breast cancer screening. In the hypotheses and research question, we refer to ‘breast cancer screening activation’ to indicate these four dependent variables.Health awareness or health consciousness refers to the degree to which health concerns are integrated into a person’s daily activities . JayantiNeed for cognition (NFC) is the intrinsic desire or the individual tendency to engage in challenging intellectual activity and enjoy thinking [thinking ,25. Priothinking ,26. The thinking . Prior rthinking . In the thinking ,10 obserAffect intensity (AI) is a stable individual difference in the strength with which individuals experience their emotions [emotions . Affect emotions ,27. Subsemotions , both inemotions ,14,15. Aemotions ,17, thatBreast cancer knowledge is the prior knowledge the individual has gathered and makes up the current understanding about broad aspects of breast cancer, such as screening, symptoms, treatments, etc. There is an association between low health literacy  and variables that affect the engagement in cancer prevention and screening activities. Prior research shows that adults with low health knowledge demonstrate a less proactive health attitude, specifically regarding cancer. This is expressed in avoiding doctor’s visits more often and having more fatalistic attitudes toward cancer. Low health literacy also leads to being less accurate in identifying the purpose of cancer screening tests and being more likely to avoid information about diseases a person did not encounter yet [nter yet  Given thTopic involvement is the degree to which an individual is involved with the topic, in this case, breast cancer. Individuals can have a higher involvement due to prior experience with the disease within the individual’s community or a higher actual risk. Involvement can also be established and further encouraged, e.g., through memorable messages. Smith et al. [h et al.  investigh et al.  investigh et al.  also indPerceived risk is the perception of an individual about his/her personal risk or chance to develop a disease, for instance due to a breast cancer family history or prior breast cancer experience [perience . Women wperience ,30 invesperience  investigperience  states tperience  concludeperience  examinedperience  found noperience  examinedSome previous research also points at the negative effects of risk perception on breast cancer screening activation. Kash et al.  investigAlthough there is some lack of consistency in the results of previous research regarding the relationship between perceived breast cancer risk and awareness activation and screening attendance, the majority of the findings in previous studies point at a positive relationship. The following hypothesis is advanced: fear-as-acquired drive model [Protection Motivation Theory (PMT) [Extended Parallel Process Model (EPPM) integrates the fear drive model and the PMT model [In the previous sections, we have developed hypotheses with respect to the relationship between personal characteristics and breast cancer screening activation. An interesting question is which mental processes explain these presumed effects. Different theories have been proposed on how intrinsically threatening messages (such as the one in this study) influence the activation of the receiver of the message, and through which processes. The ve model  claims tve model . The Prory (PMT)  defines ry (PMT) . The PMTry (PMT) , and smory (PMT) . In theiry (PMT)  confirm MT model . In thisMT model ,42,43 anMT model . Not onlMT model . Previous research only partially and indirectly documents the mediating effect of evoked threat, efficacy and anxiety on the relationship between personal characteristics and health behavior activation. Hong  found a Research question 1. What is the mediating effect of perceived threat, perceived efficacy, and evoked anxiety on the relationship between the personal characteristics of women on the one hand, and breast cancer screening activation on the other?In May 2015, all 7000 women aged 50 to 69 (and thus eligible for the free-of-charge breast cancer screening organized by the Flemish government), living in four different Flemish (Belgian) towns received an invitation to the free-of-charge breast cancer screening organized by the government, and also received a questionnaire. The study is thus based on a cross-sectional survey. The relevant population of these four towns together was fairly typical of the Flemish population in that age group. These women were invited by the government agency with a standard invitation letter to which the questionnaire was added. In this questionnaire, the variables discussed in the previous section were measured (see next section for measurement details). Seven hundreds of them returned it fully completed. A number of measurement scales are based on previously validated measures, others were self-developed. In n = 10) belonging to the target group of the main study. All analyses reported hereafter are based on information collected in the survey, apart from the actual screening attendance. The latter information was provided by the government agency, for all of the women who completed the survey. The questionnaire was pre-tested in a sample of women , need for cognition (3.19), affect intensity (3.47), breast cancer knowledge (1.34), topic involvement (3.67), and 42.4% indicated the perception to have an increased breast cancer risk. The personal characteristics are not highly correlated. There are significantly positive correlations between health awareness and affect intensity (r = 0.190), breast cancer knowledge (r = 0.119), and topic involvement (r = 0.314), between the need for cognition and breast cancer knowledge (r = 0.159), between affect intensity and topic involvement (r = 0.150), and between breast cancer knowledge and topic involvement (r = 0.185).Behind the relation between a predictor (antecedent) and an outcome (criterion), there may be a mechanism that “explains” the effect. For instance, in the context of the current study, a personal characteristic  may have an effect on an activation variable  because health awareness leads to a higher perceived threat which, in turn, leads to a stronger intention to visit a doctor. In other words, perceived threat “explains” the relation between health awareness and the intention to visit a doctor. In this example, “perceived threat” is a mediator. A mediator accounts for the relation between the predictor and the criterion. Mediators explain how a predictor influences a criterion. They clarify what would otherwise remain a black box in terms of why an antecedent predicts an outcome. To test the model in In the current study, the effects of each of the six personal variables (antecedents) on each of the four activation variables are tested. In each model, the mediating effect of threat, efficacy, and breast cancer anxiety on the relation between personal characteristics and activation variables is simultaneously investigated . This imp > 0.05 values. In Participants with higher health awareness report a higher intention to seek information and to talk to a doctor. However, participants with higher health awareness participated less in the screening program. Hypothesis 1 is partly supported. Threat fully mediates the effect of health awareness on forwarding to a friend, and partially mediates the effect of health awareness on talking to the doctor. Efficacy fully mediates the effect of health awareness on forwarding to a friend. Breast cancer anxiety partly mediates the effect of health awareness on future information seeking and fully mediates the effect of health awareness on forwarding to a friend.There is a direct negative effect of need for cognition (NFC) on forwarding to a friend. The higher the need for cognition, the lower the intention to forward the message to a friend. Hypothesis 2 is not supported. Neither threat nor efficacy mediates the effect of NFC on any of the four activation variables. Breast cancer anxiety fully mediates the effect of NFC on future information seeking, partially mediates the effect of NFC on forwarding to a friend, and fully mediates the effect of NFC on talking to the doctor. Higher affect intensity leads to a higher intention for information seeking, forwarding the message to a friend, and talking to a doctor. There is no direct effect of affect intensity on breast cancer screening. Hypothesis 3 is supported, except for screening attendance. Threat partially mediates the effect of affect intensity on forwarding to friend and talking to the doctor. Efficacy partially mediates the effect of affect intensity on forwarding to friend. Breast cancer anxiety partially mediates the effect of affect intensity on future information seeking, forwarding to friend, and talking to the doctor. breast cancer knowledge, the higher the intention to talk to the doctor. Hypothesis 4 is only partly supported. None of the mediators mediate the effect of breast cancer knowledge on any of the four activation variables. The higher the A higher topic involvement leads to a higher intention to search for more information, forward the message to a friend, and talking to a doctor. Hypothesis 5 