Pinteraction = 0.003). Having first-degree relatives with breast cancer diagnosed before 50 years was associated with lower MD only among premenopausal women (Pinteraction = 0.061). We found effects of established breast cancer risk factors on MD showed similar directions in Chinese and Western women, supporting the hypothesis that MD represents cumulative exposure to breast cancer risk factors over the life course. Our findings help to understand the biological basis of the association of MD with breast cancer risk and have implications for breast cancer prevention research in China.Elevated mammographic density (MD) is an established breast cancer risk factor. Studies examining relationships between MD and breast cancer risk factors are limited in China, where established breast cancer risk factors are less prevalent but dense breasts are more prevalent than Western countries. This study included 11,478 women  participating in an ongoing national cancer screening program in 11 urban provinces in China and predicted as having high-risk for breast cancer. Polytomous logistic regression was performed to assess associations between MD and risk factors by comparing each higher Breast Imaging Reporting and Data System (BI-RADS) category  to the lowest category . We found associations of increasing age, body mass index, weight, postmenopausal status, and parity with lower MD. Higher levels of education, increasing height, and later first birth were associated with higher MD. These associations did not vary by menopausal status. Additionally, the association between longer period of breastfeeding and lower MD was seen among postmenopausal women only ( Demographic variables linked to dense breast tissue — a strong risk factor for cancer — are similar among women living in China and the West. Xiaohong Yang from the US National Cancer Institute in Bethesda, Maryland, USA, and colleagues looked for predictors of elevated breast density, as measured on a mammogram, among participants of an ongoing cancer screening program in 11 urban provinces in China. In their analysis of 11,478 women aged 45 to 69 deemed at high-risk for breast cancer, the researchers identified many variables — incliuding age, height, weight, menopausal status, educational level and history of pregnancies — that were all related to mammographic density in some way. Similar associations were previously found among women in Western countries, suggesting that many of these risk factors are consistent across populations. Several breast cancer risk factors including age, reproductive factors, body size, menopausal hormonal therapy, and dietary factors are associated with variations in MD.21 This research suggests these risk factors can influence changes in breast tissue, manifested as variations in MD. Well-known risk factors for breast cancer explain 20–30% of the variance in percent mammographic density (PMD) in Western populations,22 suggesting that additional factors influencing MD variation remain to be identified. Knowledge of the genetic basis of MD is limited, but twin studies suggest that MD is a highly heritable trait and the majority (60–70%) of the residual MD variance can be explained by genetic factors after accounting for known MD influencing factors.23 Several studies show ethnic variations in MD and indicate that ethnicity is one of the factors that influences MD and may influence some of the associations between MD and breast cancer risk factors.28Mammographic density (MD) reflects the proportion of radiologically dense epithelial and stromal breast tissues that are visible on a mammogram. The association between higher MD and breast cancer risk has been reported in diverse populations.Accordingly, the expansion of MD studies to populations with distinct genomic architecture and environmental and lifestyle exposures may improve our understanding of factors that influence MD and have important public health implications. Compared to Western populations, Asians are known to have higher PMD but lower prevalence of well-established breast cancer risk factors associated with Western lifestyle. Therefore, MD-influencing factors might not have exactly same effects in Asians as in Western populations. In addition, it is unknown how exposures with higher prevalence among Asian women such as tea drinking would influence MD.30 or more developed Asian countries, such as Singapore,34 Japan,36 and Korea.40 Except for one large population-based study,41 MD studies conducted in China have been small and examined only a limited number of risk factors.42 Because density decreases with menopause,44 it is important to evaluate risk factor associations separately for premenopausal and postmenopausal women. However, none of these studies evaluated factors that influence MD by menopausal status.42 Therefore, we comprehensively examined the associations of MD with reproductive and lifestyle factors considering menopausal status among Chinese women who participated in a large multi-city screening program in China and had high predicted risk of developing breast cancer.Prior studies evaluating MD influencing factors among Asian women were limited to immigrant Asians2 . Thirty percent of participants had first-degree relatives with breast cancer diagnosed before age 50. Most women were postmenopausal (64%), parous (94%), and reported that they had breastfed (83%), and had never smoked (87%) or drank alcohol (74%). The distributions of MD within Breast Imaging Reporting and Data System (BI-RADS) categories are shown for different age groups in Fig. PMantel–Haenszel Chi-Square < 1.0E-30). MD also varied by family history, education, BMI, weight, age at menarche, parity, age at first full-term birth, breastfeeding, menopausal status, age at menopause, smoking, alcohol, and tea drinking , postmenopausal status , higher BMI , having first-degree relatives with breast cancer diagnosed before age 50 , and being parous  were associated with lower MD. In contrast, higher education level was associated with higher MD. Later first full term-birth was associated with higher MD . Women who had breastfed for longer than a year were likely to have lower MD . When weight and height were analyzed separately to replace BMI in the model, height was positively associated with MD  and weight was inversely associated with MD . Tea drinking was associated with lower MD in the multivariable model without the adjustment of province , however, the association became non-significant  with the adjustment due to the significant heterogeneity by province.Table trend = 1.12, 95% CI = 1.05–1.20).The distributions of risk factors for dense and non-dense groups are shown in Supplementary Table Pheterogeneity < 0.05). Figure Pheterogeneity = 0.14 and 0.007 for premenopausal and postmenopausal women, respectively), whereas the associations with breastfeeding did not show significant variation across provinces in either premenopausal or postmenopausal women  and did not investigate the potential modification by menopausal status. Using a more comprehensive multivariable model, in addition to those expected associations, we observed that increasing height, higher education level, and later age at menopause were associated with higher MD, whereas having first-degree relatives with breast cancer diagnosed before age 50 was associated with lower MD. Further, we found that longer duration of breastfeeding was associated with lower MD but only among postmenopausal women. Taken together, these findings support the hypothesis that some established breast cancer risk factors may be mediated through MD, an intermediate phenotype for breast cancer risk, among Chinese women.The goal of this study was to examine associations of MD with known breast cancer risk factors using data collected from a population-based multi-center screening program in China. Our study is one of the largest MD evaluations conducted among Asian women, which permitted stratification by menopausal status. Our results are consistent with the only other large study conducted among 28,388 Chinese, showing that MD was related to age, menopause, parity, and age at first full-term birth.46 However, it remains unclear whether the effect size for these MD-influencing factors differs by race/ethnicity. A longitudinal analysis showed that the age-related decline of PMD was slower among Japanese women compared to Caucasians,47 suggesting possible racial/ethnic heterogeneity in MD variations in relation to age. Similarly, although some researchers observed a strong inverse correlation between BMI (or weight) and PMD across diverse populations,50 the associations between absolute areas (dense or non-dense) and BMI varied significantly by ethnicity,51 which may be due to the substantial difference in body size and breast composition by ethnicity.29 Standardized quantitative MD measurements in diverse populations are needed to address this question.Similar associations of MD with age, weight, BMI, and parity observed in Asian and Western countries suggest that these factors have a similar impact on MD in different populations.46 Specifically, in Pike’s model, the decline of PMD with age parallels that of the rate of ‘breast tissue aging’, which refers to the cumulative exposure of breast tissue to hormones, growth factors, and other carcinogens and was suggested as a more relevant measure in relation to MD compared with chronological age.46 In this model, both the rates of breast tissue aging and PMD are greatest at younger ages and decline with increasing  age, and both show decreases during pregnancy and menopause. The inverse association between BMI and MD likely reflects the correlation between body fat and fatty tissue within breasts. Previous studies have shown that the effects of weight and MD on breast cancer risk both became stronger after the adjustment for each other, suggesting that BMI and MD are negative confounders of each other in their associations with the risk of breast cancer and likely to operate via independent pathways.50The inverse associations of age and BMI with MD have been consistently found and was also confirmed in our study. The seemingly paradoxical age association was explained previously by the concept of ‘breast tissue aging (exposure)’ proposed by Pike.52 and endogenous factor such as IGF-1 have been linked to underlying height, MD and breast cancer risk.54 However, prior evaluations of MD and height have led conflicting results; positive55 and null associations50 have been reported in both Asian and Western populations. More studies are needed to confirm the height–MD association.A recent meta-analysis estimated that breast cancer risk increased by 17% with every 10 cm increase in height56 and odds increased with the number of affected relatives.58 A recent genome-wide association study evaluating common genetic variants also identified shared genetic loci associated with both breast cancer risk and MD.59 Therefore, the unexpected association of lower density with positive family history of breast cancer observed in our study requires cautious interpretation. It is noteworthy that a recent Spanish study showed MD was significantly lower among BRCA2 mutation carriers compared to non-carriers in women from high-risk families.60 Therefore, it is possible that high-risk rare mutations and low-risk common variants may have different effect on MD. This notion is consistent with our observation of the significant association only among premenopausal women and women with first-degree earlier-onset family history, i.e., women more likely to carry high-risk alleles. In addition, our study participants were selected to be enriched for positive family history of breast and/or ovarian cancers, and therefore, the MD-family history association found in our study may not generalize to the general population.The genetic basis of MD remains largely unknown. Previous studies showed that women with higher MD were more likely to have first-degree relatives with breast cancer62 we found that higher levels of education were independently associated with higher MD, suggesting that the MD association with education could not be fully accounted for by measured variables such as BMI and reproductive factors. Other unmeasured lifestyle factors including dietary factors, physical activity, and socioeconomic status-related stress may also contribute and further investigation of these relationships is warranted in future studies.Consistent with several studies,63 In our study, we also found that earlier age at menarche and later age at menopause were associated with higher MD, which supports the hypothesis that the cumulative exposure to endogenous hormones has a similar impact on MD and breast cancer risk.46 Likewise, the associations of nulliparity and older age at first full-term birth with higher MD also suggest that hormone-related risk factors may potentially affect breast cancer risk through MD.We found that menopausal status was independently associated with MD after accounting for age and other confounders. This finding is consistent with previous evidence showing that age-related declines in MD are non-linear and that the rate of change may be faster among younger than older women.65 which may