is confirmed, except for screening attendance. Threat and efficacy partially mediate the effect of topic involvement on forwarding to friend. Breast cancer anxiety partially mediates the effect of topic involvement on future info seeking and forwarding to friend. The higher the perceived risk, the higher the intention to search for breast cancer information to forward the message to a friend and to talk to a doctor. However, contrary to expectations, the higher the perceived risk, the lower the participation in the screening program. Hypothesis 6 is confirmed, except for screening attendance. Threat partially mediates the effect of perceived risk on forwarding to friend. Breast cancer anxiety partially mediates the effect of perceived risk on future info seeking and forwarding to friend.In general, health awareness, affect intensity, topic involvement, and perceived risk have the most profound effect on activation, while the effect of need for cognition and breast cancer knowledge is more limited. Breast cancer anxiety, and to a lesser extent evoked threat, have a substantial mediation effect, especially on forwarding the message to a friend, while efficacy perceptions seem to be less important for activation. However, the effect of personal characteristics on actual participation in the population based breast screening program is very limited, and sometimes in the unexpected negative direction. Increased health awareness leads to less participation in the free of charge population based breast screening program. Previous research in the area of skin cancer prevention also demonstrated that a good knowledge of skin cancer among adolescents does not affect sun bathing habits or the intention to change these habits ,51. The In the present study, a higher need for cognition leads to a lower intention to forward the message to a friend. The effect of need for cognition is not mediated by perceived threat or efficacy, but only by feelings of anxiety. These results do not support previous findings ,30,38,43Although a higher level of perceived risk leads to more information seeking, forwarding the message to a friend, and talking to a doctor, it also leads to lower participation in the population based screening. These results only partially confirm earlier findings. A higher perceived risk has indeed been associated with more information seeking ,30, but As messages are more persuasive if they are consistent with personal characteristics of the message recipients and the way that they process information, these findings can provide guidance for health policy decision makers and health communication professionals, to fine-tune communication to women about breast cancer screening. Based on our results, awareness campaigns should not focus too much on the efficacy of breast cancer screening, but rather on the threat of the disease and, even more importantly, on the anxiety and fear that the disease evokes. This is even more important for women who are highly health aware and affect intense, and who are highly involved with the topic and have a high risk perception. However, focusing too much on anxiety and fear in awareness campaigns may, in the longer run, not be the best strategy. While having a normal/moderate level of concern for the risk of any disease is healthy, being overly anxious or perceiving one’s risk as higher than it really is, can be just as negative as a lack of concern/worry/anxiety and perceiving one’s risk as lower than it actually is. A woman who engages in mammography screening because of anxiety may only be doing so to alleviate higher than normal levels of anxiety, and may engage in screening more often than is recommended. Not only may high levels of anxiety create unhealthy emotions for women and possible over utilization of screening, but also it seems unethical to promote this as a method to encourage women to engage in screening. Indeed, in general, the excessive use of fear appeals could install an atmosphere of anxiety that makes people very unhappy, or could even lead to reactance whereby people effectively ignore the message. While keeping on focusing upon the threat and the anxiety woman should feel when reading a breast cancer awareness message, a broader and more ethical strategy could be to focus on developing the personal characteristics that are the prime antecedents of breast cancer screening activation. Health campaigns could therefore focus on building stronger health awareness, breast cancer involvement and perceived risk, and use emotional arguments to appeal to those with a higher affect intensity. Correctly informing women about their risk of developing breast cancer is crucially important for screening participation. Encouraging them to talk to a doctor is a necessary first step. In that sense, developing a correct risk perception could be a crucial prerequisite to further screening behavior. In the current study, only one message was tested. Messages can be differently framed, for instance, positive or negative, rational or emotional, and endorsed by different ‘authorities . These different message frames could lead to different message processing, and hence also different levels of activation for people differing in personal characteristics ,53,54. FMore health awareness, and a higher affect intensity, topic involvement and perceived risk, have the strongest effects on activation, while the effect of need for cognition and breast cancer knowledge is more limited. Breast cancer anxiety, and to a lesser extent evoked threat, substantially mediate the effect of personal characteristics on activation, especially on forwarding the message to a friend, while efficacy perceptions seem to be less important for activation. Messages are more persuasive if they are consistent with the personal characteristics and the message processing style of the message recipients. The findings can thus provide guidance for health policy decision makers and health communication professionals to fine-tune their communication. Awareness campaigns should focus on developing a reasonable level of threat and anxiety and appeal to affective responses, and at least as more importantly, should develop higher levels of health awareness, breast cancer involvement, and a realistic breast cancer risk perception. Although these factors may not always immediately lead to actual screening participation, they do activate women to seek more information, talk to a doctor, or spread the message amongst their friends.


BRCA1 and BRCA2 mutation carriers has produced conflicting results, with some studies showing an increased risk following early first pregnancy in contrast to the reduced risk in the general population of women. The present study addresses these inconsistencies.Previous research assessing the impact of pregnancy and age at first pregnancy on breast cancer risk in BRCA1 and BRCA2 carriers from North West England were assessed for breast cancer incidence prior to 50 years of age comparing those with an early first full-term pregnancy (< 21 years) to those without a full-term pregnancy. Breast cancer incidence per decade from 20 years and Kaplan–Meier analyses were performed.Female BRCA1; 1146 BRCA2) developed 990 breast cancers under the age of 50 years. Women who had their first term pregnancy prior to age 21 (n = 441) had a lower cancer incidence especially between age 30–39 years. Kaplan–Meier analysis showed an odds ratio of 0.78 for BRCA1 (p = 0.005) and 0.73 for BRCA2 (p = 0.002).2424 female mutation carriers (1278 BRCA1 and BRCA2 mutation carriers.The present study demonstrates a clear protective effect of early first pregnancy on breast cancer risk in both  BRCA1 and BRCA2 pathogenic mutation carriers (with a very high lifetime risk of breast cancer) is conflicting [BRCA1 mutation carriers but an increase in breast cancer risk in BRCA2 carriers [BRCA1 carriers with early compared to late first pregnancy [BRCA2, early first pregnancy was protective), but no overall protective effect of pregnancy for either gene. In 2007, a case control study demonstrated no effect of either pregnancy or age at first live birth in breast cancer risk for either gene [BRCA1, this was confined to individuals with pathogenic mutations in the central portion of the gene [Older age at first pregnancy is a strong predictor for increased risk of later onset breast cancer both in the general population  and in wflicting –8. Takinflicting . Cullinacarriers . A furthregnancy   and testing for whole exon deletions or duplications by multiple ligation dependent probe amplification (MLPA). Once a pathogenic variant is identified, predictive genetic testing for the familial mutation is offered to other affected and unaffected at risk relatives. Mutation carriers are identified by testing positive for the family pathogenic mutation, or by inference as an obligate carrier by segregation within a family. Family members have been tested in a total of 623 families with BRCA1 pathogenic mutations (98 notified from other centres) and 584 BRCA2 pathogenic mutations (103 notified from other centres). Age at first full-term pregnancy (FFTP) was calculated from date of delivery of first full-term