be due to limited sample sizes in these studies, as well as a lack of information on breastfeeding duration. We observed that longer breastfeeding was associated with lower MD among postmenopausal women. The reason for difference by menopausal status is not clear, but it may partly involve the long-term reduction in prolactin levels among parous women,66 as circulating prolactin levels have been positively associated with MD among postmenopausal women in other studies.68 On the other hand, the lack of significant association among premenopausal women may be due to the relatively lower proportion of women with longer breastfeeding duration . Additionally, we cannot exclude the possibility that the association with breastfeeding is mediated through parity since older Chinese women would have been more likely to have more children than younger women because of the one-child policy in China that started in the late 1970’s. This is an area for future exploration.The literature regarding breastfeeding and MD is inconsistent,70 smoking,69 and tea,71 however, these factors were not associated with MD in our study. We found that tea drinkers were less likely to have dense breast, which is a potentially interesting finding since tea drinking has been shown to be protective for breast cancer by previous studies and the prevalence of tea drinking is high in China. However, the association was only seen in a few provinces (Chongqing and Gansu) and there was significant heterogeneity across provinces resulting in an overall lack of association after adjusting for province. In addition, detailed tea drinking behaviors  were not collected in this study. Future studies with detailed exposure measures are warranted to clarify the relationship between tea consumption and MD in Asian populations.Previous studies reported associations of MD with lifestyle factors such as alcohol consumption,73 Despite the centralized and on-site training to enforce the uniform MD measurement, measurement variability across different radiologists and screening sites is likely to exist. This subjectivity and variability may cause potential misclassification of MD levels and confound MD-risk factor associations. In addition, the MD associations observed in our study may also be confounded by other unmeasured or unknown factors such as lifestyle, social, and environmental factors and these factors are likely to vary across provinces , which may partly explain the observed heterogeneity by province. Nevertheless, the associations between most factors examined and MD were consistent across different regions, suggesting that the observed associations were internally valid. Our study was also limited by the categorical BI-RADS measurement and the two-dimensional view. A quantitative measurement that assesses different phenotypes of MD  accompanied by three-dimensional views or a volumetric approach may be more useful in establishing relationships between breast cancer risk factors and MD. Additionally, mammography was only performed on urban Chinese women who were predicted at being high-risk for breast cancer, and thus they are not representative of the general population. This design may account for the slightly higher proportion of dense breasts  compared with the previous report (49.2%) of Chinese women within the same age groups.41Major strengths of our study include the large number of study participants in an understudied Asian population, a comprehensive collection and analysis of multiple exposures of interest, centralized data collection, management, quality control, and quality assurance. All participating sites are first class tertiary hospitals in each province and all radiologists participating in the screening program have radiology certificate from the Department of Health and are required to have at least 5 years of clinical experiences in breast imaging. In addition, all participating radiologists received an intensive training before the screening program started followed with on-site training sessions during the screening program to enforce uniform standards for mammographic procedures and diagnosis and density reporting. Additionally, multi-regional participation has provided a distinct opportunity to assess regional heterogeneity in MD influencing factors. Several limitations of our study should be noted. First, MD was assessed using BI-RADS, which is subjective and known to vary across radiologists.In summary, we found that later age at first full-term birth, later age at menopause, height, and higher education level were positively associated with MD, and age, BMI, family history of breast cancer, parity, and longer durations of breastfeeding were negatively related to MD among Chinese women at elevated breast cancer risk. Except for age, BMI, and family history of breast cancer, other established breast cancer risk factors showed the same direction of effect on MD, suggesting that the effect of these risk factors may be mediated through their influence on MD, an intermediate phenotype for breast cancer. Most associations were similar for premenopausal and postmenopausal women, except for breastfeeding duration, which showed stronger association among postmenopausal women. Further studies using standardized MD measures in diverse populations are warranted and may provide useful information to identify high-risk women particularly in low-resource countries where mammographic screening is not readily available to the general population.Study subjects were a subset of participants aged 40–69 in an ongoing cancer screening program in urban China led by the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences (CHCAMS). The goal of this program is to screen for the five most common cancers in China, including lung, breast, colorectal, upper digestive tract, and liver cancers. The program was initiated in 2012 and covered 12 provinces Fig.  in China74 based on prevalence of risk factors and relative risks in the Chinese population  modified from the Harvard Risk Prediction Modelion Fig. . A subsen = 443) since most women (96%) were classified as having heterogeneously dense breasts (BI-RADS density score = 3) and we suspected potential MD misclassification. Our final analytic sample included a total of 11,478 women. The distribution of number of participant, age, and menopausal status by province was shown in Supplementary Table This study included women who participated in the screening program in 2013–2014 and had mammogram data available Fig. . Our eli75 MD was categorized into four levels using the BI-RADS density scoring system: almost entirely fat (1), scattered fibroglandular densities (2), heterogeneously dense (3), and extremely dense (4). Maximal values for BI-RADS diagnostic and density categories were used across the two breasts.Full-field digital mammograms were obtained in each participating hospital. A total of four films capturing craniocaudal and mediolateral oblique views of both breasts were obtained for each woman. Imaging results were read by trained radiologists in each designated hospital and categorized using the BI-RADS guidelines (BI-RADS diagnostic category (0–6) and BI-RADS density scoring system (1–4)) recommended by the American College of Radiology (4th edition).2.Data on breast cancer risk factors were extracted from the baseline questionnaire, including age, family history of breast and/or ovarian cancers, education level, lifestyle factors , and reproductive history . Height (cm) and weight (kg) were measured and BMI was calculated from weight and height as kg/mχ2 test. To assess associations between MD and risk factors, we used polytomous logistic regression to compare each higher MD category  to BI-RADS = 1 . Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using the PROC LOGISTIC procedure with the GLOGIT option. ORtrend  across BI-RADS categories were also obtained using cumulative logistic regression with treating BI-RADS categories as an ordinal variable.Differences in the distribution of each risk factor by BI-RADS density categories were assessed using one-way analysis of variance (ANOVA) or P < 0.05 in the base model. The final multivariable model included province, age (per 2 years), family history of breast and/or ovarian cancers , menopausal status , education , BMI (per 2 kg/m2), age at menarche , and parity (parous or nulliparous). Among parous women, age at first full-term birth , and breastfeeding duration  were also included in the model. We also ran models in which we replaced BMI with height (per 2 cm) or weight (per 2 kg) to examine height and weight separately. Variables such as smoking , alcohol consumption , and regular tea drinking (yes or no) were not associated with MD in base model and therefore, were excluded from the final multivariable model. In the sensitivity analysis, the additional adjustment for these factors did not change the magnitude of the associations with other variables (data not shown).The base model included age, BMI, and province as covariates. For the multivariable analysis, we included all variables that had 43 we therefore stratified our analysis by menopausal status. In stratified analyses, BI-RADS categories were collapsed into dense  and non-dense  groups because of small number in some extreme categories. Models for postmenopausal women were additionally adjusted for age at menopause . The potential effect modification by menopausal status was tested by including an interaction term between each explanatory variable and menopausal status in the analysis. Since family history was associated with MD only among premenopausal women, it was only included in the analysis for premenopausal women.Because density is known to decrease with menopause,I2 statistics.To assess the potential heterogeneity across different provinces, we also stratified analyses by province and provided summary statistics using meta-analysis based on a random-effects model. Tests for heterogeneity across provinces were assessed by All statistical tests were two-sided. Meta-analysis was conducted using Stata/SE  and all other analyses were conducted using SAS .The data sets and code used and analyzed for the current study will be available from the corresponding author upon reasonable request without undue qualifications.Supplementary Material LegendSupplementary Table 1Supplementary Table 2Supplementary Table 3


BRCA testing and other multipanel genetic testing compared to White women, despite having a higher incidence of early‐age onset breast cancer and triple‐negative breast cancer (TNBC). Our study identifies predictors of BRCA testing among Black women treated for breast cancer and examines differences between BRCA testers and nontesters. We conducted an analysis of 945 Black women ages 18–64 diagnosed with localized or regional‐stage invasive breast cancer in Pennsylvania and Florida between 2007 and 2009. Logistic regression was used to identify predictors of BRCA 1/2 testing. Few (27%) (n = 252) of the participants reported having BRCA testing. In the multivariate analysis, we found that perceived benefits of BRCA testing (predisposing factor) , income (enabling factor) , and BRCA mutation risk category (need factor)  predicted BRCA testing. These results suggest that interventions to reduce disparities in BRCA testing should focus on identifying patients with high risk of mutation, increasing patient understanding of the benefits of BRCA testing, and removing financial and other administrative barriers to genetic testing.Evidence shows that Black women diagnosed with breast cancer are substantially less likely to undergo  BRCA1 and BRCA2 genetic testing persist despite clinical availability of testing for mutations over the past 20 years BRCA1/2 genetic testing compared to White women with the disease BRCA1 gene mutation BRCA and other high penetrance gene mutations among Black women with breast cancer Racial disparities in BRCA1 and BRCA2 tumor suppressor genes are associated with an increased risk of breast and ovarian cancers BRCA1 mutation carriers have a 55–65% risk and BRCA2 carriers have a 45% risk of developing breast cancer by age 70 BRCA1 mutation carriers have a 39% risk and BRCA2 carriers have a 11–17% risk of developing ovarian cancer by age 70 BRCA1 or BRCA2 mutation can reduce her cancer risk through risk‐reducing surgeries Germline mutations in BRCA1/2 testing in women diagnosed with breast cancer at age 45 and younger and those diagnosed with triple‐negative breast cancer at age 60 and younger BRCA testing between Black and White patients that were driven by patient and healthcare‐provider‐related factors BRCA testing was not eliminated after adjustment for mutation risk, sociodemographic and clinical factors, and attitudes about BRCA testing. The authors also found that Black women were less likely to report a recommendation from their physician to have BRCA testing even after adjustment for mutation risk. In this current analysis, we focus on patient‐level factors to identify predictors of BRCA testing among Black women with breast cancer. We also examine differences between Black women who had BRCA testing and those who did not. Our study is guided by the Andersen Behavioral Model of Health Care