child and date of birth of mother. Dates of first breast cancer were identified from pathology records or from the North West Cancer Intelligence service. Women were censored at date of breast cancer, risk reducing mastectomy, risk reducing oophorectomy (there is at least an effect in BRCA2), ovarian cancer, date of death, or date of last follow-up, whichever was earliest. Follow-up was taken from age 20 years to 50 years. Women who were nulliparous were treated as having no FFTP (group 0). Women with FFTP aged 20-and-under were treated as the study comparator group (group 1). For women with a FFTP after the age of 20 (21–46 years), follow-up from age 20 to date of FFTP was included in the nulliparous group (group 0), whilst follow-up after FFTP to censor date was included in group 2 for FFTP 21–29 years, group 3 for FFTP 30–39 years and group 4 if FFTP > 39. Therefore, all follow-up prior to FFTP in any women with a first pregnancy after the age of 20, was included in the nulliparous group. In order to correct for ascertainment bias, a second analysis was carried out to include only follow-up and breast cancers from date of family ascertainment to the Department of Genomic Medicine.Testing for Assessment of breast cancers occurring aged < 50 years in untested female first degree relatives was undertaken to assess any potential testing bias.BRCA1, BRCA2 and TP53 testing.A subgroup analysis was carried out in our previously reported 30-years and-under breast cancer study . Women dMedian age at first pregnancy as a control was taken from women entered onto the Manchester Regional BRCA family register database as mutation carriers or tested or untested first degree relatives.Rates of breast cancer per 1000 women were calculated by age group  at breast cancer diagnosis for each group . Cumulative incidence curves were compared using Kaplan–Meier analysis and the log rank test. The cumulative incidence rate at age 40 and 50 is reported and odds ratios calculated as the ratio of the cumulative incidence rate for group 1 compared to group 0. Analysis was conducted using Stata version 14.Ethics approval for the study was through the North Manchester Research (08/H1006/77) and University of Manchester (08229) ethics committees.BRCA1; 194-BRCA2) with age at FFTP of < 21 years. A total of 448 female carriers had not had a full-term pregnancy at last follow-up . Follow-up in 1535 women with FFTP aged 21–29 , 30–39  and 40–46  was available  resulting in 2424 female carriers in total. These 1535 women in groups 2–4 contributed 10,302 years of follow-up between age 20 and the date of their first birth and developed 20 breast cancers before their first birth or within 1 month thereof. These data were included in the nulliparous control group (group 0) in Table p < 0.001 odds ratio for group 1 compared to group 0 = 0.76. Results remained significant for both BRCA1 OR 0.78 (p = 0.005) and BRCA2 OR 0.73 (p = 0.002). At age 40, corresponding values are 28.1% for group 0 and 20.6% for group 1, p = 0.004.There were 441 females with pathogenic mutations (247-p = 0.005). group 2 was intermediate at 40.9% (95% CI 34.1–48.6) risk by age 50 years still significantly less than the nulliparous group (p = 0.01).In prospective analysis, group 1 was significantly less likely to develop breast cancer with 33.2% risk by age 50 (95% CI 22.4–47.3) compared to 54.6% (95% CI 42.1–68.0) in group 0 (BRCA1/2 mutation carriers (40.5%) who had completed their first pregnancy between 21 and 47 years of age had developed breast cancer after their FFTP but before 50 years of age. Risks for these groups are presented in Tables Breast cancer developed in 622 of 1535 Eighty-three first degree relatives of mutation carriers who were affected with breast cancer had not undergone mutation testing, which included 55 women who had completed a pregnancy and 14 (20%) who had not (14 not known). This constituted 5/20 (25%) of those with breast cancer aged < 40 years. Amongst those unaffected, first degree relatives who had not undergone presymptomatic testing and were aged 40 years of age or older 106/543 (19.5%) were nulliparous. As such, only 20/541 (3.7%) breast cancers aged < 40 years were of unknown mutation status and 548/1639 (33.4%) of those unaffected female first degree relatives who were over 40 years of age had not undergone testing.BRCA1 (n = 22) or BRCA2 (n = 9). 16/31 (51.6%) had completed a FFTP before their breast cancer diagnosis with 15 either having their first pregnancy after breast cancer (n = 4) or remaining nulliparous (n = 11). Median age at breast cancer diagnosis was 28.9 years. From the Manchester BRCA database of women with years of birth from 1950 to 1977 (the same range as in the BRCA cases from 30-and-under), 58.9% (1486/2521) had completed their FFTP before their 29th birthday. Amongst 31 BRCA carriers, this would have given an expected number for those having completed an FFTP by 29 of 18.25, whereas slightly less than this (n = 16) had completed a FFTP by this time. This means there was a non-significant over representation of women who had not yet had a completed pregnancy by the time they were diagnosed with breast cancer, suggesting there was not a testing bias towards nulliparous women.In the 30-and-under study, blood was screened on 122 women (72.2%) out of a possible 169 who were alive during study recruitment (1991–1998). Twenty-seven women declined the study and in 20, the clinician responsible refused access to the woman. A total of 31/122 (25.4%) had mutations in BRCA1 or BRCA2 mutations. Nulliparity results in an approximately 30% higher likelihood of developing breast cancer by 50 years of age than if a woman had completed a pregnancy by age 21 years. The present study also shows that the effect is sustained in unbiased prospective analysis. It is possible that previous studies have been subject to ascertainment bias. Women with early onset breast cancer who have children may have been more likely to opt for BRCA testing to help ascertain risks for their children. This bias may decrease with BRCA testing now being driven by the need to alter treatment to platinum based chemotherapy or PARPi treatments [The present study demonstrates a clear protective effect of early first pregnancy on breast cancer risk in women with pathogenic eatments , 11. BRCeatments –14.BRCA1 and BRCA2 pathogenic mutation carriers and with young age at first pregnancy only in BRCA2 mutation carriers [BRCA1 and BRCA2 mutation carriers, respectively, and in prospective analysis, an even better odds ratio for both combined at 0.61. Another recent study of 197 BRCA mutation carriers has also shown an effect with mean age at breast cancer of 36.2 years in nulliparous carriers compared to 40.9 years (p = 0.001) in parous carriers [Previous analysis from our group 10 years ago on 789 mutation carriers, demonstrated a protective effect of pregnancy in both carriers . Howevercarriers .Whilst informing women about the potential benefits of early first pregnancy may be difficult, particularly if they are already over 30 years of age, some women may wish to complete their family earlier if they know this could reduce their risk. Any pregnancy in a BRCA carrier over 30 years of age will have the a greater potential (around 1–2%) of a pregnancy associated breast cancer, which is likely to be detected at a later stage as mammography and MRI are not possible during, and for some time after, pregnancy and/or breast feeding. Even though it is unlikely to change many women’s minds, (even if they are able to plan it) some women in stable relationships who may otherwise have delayed pregnancy for career aspirations, may decide on early pregnancy to avoid the later risk of pregnancy associated breast cancer and to reduce their overall breast cancer risk.There are some limitations to the current study. Not all eligible women chose to have testing. This may result in a testing bias. However, if anything, the proportion of nulliparous women was higher at 25% of those diagnosed with breast cancer at < 40 years of age, suggesting that if any testing bias existed, it was towards not testing young onset breast cancers in nulliparous women. Overall, there were only 20 untested relatives with breast cancer < 40 years of age compared to 235 in group 0 and group 1 in the study who were known to be mutation carriers. The breast cancer rates and penetrance to age 40 and 50 years are likely to be overestimates since some first degree relatives were not tested, the majority of which were unaffected. These rates should not be quoted to unaffected mutation carriers. However, results of the prospective analysis with risk of 33% by age 50 in women with an early FFTP compared to 55% in nulliparous women are likely more accurate although confidence intervals are larger due to smaller numbers.In conclusion, the current study of nearly 2500 female BRCA pathogenic mutation carriers shows a clear protective effect of early FFTP, which adds to the weight of evidence that risk factors are very similar in BRCA mutation carriers to those in the general population. Women who undergo testing in the late teenage years and early twenties should be informed of this.