Utilization, shown in Figure predisposing, enabling, and need factors The National Comprehensive Cancer Network (NCCN) guidelines recommend We conducted an analysis of 945 Black women ages 18–64 diagnosed with localized or regional‐stage invasive breast cancer in Pennsylvania (PA) and Florida (FL) between January 1, 2007 and December 31, 2009 who were enrolled in a population‐based study. Eligibility criteria, methods of patient recruitment, and study design of this study have been previously described N = 5), or they were diagnosed with stage 3 or 4 breast cancer or unknown stage at diagnosis (N = 77). These exclusions resulted in the final study population of 945. This study was approved by the institutional review boards at the University of Pennsylvania, the Pennsylvania (PA) State Cancer Registry, Florida (FL) State Cancer Registry, and Massachusetts General Hospital (MGH).The overall response rate was 61% (58% for Black women and 62% among White women) BRCA testing, and use of genetic testing. BRCA1/2 testing was assessed with a single item that provided the following explanation, “BRCA testing: this is a blood test (not a test on the tumor) that looks for genetic mutations in the BRCA1 and BRCA2 gene. Results can tell if a woman is at increased risk for developing ovarian cancer and a second breast cancer. Results can also help determine if relatives are at risk for these cancers.” Participants were asked if they completed BRCA testing. Education, employment, income, health insurance type, and comorbidities were assessed using previously established survey items. Age, stage at diagnosis, and receptor status were determined from FL and PA cancer registry data files.Participants completed a written survey including, but not limited to, items on patient demographics, personal and family cancer history, attitudes about BRCA1/2 mutation was categorized into mutually exclusive categories based on high, moderate, and low risk as shown in Table Risk of carrying a BRCA testing were measured using a multidimensional scale that included four items about the potential benefits of testing, one item about the cost of testing as a barrier, and three items about the potential adverse effects. Participants rated their level of agreement with each item on a five‐point Likert scale. First, benefits of testing were assessed with the following four items: (1) BRCA 1/2 testing would help my family members manage their cancer risk; (2) My BRCA 1/2 test results would help me manage my cancer risk; (3) My BRCA 1/2 test results would help my doctor manage my cancer risk; and (4) Testing negative for a BRCA mutation would be reassuring about my cancer risk. Second, participants were asked the following item related to cost of testing, BRCA 1/2 testing is too expensive for me to afford. Third, adverse effects of testing were assessed with the following three items: (1) BRCA 1/2 testing would lead to problems in my family; (2) Testing positive for a BRCA mutation would lead to problems with my job; and (3) Testing positive for BRCA mutation would lead to problems with my health or life insurance. The scale was developed through extensive qualitative research with women considering genetic testing that included identification of themes and item generation. The scale was validated through an expert panel of genetic counselors and cancer genetics specialists as well as prior studies BRCA testing on test utilization among Black women, we examined the subscale scores for benefits (Cronbach's Alpha = 0.91), costs (single item), and concerns (0.76) in a sensitivity analysis.Attitudes about We assessed healthcare system distrust using a nine‐item scale that includes two primary domains, one that assessed values congruence  and the other assessed technical competence of the healthcare system (Cronbach's Alpha = 0.85) Participants were also asked about family support using four items from a shorter version of the Perceived Social Support from Family Measure (Cronbach's Alpha = 0.73) Trust in provider was measured using seven items from the Trust in Physician scale and measures different aspects of a trusting physician relationship from a patient's perspective (Cronbach's Alpha = 0.81) BRCA testing and those who did not use two‐sample t‐tests for continuous variables and chi‐squared tests for categorical variables. We used descriptive statistics to characterize the study sample. Patient characteristics included age at diagnosis, stage at diagnosis (I or II) BRCA testers with nontesters based on BRCA attitude scale (continuous), healthcare system distrust scale (continuous), family support scale (continuous), trust in healthcare provider scale (continuous), and risk group . In a multivariate analysis, we assessed the association between predisposing ; enabling (insurance type and income); and need factors (BRCA mutation risk categories) and BRCA 1/2 testing using logistic regression. Model fit was assessed using the Hosmer–Lemeshow Goodness‐of‐Fit Test. We also performed sensitivity analyses excluding women in the low mutation risk group and assessing associations of BRCA attitude subscales with BRCA testing. A two‐sided P < 0.05 was used as the statistical significance level. Statistical analyses were performed using STATA/IC version 14, .Comparisons were made between women who reported having n = 252) of the women reported having BRCA testing and 73% (n = 693) did not have BRCA testing. Among women who had BRCA testing, 49.2% (n = 124) had a high BRCA mutation risk; 34.9% (n = 88) had a moderate risk; and 15.9% (n = 40) had a low mutation risk. Of those who reported not having BRCA testing, 22.2% (139) had a high BRCA mutation risk; 39.5% (n = 247) had a moderate risk; and 38.2% (n = 239) had a low mutation risk. Sample characteristics of BRCA testers and nontesters are presented in Table predisposing, enabling, and need factors based on the theoretical framework. In an unadjusted analysis, predisposing characteristics revealed that Black women who reported having BRCA testing were younger ; more likely to have completed graduate education ; had more positive attitudes about BRCA testing ; were less likely to have two or more comorbidities ; and had higher levels of trust in their healthcare providers . Additionally, women who received testing were more likely to agree with statements of the benefits of BRCA testing (P < 0.001). There were no significant differences in agreement with BRCA testing being too expensive, or concerns about BRCA testing between women who did and did not receive testing. Among women who completed testing, enabling factors were being employed for wages , having employer‐based health insurance (47.6 vs. 35.8 P < 0.001); and having an annual income level of >$70,000 . After aggregating risk factors based on need for genetic testing, women with a high mutation risk  were more likely to report having BRCA testing compared to those with lower mutation risk.A total of 945 Black women ages 18–64 diagnosed with localized or regional‐stage invasive breast cancer were included in this study. Overall, 27% . In addition, women with an income of $70,000 and higher were twice as likely to have testing compared to women with a lower income . BRCA mutation risk category was associated with testing and women with a high mutation risk were nearly four times likely to have testing compared to low‐risk women . Education level, comorbidities, insurance type, and trust in provider were not significantly associated with BRCA testing after multivariate adjustment. Healthcare system distrust was not significantly associated with BRCA testing in the univariate or multivariate analyses. The Hosmer–Lemeshow goodness‐of‐fit test indicated that our model fit the data well (P = 0.487). We performed sensitivity analysis excluding the low mutation risk group, and the associations of predictors with BRCA testing were similar (data not shown). Additionally, we performed sensitivity analysis using the BRCA attitudes subscales of benefits, costs, and concerns . Greater agreement that BRCA testing was too expensive was associated with significantly lower odds of testing . Cost of BRCA testing was a significant predictor of testing when entered as a continuous variable in the multivariate adjusted model, despite the fact that it did not reach statistical significance in the unadjusted analysis in Table BRCA testing would lead to problems with family, job, or insurance were not significantly associated with testing use. Including the BRCA attitudes subscales rather than the full scale did not meaningfully change the associations of other variables with BRCA testing (data not shown).In a multivariate logistic regression model of the factors that predicted ng Table , only atBRCA1/2 genetic testing among Black women with breast cancer. Our study found that few (27%) Black women with breast cancer reported having BRCA testing. For participants who reported not having BRCA testing, 22% had a high mutation risk but did not receive genetic testing suggesting an unmet need. These findings indicate a critical need for healthcare providers to assess mutation probability of women with breast cancer and order genetic counseling and testing when appropriate. There is an urgent need for a greater number of Black women to receive genetic testing as they suffer disproportionately from breast cancer and experience higher rates of variants of unknown significance (VUS) compared to Caucasian populations This study is, to the best of our knowledge, the largest population‐based study that comprehensively examined predictors of BRCA testing (predisposing factor), income (enabling factor), and BRCA mutation risk category (need factor) remained significant predictors of BRCA testing. When we examined subscales of attitudes toward BRCA testing, we found that perceived benefits of BRCA testing was positively associated with testing, while women who agreed that BRCA testing was too expensive had lower odds of testing. Concerns about problems raised by testing for family members, employment, and insurance were not associated with BRCA testing. In contrast, prior studies found that Black women expressed greater concern about the risks associated with genetic testing and genetic discrimination compared to women of other races BRCA testing and its benefits could be increasing, diminishing concerns about risks of testing. Based on our results, educating Black women about the benefits of BRCA testing is important and can lead to more positive attitudes and greater uptake of BRCA testing among this population. In one recent study among 1536 breast cancer patients, Jagsi et al. FORCE), BrightPink Organization, Bring Your Brave Campaign and Know: BRCA Tool, which were created by the Centers for Disease Control and Prevention (CDC), can be used to increase awareness of BRCA and other gene tests among this population. Our study did not assess participation in genetic counseling, which has been shown to have positive psychosocial outcomes on patients Interestingly, after categorizing our variables using the Andersen Behavioral Model of Health Care Utilization theoretical framework and conducting a multivariate adjustment, we found that perceived attitudes about BRCA testing for this population and concerns about cost were associated with lower odds of testing. Similarly, in a recent analysis of a national sample of 3628 individuals whose clinicians ordered a comprehensive BRCA testing, most were White, college educated, with higher incomes BRCA testing among 440 Black breast cancer patients and found that healthcare provider referral, private health insurance, and household income greater than $35,000 were associated with genetic counseling and testing BRCA testing. While the cost of genetic testing has substantially decreased, racial and socioeconomic disparities in the use of testing still exist Consistent with previous studies BRCA mutation risk category, created using age at diagnosis, family history, and Ashkenazi Jewish heritage based on the NCCN 2007 clinical practice guidelines, strongly predicted BRCA testing in this study. As expected, Black women with a higher mutation risk based on age at diagnosis and family history were more likely to report having testing. The 2007 NCCN guidelines recommend genetic testing for women diagnosed at age 40 and younger; in our sample, approximately 30% of the Black women diagnosed with breast cancer were categorized as having a high BRCA mutation risk. The NCCN guidelines has been recently updated and testing is now recommended for women with a personal history of breast cancer diagnosed at age 45 and younger and individual's diagnosed with TNBC at age 60 and younger BRCA testing in our study. One possible explanation is that while women may distrust the healthcare system, in general, they may have higher levels of trust in their particular provider, which results in women following through with testing that the provider recommends. While this current analysis focused on identifying patient‐level factors that are predictors of BRCA testing and did not include healthcare provider recommendation as a variable, the parent study, conducted by McCarthy et al. BRCA testing between Black and White breast cancer patients