The assessment of a woman’s risk for developing breast cancer has become increasingly important for establishing personalized screening recommendations and forming preventive strategies. Studies have consistently shown a strong relationship between breast cancer risk and mammographic parenchymal patterns, typically assessed by percent mammographic density. This paper will review the advancing role of mammographic texture analysis as a potential novel approach to characterize the breast parenchymal tissue to augment conventional density assessment in breast cancer risk estimation.The analysis of mammographic texture provides refined, localized descriptors of parenchymal tissue complexity. Currently, there is growing evidence in support of textural features having the potential to augment the typically dichotomized descriptors (dense or not dense) of area or volumetric measures of breast density in breast cancer risk assessment. Therefore, a substantial research effort has been devoted to automate mammographic texture analysis, with the aim of ultimately incorporating such quantitative measures into breast cancer risk assessment models. In this paper, we review current and emerging approaches in this field, summarizing key methodological details and related studies using novel computerized approaches. We also discuss research challenges for advancing the role of parenchymal texture analysis in breast cancer risk stratification and accelerating its clinical translation.The objective is to provide a comprehensive reference for researchers in the field of parenchymal pattern analysis in breast cancer risk assessment, while indicating key directions for future research. The incidence and mortality rates of breast cancer remain extremely high despite advances in screening and treatment . In the the individual woman [Unfortunately, to date, the broadly available risk assessment models cannot identify high-risk women reliably within the general population. Current models predict either the risk of carrying a high-risk genetic mutation such as BRCA1/2  or the risk of developing breast cancer over time with or without such a mutation  . These mal woman  it is crWhile mammography remains the cornerstone of early breast cancer detection , it alsotextural features have been proposed as not only imaging markers that could identify parenchymal changes associated with breast cancer development [Compared to the global image measure of breast density, parenchymal texture descriptors can provide more refined, localized descriptors to characterize the complexity as well as the morphological distribution of the breast parenchymal patterns. Breast density measures are generally dichotomous, or each area or voxel of breast density measured in the mammogram is compared to a threshold of “dense” or “not dense” without reflecting the broader range and spatial distribution of the various breast parenchymal elements. Parenchymal elopment –19, but elopment –22. In aelopment –25. TherThis article reviews approaches to quantitate mammographic textural features and methods to incorporate these features into breast cancer risk assessment models, focusing primarily on novel computerized approaches. A systematic review of the literature in PubMed was performed to identify all original articles published up to April 2016 that evaluated computational measures of mammographic texture in breast cancer risk assessment. The following keywords were used in combination: “texture” or “parenchymal patterns” or “image features”, “mammography” or “mammogram”, and “breast cancer risk” or “mammographic risk”. To broaden the search, the “related articles” function provided in PubMed was also used, and all articles and citations obtained were reviewed. The references from all the articles identified were also examined for further relevant studies. The last search was conducted on 29 April 2016. Studies not considered relevant to the scope of the review were excluded; other exclusion criteria included: study not published in the English language, full text not available, letter to the editor, and duplicate publication. In the rest of this manuscript, we summarize key methodological details and evaluation results from the 44 research papers identified by the search and discuss future challenges in this promising research field.The value of characterizing the mammographic texture of the breast parenchyma in breast cancer risk estimation was originally demonstrated in the pioneering studies of Wolfe , 27, Boy2) are used. Multiple ROIs defined at various scales of breast tissue density were used by Sun et al. [In most studies, texture analysis has been performed within a single ROI in the breast Table . This sin et al. , where iThe texture descriptors used in breast cancer risk assessment to date can be broadly classified into five feature groups Table , each ofThe proposed methodologies have been applied primarily to digitized film-screen mammograms and more recently on full-field digital mammograms. Texture descriptors have been evaluated in a few prospective and a larger number of retrospective case–control studies, where their discriminatory capacity in breast cancer prediction was typically assessed in terms of the area under the ROC curve (AUC) measuring their ability to distinguish between cancer cases and controls Table . The pot2 patches in the breast and the fractal dimension estimated by considering the entire breast as a single ROI. For both features, the results showed moderate relative risk (RR) after adjustments for the effects of other risk factors, i.e., age at menarche, menopausal status, age at first time pregnancy, number of live births, family history of breast carcinoma, height, and weight , while no additional contribution to risk was found in models that incorporated breast density measures. Similar conclusions were reported by Torres-Mejia et al. [Byng et al.  were thea et al.  who estiThe promising results of these early studies were followed by retrospective studies using more complex parenchymal texture descriptors , 73–76. In an attempt to identify highly discriminative texture descriptors from multiple feature groups and develop optimal combinations that maximize the case–control classification performance, research groups have also explored comprehensive sets of multi-parametric features reflecting various aspects of mammographic texture , 77, 78.Promising results from rich feature sets were also recently reported for digital mammograms. In a study with CC-view digital mammograms of 141 cases and 199 controls, a total number of 765 features were computed from ROIs defined at multiple density scales . From th2 retro-areolar ROI in CC mammographic views were shown to predict a woman’s risk of carrying this high-risk genetic mutation. The first study addressing this topic extracted a comprehensive feature set of grey-level intensity statistics, co-occurrence features, and multi-scale texture measures based on Fourier transform analysis [The potential of mammographic texture in breast cancer risk assessment has also been demonstrated in studies with BRCA1/2 carriers, where texture features from a single 25.6 × 25.6 mmanalysis . In filmanalysis . Using tanalysis , for difanalysis , 82, andanalysis .These results were recently replicated and validated in datasets with digital mammograms , 84 and A comparison of the evaluation results published to date Table , focusinIn addition, a number of related findings suggest that texture analysis is able to provide complementary information about a woman’s risk of developing breast cancer which cannot be captured by breast PD and other established risk factors. Texture descriptors have been weakly or moderately correlated with breast PD , 85–87, Moving forward, experiments evaluating the relative performance of different implementations of texture analysis, using the same evaluation methodology , are necessary to develop more robust and reproducible quantitative mammographic phenotypes of breast cancer risk. Future studies to test the incremental value added by computerized textural measures in predicting breast cancer will require: (a) the design of large age-matched datasets; (b) the selection of an effective classification model, where different previously used models Table  could beIn an attempt to add an anatomical meaning in texture analysis which may also give additional discrimination power to feature classification, increasing attention is currently given to the incorporation of breast anatomy in texture analysis pipelines. Brandt et al.  first inAnother emerging technology is deep learning , which mDigital breast tomosynthesis (DBT), an emerging x-ray technology  in whichAnother challenging future step which would establish the predictive value of texture analysis is the validation of parenchymal texture measures in prospectively collected data. Large-scale studies involving multiple screening centers, imaging machines, and image acquisition settings are also of major importance towards validating their predictive capacity and robustness to heterogeneous image data . FurtherThe valuable risk markers provided by parenchymal texture analysis could also leverage the relatively new, yet promising, paradigms of radiomics  and radiAutomated breast parenchymal texture analysis has the potential to elucidate imaging phenotypes of breast cancer risk, which is valuable in accelerating the translation of individualized risk stratification into routine breast cancer screening and prevention strategies. Future work addressing technical challenges in this field and large prospective studies are expected to further enhance and establish the predictive value of parenchymal texture measures for inclusion in breast cancer risk assessment models in clinical practice.