and found that having a provider recommendation for BRCA testing was a strong predictor of testing.Historically, healthcare system distrust among African Americans has contributed to lower utilization of healthcare services and lower participation in research studies BRCA1/2 and other high penetrance genes, has now become the standard of care for breast cancer patients with a personal and family history indicative of mutation risk Testing for mutations in cancer predisposing genes, such as N = 1235) included 24% Hispanic and 22% Black women. The authors found that BreastCARE increased discussions of family cancer history, personal breast cancer risk, and genetic counseling/testing. Apple et al. Evidence‐based interventions are needed to engage high‐risk Black women in having genetic testing. This study has identified relevant factors that could be the target of a theoretically based intervention. Randomized controlled trails of studies to engage Black women in cancer risk assessment and to improve uptake of genetic testing for hereditary cancer syndromes are lacking. Few promising interventions exist that have included samples of Black women with a HBOC risk or exclusively among Black women BRCA attitudes and genetic testing. We were also unable to obtain information from each participant's medical records on TNBC tumor subtype and did not include this as a variable, which we recognize as a limitation given the high incidence of TNBC among Black women. In addition, the results of BRCA testing were not ascertained at the time of the study. We focused on self‐reported use of BRCA testing and although the research team found that patient report of BRCA 1/2 testing had high positive and negative predictive values  with several medical records at the Penn Medical System, we were unable to confirm testing for all participants. Although the cancer registries in FL and PA were comprised of diverse samples, we cannot be sure that our results are generalizable to other states with similar demographic patterns. Additionally, we included only Stage I and II breast cancers, and therefore our results may not be generalizable to women diagnosed with late‐stage disease.The strengths of our publication are its large population‐based design and its focus on hereditary cancer risk among Black women diagnosed with breast cancer, an understudied population. Our study expands the literature as it addresses a critical barrier to progress in the field, the underutilization of genetic testing among Black women with breast cancer. Our findings present relevant factors that can be the target of a program to improve utilization of genetic testing for breast cancer risk among this population. Until the racial disparity of genetic testing is addressed, the benefits of genetic testing will not be realized for all Americans. Our study has some limitations. As breast cancer patients were surveyed several years after their cancer diagnosis and them undergoing genetic testing, we cannot establish causality between factors such as BRCA testing among Black women diagnosed with breast cancer, such as perceived benefits of BRCA testing, income level, and BRCA mutation risk. Interventions to reduce disparities in BRCA testing should focus on identifying patients with high risk of mutation, increasing patient understanding of the benefits of BRCA testing, and removing financial and other administrative barriers to genetic testing. Women diagnosed with breast cancer, specifically those with early‐age onset breast cancer and TNBC are at‐risk for harboring a cancer predisposition gene. Therefore, it is critical that healthcare providers recognize these red flags, assess mutation probability among Black women with breast cancer, and order genetic counseling and testing when appropriate.In conclusion, Black women suffer disproportionately from breast cancer and should have genetic testing when appropriate. Our study shows that multiple factors influence uptake of None declared.


Editorial on the Research TopicHow Reproductive History Influences Our Breast Cancer RiskReproductive history has profound effects on women’s breast cancer (BCa) risk. With fertility rates falling, the age of childbearing increasing, and the age of menarche decreasing each decade, it is critically important that we define the biological pathways linking reproductive history to BCa risk. In this special series on reproductive history and breast cancer risk, we hear from six groups who have expertise in this area and share their thoughts on the most pressing questions in the field.Dall and Britt have an interest in the effects of hormones and reproductive events  on breast cancer risk. They describe the increased risk of breast cancer in nulliparous nuns and discuss the current studies attempting to define the role of the mammary stem cells, ER+ cells, and growth factors in parity-induced protection  on the mammary epithelial cells, immune cells, and extracellular matrix. The ability of transformed cells to evade the immune response is a hallmark of cancer  in parity-induced protection against breast cancer. They dissected mammary glands from parous mice and age-matched virgins and a found Igf1r to be hypermethylated and silenced in parous mammary glands  is increased in tumor-bearing breast tissue and systemic antiestrogen therapies are widely used to target this in ER+ BCa patients. These hormonally driven BCa are more prevalent in postmenopausal women where an increased BMI has been associated with increased local breast estrogen (Au and colleagues have tried to find a factor that inhibits aromatase expression in the adipose as a novel targeted antiestrogen therapy. They found that the gut-derived hormone ghrelin (produced in the stomach to regulate appetite and growth hormone release) inhibits aromatase expression in adipose cells  but are being used for women at all ages. Of the gene expression tests available  were developed in postmenopausal women and now not performing well in premenopausal women who make up 25% of all patients (In order to define how aggressive a tumor is and possibly identify if it would be responsive to endocrine therapy, clinics are adopting gene-expression profiling on the tumors to provide an intrinsic, molecular portrait of the tumor and identify the likelihood of recurrence. patients –58. It ipatients , 60. Thepatients , 62 is pRA: this author assisted in the design and was involved in reviewing articles. Assisted with drafting the editorial and approved final version. WI: this author wrote two review articles and was involved in reviewing articles. She assisted with drafting the editorial and approved final version. KB: this author was the lead editor and conceived the special issue. Invited all contributors, wrote a review article, and assisted with reviewing articles. Wrote the editorial.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