In 2017, breast cancer became the most commonly diagnosed cancer among women in the US. After lung cancer, breast cancer is the leading cause of cancer-related mortality in women. The breast consists of several components, including milk storage glands, milk ducts made of epithelial cells, adipose tissue, and stromal tissue. Mammographic density (MD) is based on the proportion of stromal, epithelial, and adipose tissue. Women with high MD have more stromal and epithelial cells and less fatty adipose tissue, and are more likely to develop breast cancer in their lifetime compared to women with low MD. Because of this correlation, high MD is an independent risk factor for breast cancer. Further, mammographic screening is less effective in detecting suspicious lesions in dense breast tissue, which can lead to late-stage diagnosis. Molecular differences between dense and non-dense breast tissues explain the underlying biological reasons for why women with dense breasts are at a higher risk for developing breast cancer. The goal of this review is to highlight the current molecular understanding of MD, its association with breast cancer risk, the demographics pertaining to MD, and the environmental factors that modulate MD. Finally, we will review the current legislation regarding the disclosure of MD on a traditional screening mammogram and the supplemental screening options available to women with dense breast tissue. Breast cancer is the leading cause of cancer-related mortality worldwide, with the most incidents occurring in the United States and in Western Europe . ScientiMammographic density refers to the percentage of dense tissue of an entire breast. The percent mammographic density (PMD) is based on the appearance of MD in accordance to the different X-ray attenuation characteristics of breast tissue composition . Fat is Mammographic density (MD) poses two major problems for women who have it. First, MD decreases the detection sensitivity of screening mammography; second, MD is an independent risk factor for breast cancer. Furthermore, women with highly dense breasts are shown to be at greater risk for developing breast cancer during their lifetime, compared to women with low dense breast tissue.Mammography still remains the most widely used method for the detection of breast cancer. Yet, recent studies have revealed the limitations of mammography, especially in women with high-density breast tissue. A standard screening mammogram cannot detect all cancers because the sensitivity of mammogram depends on the density of the breast tissue . On a scThe presence of dense breast tissue greatly and independently increases the risk for developing breast cancer . Wolfe wIn this review article, we will summarize a few of the environmental and genetic factors that can influence MD, and ultimately play a role in breast cancer initiation and progression. Additionally, we highlight the problems with detecting breast cancer on a traditional screening mammogram and provide an overview of the alternative screening options, including a novel antibody.Mammographic density is shown to be heritable in a couple of studies , 37. In In one study, parity status and number of births were significantly and inversely associated with percent collagen in the breast tissue/breast tissue density . SmallerIn a large study  includin2, have a 17% higher PMD compared to non-drinkers [Mammographic density (MD) can differ in women when comparing dietary differences. In one study , women wdrinkers . TogetheHormonal replacement therapies and treatment with tamoxifen such as combination of estrogen and progesterone as well as treatments with tamoxifen are known to increase MD . HoweverTaken together, these findings suggest that several factors, including race, genetics, parity, menopausal status, HRT, and diet can modulate MD, and can, therefore, have an effect on a woman’s risk for breast cancer. However, additional studies need to be done to support these findings.− HER2− breast cancers in women younger than 55 compared to women who were older than 55 years of age [− tumors in women younger than 55 years of age [Data from 6 studies showed a positive association between MD and the risk for invasive tumors across all ages, where the highest level of dense tissue showed a twofold increase in risk compared to the average level of dense tissue . In one s of age . Human es of age . This sus of age . In anots of age , there ws of age . An assos of age . Future The tumor microenvironment, which is integrated within the ECM, consists of several cell types, such as endothelial cells, smooth muscle cells, carcinoma-associated fibroblasts (CAFs), and immune cells. The ECM, sometimes referred to as stroma, is a complex and dynamic matrix that includes proteins such as laminin, fibronectin, collagen, proteoglycans (PGs), and proteases . These pCollagen type I is one of the major components of the stromal ECM network that influences tissue density [ density . Collage density . In the  density .Small leucine-rich proteoglycans (SLRPs) also make up a large portion of the ECM, and high levels of PGs increase tissue density and carcinogenesis [ogenesis . Lumicanogenesis . High exogenesis . Higher ogenesis . Decorinogenesis . The rolExpression of Ki-67, a cell proliferation marker, in high versus low density tissue remains controversial, with few studies suggesting no association, while one study suggested higher Ki-67 in stroma of high versus low density tissue , 60, 61.Since highly dense stromal tissue can trigger proliferation in the breast epithelium in women with high MD, there must be cross-talk between stromal cells (fibroblasts) and epithelial cells in a dense microenvironment . Indeed,Screening for breast cancer is predominantly done by mammography and clinical breast exams which has increased the chances of survival. While mammograms have resulted in early diagnosis for many women, 27% of breast cancers are missed in women with dense breasts due to lesion obscuration . Given tO-glycan branching on its N-terminus domain. However, in a tumor microenvironment, MUC1 loses its O-glycan branching and dissociates from its C-terminus domain, which is attached by hydrogen bonding. The low glycosylation on tMUC1 exposes its variable number tandem repeat (VNTR) region, which allows TAB 004 to bind and be detected [TAB 004 is an antibody developed to target tumor-associated MUC1 (tMUC1), an antigen that is present at high levels in the serum of cancer patients, including pancreatic and breast cancer . MUC1 isdetected . TAB 004detected . In a lohttps://www.areyoudense.org/) which has raised awareness about the decrease in mammography sensitivity because of the presence of high MD. The mammography quality standard act (MQSA) which is set forth by the US food and drug administration (FDA), ensures that a written mammography report is sent to each patient. However, currently there is no federal law mandating mammography reports to include information regarding the patient’s MD. Due to this shortcoming, law makers have been passing legislation state-by-state to ensure that these mammography reports include density status [It has been known for decades that MD masks breast cancer on a standard screening mammogram. Yet, only recently the general public and the medical community have started discussing this topic. This is in part due to the great efforts of Dr. Nancy Cappello. Dr. Nancy Cappello was diagnosed with stage III breast cancer after many years of negative mammograms, which failed to report the status of her MD. Because of Dr. Cappello’s great efforts, in 2009 Connecticut became the first state to mandate that mammogram reports must include information regarding the status of a woman’s MD. Dr. Cappello has since started an organization entitled “AreYouDense.org”,  late diagnosis of breast cancer due to poor sensitivity of mammographic screening and (b) higher risk for developing breast cancer. Although heritable, breast tissue density may be modulated to a certain extent by external factors and therapies, as summarized in Fig.


Falling increases the risk for fracture. The impact of adjuvant aromatase inhibitors (AI) on the risk of falls is undefined.A retrospective case control study was performed examining women with early stage breast cancer on adjuvant AI and matched controls without cancer. Fall and fracture data were abstracted from the medical record.vs. 63 years p = 0.0003).Matched pairs of 332 women were identified . There was no statistically significant difference in the odds of a fall between cases and controls, p = 0.86. Similarly, the odds of a fracture between cases and controls was not significantly different, p = 1.0. There were 35 pairs in which the case fractured but the control did not and equal number of pairs where the control fractured but the case did not. For pairs in which control fractured but case did not, the median age at fracture was significant higher than that for pairs in which case fractured but the control did not (71 This study did not identify a difference in the incidence of falls or fractures in women on adjuvant AI compared to their age matched controls without breast cancer. Prospective studies of falls and fracture in women on adjuvant AI therapy compared to age match controls would aid in the identification of fracture risk. Breast cancer and osteoporosis are both common diagnoses in women. Approximately 12% of women in the US will develop invasive breast cancer . FracturApproximately 75% of postmenopausal breast cancers express either estrogen or progesterone receptors and often called hormone receptor positive (HR+) . The depAI associated arthralgia, affects approximately 40% to 50% of patients and often develops within the first 6 months of AI initiation , 13. PaiThe primary objective of this study was to generate data on the reported prevalence of falls and fractures in postmenopausal women treated for early stage breast cancer with an AI compared to matched controls who are cancer free and not exposed to an AI. Although falls are a significant risk factor for fractures, there is insufficient data on the proportion of patients on AIs who fall, therefore this retrospective study was designed to explore falls in this population. In this case control study, we hypothesized that women treated for breast cancer with an AI have a higher risk of falling compared to women without breast cancer and without AI exposure. We also examined prevalence of osteopenia and osteoporosis in these two groups and use of calcium and bisphosphonates.The University of Michigan (UM) Health System Electronic Medical Records Search Engine (EMERSE) the UM Health System (UMHS) data warehouse, the UM Cancer Registry and Institutional Review Board (HUM00063088) approved this retrospective study . UMHS prThe cases were defined as postmenopausal women who have received an adjuvant AI  for HR+ breast cancer. Cases were identified using the EMERSE and the UM Cancer Center Registry. The search identified 332 postmenopausal women with early-stage breast cancer treated with an AI initiating therapy between the years 2004–2007, with five year follow up. Records past 2012 were excluded due to the change in electronic medical record formatting. These women represent the case cohort. Controls were defined as not having cancer and thus not exposed to an aromatase inhibitor in the same time frame. In addition, controls were required to have at least three separate UMHS medical encounters to ensure adequate follow up.Using the UM Health Systems data warehouse 674,072 controls were identified. Potential controls were race and age matched based where age of the case was defined as the time of breast cancer diagnosis +/−30 days . The first alphabetically listed control that met the criteria was selected for study inclusion. One control was selected for each of the 332 cases. The study population consists of 332 matched pairs comprising of cases  and matched controls with a total sample size of 664.Using EMERSE, data were abstracted from the medical record for both the controls and cases. Data abstracted was limited to the study specific time frame. Age at first fall, age at first fracture, femoral neck T score measured via dual energy X-ray absorptiometry (DXA), diagnosis of osteopenia or osteoporosis, use of calcium and use of bisphosphonate were abstracted from the time of initiating an AI to 3 months after stopping an AI and during the same period for controls. The subjects were followed for a period of 5 years. Data was compiled for each pair of cases and controls.The association between case and control status and the rate of falls and fractures was assessed with conditional logistic regression models accounting for the matched data. Age at time of first fall or first fracture between pairs where cases or controls fell or fractured but the other cohort did not was compared using a two-sample t-test. For pairs in which both the cases and control fell and fractured, the difference in age at first fall or fracture was calculated and analyzed using a sign test. The association between case or control status and calcium use was assessed using McNemar’s test. Within the AI users (cases), chi-square tests were used to investigate the association between bisphosphonate use, falls and fractures. Analysis was completed using SAS v9.3.The median age of the 664 postmenopausal women serving as cases and controls was 67 years (range 34–95). The majority (91.9%) of patients were white with 4.5% African American and 3.6% other or unknown race .vs. and 81 controls 24.4%). For the matched pairs, there were 190 pairs (57.2%) where neither the case nor control fell. In 61 pairs (18.4%) the case fell but the control did not. In 59 pairs (17.8%) the control fell but the case did not. There was no statistically significant difference in the proportion of women who experienced at least one fall in age-matched cases and controls, p = 0.86 . In the entire study population 164 (24.7%) patients experienced a fall within the five-year study period , compared with median age of 67 years (range of 35–95 years) for pairs in which control fell but case did not. Although numerically the women on AI therapy experienced their first on study fall at a younger age, this was not statistically significant, p = 0.17. For the 22 pairs in which both case and control fell there was no difference in the age at time of fall, p = 0.19. Specifically, in those pairs where both case and control experienced falls, the median age at time of fall was 71 years (range 49–91 years) for cases and 71 years (range 45–91 years) for controls.Approximately 84 women (12.7%) of the entire study population experienced a fracture within the 5-year study period (42 cases (12.7%) and 42 controls (12.7%). Accounting for matching, there were 255 pairs (76.8%) where neither the case nor control had a fracture. In 35 pairs (10.5%) the case experienced a fracture but the control did not, and there were an equal number of pairs (35) where the control experienced a fracture but the case did not  which was significantly younger than pairs in which control fractured but case did not . From the available data on the age of fracture, in pairs where both the case and control experienced a fracture, the median age of the case at fracture (n = 7) was 73 years and for controls (n = 6) was 67. However this difference is not significant (p = 0.22) is limited by low power.Data on the presence or absence of osteopenia/osteoporosis as ascertained via DXA was not available for 327 (49.2%) of the 664 women in this study. BMD was available in 259 cases (78.0%) and only 78 controls (23.5%). Due to the low number of BMD results available, especially for controls, no statistical comparisons could be made on T scores or the presence of osteopenia or osteoporosis between cases and controls or incidence of fracture with relation to BMD.Medical records were reviewed to determine use of calcium and bisphosphonates. Data on calcium supplementation in 5 pairs was not available, thus 322 pairs were analyzed for associations with calcium. Data on the use of bisphosphonate was not available for one pair, thus 331 pairs were analyzed for associations with bisphosphonates.In 99 pairs (30.7%) both cases and controls reported use of calcium supplements. In 48 pairs, both case and control reported that they did not use calcium. There were significantly more pairs where the case was taking calcium supplements than the controls (p < 0.0001). Specifically, there were 134 pairs (41.6%) where cases reported use of calcium supplements but the controls did not and in 41 pairs (12.7%) where the controls reported use of calcium supplements but case does not. Calcium supplementation was not significantly associated with the odds of a fall, p = 0.16 . In addition, when controlling for calcium use, neither case nor control status, was significantly associated with the odds of a fall . Calcium supplementation was borderline statistically significant in the increased odds of fracture, p = 0.05 . Controlling for calcium use, there was no statistically significant difference between cases and controls with the odds of fracture .There were 16 pairs (4.8%) where both cases and controls were taking bisphosphonates, and 191 pairs (57.7%) where neither case nor controls were taking a bisphosphonate. There were significantly more pairs where the case received bisphosphonates and the control did not, p < 0.0001. Specifically, there were 102 pairs (30.8%) where the case received a bisphosphonate but the control did not and only 22 pairs (6.6%) where the control received a bisphosphonate but the case not. Taking a bisphosphonate was not significantly associated with the odds of a fall . Controlling for the use of bisphosphonates, there was no difference in the odds of fall between cases and controls . Similarly taking a bisphosphonate was not significantly associated with odds of fracture, p = 0.11  and controlling for bisphosphonate use, there was not a significant difference between cases and controls in the odds of a fracture, p = 0.64 . In the subgroup of women who took an AI (n = 332 the cases), use of bisphosphonates was not significantly associated with fractures (p = 0.29), but there was a significant association between taking bisphosphonates and falls, p = 0.025. Specifically, taking a bisphosphonate was significantly associated with an almost two-fold increase in the odds of a fall .This retrospective case-control study of 332 matched pairs demonstrated that postmenopausal women with breast cancer on adjuvant AIs did not have an increased risk of fall or fracture as compared to similar women without cancer who were not on an AI. However, the median age of those AI patients fractured was significantly younger (difference in median ages of 8 years) than the controls that fractured. There was no difference in age among the women on an AI who fell compared to matched controls.This novel data suggest that although the frequency of falls and fractures did not differ significantly between cases and controls, the women on AI therapy were receiving a more intensive bone health regimen than the controls as noted by the greater number of women undergoing BMD testing and the use of calcium supplements and bisphosphonates. Approximately three times as many cases had undergone BMD testing than their matched controls. The heightened awareness for AI therapy linked with the risk of bone loss and fracture was likely the factor promoting this difference in BMD testing and treatment , 17.The retrospective design of this study does not permit full assessment of risk for fracture or falls, or evaluating the reason so few controls had BMD data, particularly given that the median age was 67 and BMD testing is recommended for women over the age of 65 . The repAlthough the retrospective study design is associated with limitations in capturing events, that limitation is equal across the cases and controls. The number of falls, data on fracture, the use of calcium supplements and bisphosphonates may be under reported in this study. Each year approximately one third of adults over the age of 65 fall although only less than half discuss the fall with their health care provider , 20. ForOur data are novel, as our comparator group did not have cancer or history of previous AI use. Compared to tamoxifen, AI are associated with a greater risk of loss of BMD and fracture . TamoxifA prospective observational pilot study of postmenopausal women under the age of 70 with a history of breast cancer on adjuvant chemotherapy and/or endocrine therapy reported that 58% study participants reported a fall within the last year and 53% experienced one or more falls during the six-month follow up period . The aveThe results of this retrospective case control study are consistent with expected falls and fracture data for postmenopausal women receiving adjuvant AI therapy, and generates provocative, novel findings by pairing the AI treated subjects to matched controls. The suggestion that adjuvant AIs may not have a profoundly negative effect on fracture compared to matched controls warrants prospective studies. Greater knowledge to define the risk of falls and fractures, measuring BMD, and appropriate optimization of calcium and other anti-resorptive agents can help protect the health, independence, and mortality of women with breast cancer undergoing active treatment as well as survivors.


Breast magnetic resonance imaging (MRI) has been reported to frequently result in false-positive diagnoses, limiting its positive predictive value (PPV). However, for PPV calculation, all nonmalignant tissue changes are equally considered false-positive, although the respective prognostic importance, and thus patient management implications, of different pathologies may well differ. We investigated the pathology of false-positive diagnoses made by MRI compared with radiographic  screening.n = 344) or MRI (n = 366) findings. We compared the frequency of false-positive biopsies (given by PPV3), as well as the types of nonmalignant tissue changes that caused the respective false-positive biopsies. In an order of increasing relative risk of subsequent breast cancer, pathologies of false-positive biopsies were categorized as nonproliferative, simple proliferative, complex proliferative, or atypical proliferative . The Mann-Whitney U test was used to compare distributions.We conducted an institutional review board-approved prospective analysis of 710 consecutive asymptomatic women at average risk for breast cancer who underwent vacuum biopsy with or without surgical biopsy for screen-detected DM/DBT (p < 0.0001). On the basis of MRI, high-risk atypical proliferative changes  were most common, followed by complex proliferative changes . In DM/DBT, low-risk, nonproliferative changes were the dominant reason for false-positive diagnoses , followed by simple proliferative changes . Low-risk nonproliferative changes resulted in false-positive diagnoses based on MRI as infrequently as did high-risk atypical proliferative changes based on DM/DBT (18.8% [38 of 202] vs. 18.0% [35 of 195]). The likelihood of a false-positive diagnosis including atypias was twice as high in women undergoing biopsy for MRI findings  as for those with DM/DBT findings .Histology yielded nonmalignant tissue in 202 of 366 biopsies done for positive MRI studies and 195 of 344 biopsies for positive DM/DBT studies, respectively, yielding a similar PPV3 percentages of 44.8% (164 of 202) and 43.3% (149 of 202) for both methods. However, the distribution of tissue types that caused false-positive diagnoses differed significantly . Current benchmarks that rate the utility of breast cancer screening programs  do not reflect these substantial biological differences and the different prognostic implications. Breast magnetic resonance imaging (MRI) is used not only for diagnostic purposes and screening women at high risk of breast cancer but also is increasingly considered as a supplemental screening tool for women at average risk who have dense breast tissue –4. In alYet, breast MRI has frequently been reported to result in a large number of false-positive diagnoses. Such false-positive diagnoses add to the overall cost of screening because they necessitate additional workup by imaging or biopsy, may cause physical harm because of additional morbidity associated with biopsy procedures, and may cause emotional harm because they may generate breast cancer anxiety in the patient –9. AccorFalse-positive diagnoses in breast imaging are caused by a quite heterogeneous group of tissue changes. In principle, all positive diagnoses that prompt biopsy but yield nonmalignant tissues, including lobular carcinoma in situ/lobular intraepithelial neoplasia (LIN), are equally considered “false-positives.” Current guidelines distinguish between nonproliferative tissue changes , proliferative tissue changes without atypias , and proliferative changes with atypias  –16. ThisThe objective of this study was therefore to investigate the biological or prognostic significance of tissue changes that cause false-positive imaging diagnoses in MRI vs. radiographic breast imaging. Our aim was to provide a more differentiated, nuanced analysis of the clinical implications of so-called false-positive diagnoses. Because the prevalence of atypical or precancerous tissue changes depend on a woman’s risk of breast cancer, we took care to include only women without breast cancer-associated risk factors. To avoid bias secondary to underestimation or undersampling, the final analysis also included the results of all possible secondary excisional surgical biopsies and procedures done in the cohort.This prospective, institutional review board-approved cross-sectional study was conducted between June 2010 and January 2014 in an academic breast center. All patients provided written informed consent after the risks and benefits of the procedure had been thoroughly explained. We included all consecutive asymptomatic women at average risk who underwent mammography/digital breast tomosynthesis (DBT)-guided or MRI-guided biopsy during the study period.Asymptomatic refers to the fact that we included only women whose biopsy was done for screening-detected imaging findings. Average risk refers to the fact we included only women without relevant breast cancer-associated risk factors such as a personal or family history of breast cancer, a prior tissue diagnosis with proliferative breast disease or atypias, or chest irradiation for Hodgkin’s disease.This implies that women who had undergone DM/DBT alone, as well as women who had undergone supplemental MRI, for screening were included. Whether women underwent DM/DBT alone or DM/DBT plus MRI for screening depended on their breast tissue density and their willingness to undergo supplemental breast MRI screening.MRI-guided biopsy is performed only in patients who have MRI-only visible findings. All women who had MRI had also had DM/DBT. Accordingly, all women who underwent MRI-guided biopsy had a negative DM/DBT at the site of the MRI finding. However, women who underwent DM/DBT-guided biopsy could have had (a) no MRI or (b) a negative MRI or (c) a positive MRI at the site of the DM/DBT abnormality requiring biopsy.All screening studies (DM/DBT and/or MRI) had been read and classified according to the Breast Imaging Reporting and Data System (BI-RADS) lexicon  by one oIn the first half of the study period (2010–2011), women underwent mammographic screening by bilateral two-view full-field DM . In the second half of the study period (2012–2013), women underwent two-view DBT in addition (Selenia Dimensions).All MRI studies were performed on a 1.5-T system  with a four-element breast coil  as described previously . For scrBefore DM/DBT- or MRI-guided biopsy was considered, women had undergone an appropriate diagnostic assessment including additional mammographic views and cone views. Only if, after this workup, the final diagnosis was BI-RADS 4 or 5, did the patient proceed to undergo mammographic (DM- or DBT–guided) vacuum biopsy or DM/DBT-guided needle localization . Women uDM/DBT or MRI-guided vacuum biopsy was performed in close adherence to national and international practice guidelines . Vacuum All biopsy specimens were processed according to a standard protocol based on recent European guidelines and were reviewed by a certified breast pathologist with more than 20 years of experience. If necessary for classification, further pathological assessment was performed at the discretion of the pathologist and included additional layering or immunohistochemical examination , CK14, CK17, E-cadherin, p63, Ki-67, smooth muscle actin).A careful interdisciplinary radiologic-pathologic correlation was performed for each target lesion. If discordance between the imaging finding and the pathologic result occurred, the patient was recalled for repeat diagnostic imaging to check whether the target had been biopsied successfully. If doubt persisted, rebiopsy, usually as surgical excisional biopsy, was done. All women with a diagnosis of cancer  and all women with a biopsy-based diagnosis of cellular atypias  underwent subsequent surgical excision. This was also performed for core biopsies that, according to the European Breast Cancer Screening Pathology Classification System, were categorized as B3  .In women undergoing surgery, the final surgical pathology report was used in addition to the core biopsy diagnosis for further analysis. For women who did not proceed to surgical resection, the needle biopsy tissue diagnosis was used. These latter women underwent follow-up to confirm lesion stability and thus rule out breast cancer for at least 18 months .All cases with nonmalignant breast pathology diagnoses—obtained by needle biopsy and/or by surgical excisional biopsy—were categorized according to the method of Dupont and Page  into oneTypical histological findings that were categorized as nonproliferative were apocrine and fibrocystic changes, inflammatory changes, fat necrosis, and fibroadenomas. Findings categorized as simple or complex proliferative were all types of adenosis, including sclerosing adenosis, UDH, papilloma without atypia, and complex sclerosing lesions. Findings categorized as proliferative with atypias were ADH, flat epithelial atypia, papilloma with atypia, and LIN.The following data were prospectively recorded: family and personal history, history of prior breast biopsy, demographic data, imaging features of target lesions at DM/DBT and MRI, and final histological result. PPV 3 (PPV of biopsy) of MRI and DM/DBT were calculated considering only malignant lesions (invasive cancer and DCIS) as test-positive findings.To avoid data clustering and risk confounders, all analyses were done on a per-patient basis; that is, we included only the dominant lesion in the analysis. The dominant lesion was identified on the basis of its therapeutic or prognostic implication as follows: nonproliferative < simple proliferative < complex proliferative < proliferation with atypias < DCIS or invasive cancer. This implies that a tissue diagnosis of proliferation with atypias identified in a patient who also had a diagnosis of DCIS or invasive cancer elsewhere in the same or the opposite breast was not included in the analysis of distribution of nonmalignant lesions. This also implies that in a patient with proliferation with atypias of any type, coexisting simple proliferative or complex proliferative tissue changes were not considered for further analysis.U test. For all distributions, 95% Clopper-Pearson CIs were calculated. A two-sided p value ≤ 0.05 was considered statistically significant. All analyses were performed using IBM SPSS Statistics version 22.0 software .We compared the distribution of the different categories  using the Mann-Whitney During the study period, a total 710 consecutive asymptomatic women at average risk received the final DM/DBT or MRI diagnosis of a suspicious finding (BI-RADS 4 or 5) and thus underwent image-guided biopsy. Of these, 344 women aged 56.4 ± 10.8 years underwent DM/DBT guided biopsy, and 366 women aged 54.1 ± 10.4 years underwent MRI-guided biopsy. Of the 344 women who underwent biopsy for DM/DBT findings, 39 (11.9%) had also undergone MRI. In 5 (1.5%) of these 344 patients, the MRI finding was positive at the site of the DM/DBT abnormality. Because the finding was visualized by DM/DBT, patients proceeded with DM/DBT-guided biopsy. Of the 366 women who underwent biopsy for MRI findings, all had undergone DM/DBT, but none had a DM/DBT correlate for the MRI finding, and therefore they proceeded to MRI-guided biopsy.Details on patient demographics and the distribution of breast densities are given in Table A similar rate of benign lesions  was observed for DM/DBT  and MRI ; accordingly, PPV3 was similar (Table p < 0.0001). In summary, the distributions of tissue categories was more or less reversed  were nonproliferative changes  and without (n = 2) atypias.The second most important reason for false-positive diagnosis based on MRI was complex proliferative tissue changes , whereas with DM/DBT, the second most important reason was simple proliferative changes . The five patients with positive MRI findings at the site of the mammographic abnormality all had proliferative tissue changes with  was similar, with 43.3% for DM/DBT and 44.8% for MRI. However, the biological or prognostic significance of tissue changes that caused the respective false-positive diagnoses was clearly dissimilar. Whereas nonproliferative, regressive changes were the single most important cause of false-positive diagnoses based on radiographic breast imaging  , the single most important cause of false-positive MRI diagnoses  was atypical proliferation. Nonproliferative tissue changes were as rarely seen to cause false-positive diagnoses based on MRI as were atypical proliferative tissue changes seen to cause false-positive diagnoses based on DM/DBT (18.8% [38 of 202] vs. 18.0% [35 of 195]).The benchmarks used for auditing breast cancer screening efficacy are the respective programs’ cancer detection rates and the PPVs . The PPVFor breast MRI screening, although the cancer detection rate is consistently higher than that achievable with mammographic or ultrasound screening, the high number of false-positive diagnoses  that have been reported limit the perceived net benefit of this screening method –39. HoweIt is well established that MRI-guided biopsies yield many high-risk tissue changes –47. HoweOn pathological or pathophysiological grounds, it is plausible that the majority of false-positive diagnoses made on the basis of DM and DBT are due to regressive tissue changes. Microcalcifications, especially those caused by benign histological changes, usually represent regressive changes and are not correlated with cell proliferation . In contThe association of atypical tissue changes with subsequent breast cancer has been consolidating over the past years. As evidenced by common patterns of genomic additions and deletions, breast cancer progression is a biological continuum, starting from normal breast tissue via flat epithelial atypia, ADH, to DCIS, and then to invasive breast cancer , 51. TisAccordingly, we propose a careful discussion on what constitutes a true-positive vs. a “false-positive” diagnosis in women at average risk who undergo screening for breast cancer. If it is agreeable that a true-positive diagnosis should be one that has an impact on a woman’s further management , then diagnosis of atypical tissue changes could indeed be considered a true-positive diagnosis. Most practice guidelines recommend intensified surveillance, preventive surgery, or even chemoprevention for women with a tissue diagnosis of ADH, ALH, or LIN –29. RegaA possible limitation of our study is the fact that the breast density distribution of the study population that underwent MRI was slightly shifted toward those with denser breast tissue, in accordance with the clinical use of MRI for supplemental screening of women with dense breast tissue. However, it has previously been shown that breast density and rate of proliferative breast disease are not correlated . The swiOne may argue that the MRI cohort was “enriched” for high-risk lesions because the lower-risk lesions were verified by DM/DBT. However, the null hypothesis of our study was that the distribution of low- and high-risk tissue changes is identical in women with DM/DBT-positive vs. MRI-positive screening findings. If the null hypothesis was to be accepted, then no enrichment would be possible, because high- and low-risk lesions would have been biopsied with similar frequency. Yet, our null hypothesis must be rejected; the distribution is indeed quite dissimilar. Accordingly, just because DM/DBT will indeed preferably pick up low-risk findings is an enrichment at all conceivable. Such enrichment would thus be a consequence of the very findings made in this study. Furthermore, the degree of enrichment is determined by the degree of overlap . However, this number was small, with 1.5% of DM/DBT-positive findings also yielding MRI-positive results, all representing intermediate- or high-risk lesions based on histology. Accordingly, the effect of enrichment in our cohort is likely negligible.Our study does not merely confirm previous results on the similar PPVs (PPV3) of radiographic (DM/DBT) and breast MRI. We demonstrate that the prognostic relevance of the false-positive diagnoses that drive the respective PPVs differs depending on the imaging method, with high-risk lesions being the predominant cause of false-positive MRI diagnoses, as compared with low-risk lesions being the predominant cause of false-positive radiographic diagnoses. This should be considered when discussing the rate of false-positive findings in MRI vs. radiographic breast cancer screening and should be explained when counseling women about their choices and the risks and benefits of supplemental screening.