A woman has an increased risk of breast cancer if her lifelong estrogen exposure is increased due to an early menarche, a late menopause, and/or an absence of childbearing. For decades, it was presumed that the number of years of exposure drove the increased risk, however, recent epidemiological data have shown that early life exposure (young menarche) has a more significant effect on cancer risk than late menopause. Thus, rather than the overall exposure it seems that the timing of hormone exposure plays a major role in defining breast cancer risk. In support of this, it is also known that aberrant hormonal exposure prior to puberty can also increase breast cancer risk, yet the elevated estrogen levels during pregnancy decrease breast cancer risk. This suggests that the effects of estrogen on the mammary gland/breast are age-dependent. In this review article, we will discuss the existing epidemiological data linking hormone exposure and estrogen receptor-positive breast cancer risk including menarche, menopause, parity, and aberrant environmental hormone exposure. We will discuss the predominantly rodent generated experimental data that confirm the association with hormone exposure and breast cancer risk, confirming its use as a model system. We will review the work that has been done attempting to define the direct effects of estrogen on the breast, which are beginning to reveal the mechanism of increased cancer risk. We will then conclude with our views on the most pertinent questions to be addressed experimentally in order to explore the relationship between age, estrogen exposure, and breast cancer risk. Breast cancer remains one of the most prevalent diseases in the western world, with one in eight women predicted to be affected by breast cancer in their lifetime. Improvements in detection, anti-estrogen therapies, and cytotoxic chemotherapy have led to increased survival rates, from 72% in 1980s to 89% in 2010. Despite this, the incidence of breast cancer has increased over the same period –5. EstroChildbearing and a lack thereof have been known to influence breast cancer risk ever since Bernardino Ramazzini documented an increase in breast cancer incidence in nuns in the eighteenth century . Over thThe older a mother is at the age of the first full-term birth, the less the protection that is instilled by the pregnancy , 26–28. Considering the influence of age at first birth, number of births, and birth spacing on breast cancer risk, it is not surprising that breastfeeding is also able to modulate risk , 39. TheIn addition to the epidemiological studies in women, parity-induced protection against breast cancer has also been shown experimentally through the use of rodent models. Rodents have been used due to the similarities in morphological structure between the mammary gland and human breast and the conservation of genes and pathways between rodent and human mammary epithelial cell subpopulations . Parity Menopause is defined as the final menstrual period. It occurs when there has been a change in a woman’s reproductive hormones and the ovaries no longer release any eggs. Menopause itself is not a breast cancer risk factor, but over 70% of all breast cancer diagnoses are made in women who are 50 or older, and thus postmenopausal women have a higher risk than premenopausal women. The timing of menopause has been shown to significantly affect breast cancer risk. While not documented historically, the duration of reproductive years was identified as a breast cancer risk factor in early epidemiological studies , 55. LarThe age at which a woman undergoes menopause varies considerably between and within ethnicities ; howeverMouse models exploring the effects of menopausal age on breast cancer risk are challenging as mice do not undergo natural menopause. This may explain the lack in experimental data exploring or even confirming the abovementioned polymorphisms associated with age at menopause in animal models. However, like humans, menopause can be induced in mice by surgical removal of the ovaries. Using such a system one group have assessed the effect of timing of HRT on the postmenopausal mammary gland in an effort to explain the increase in breast cancer risk observed following HRT . They foAge at menarche, like menopause, is also associated with breast cancer risk. However, unlike age at menopause, the older a woman is at age at menarche, the lower her risk of breast cancer. Several groups have now shown that starting menses prior to 11 years of age increases the risk of breast cancer, while a later age at menarche (14 years) reduces the risk , 77–81. During the last decade, epidemiological studies reporting on trends in age at menarche have shown that irrespective of ethnicity, the average age of menarche is ~12 years , 82–84. Factors that have been shown to affect the age at menarche include gestational exposure to smoke , diet 9, psycholIt is unexpected that genome-wide sequencing studies did not find a strong association of estrogen-regulated genes and pathways with age at menarche, as was shown in the age at menopause studies , 96, 97.Despite the identification of candidate genes involved in the timing of menarche, experimental work to define the mechanism/s underlying pubertal timing has been limited. Most studies have been restricted to exploring the effects of environmental determinants such as exposure to seasonal changes , diet, and social status. This is due to the required use of macaques and non-human primates who also undergo a defined menarche . Of the The observation that lengthening the reproductive life of a woman, either by an earlier menarche or later menopause, increases the risk of breast cancer would suggest that the overall duration of the exposure to estrogen is underlying the risk. However, a recent meta-analysis of reproductive events and breast cancer risk has found that age at menarche may be more of a deciding factor on the risk than age at menopause .vice versa. This has been identified in a number of epidemiological reports with Forman and colleagues meta-analysis observing that of 36 studies investigating age at menarche and menopause, just 12 found a significant association between the 2  for women who began OCP use before the age of 17 compared to an RR 1.2 (SD 0.047) in women commencing treatment after 22 years of age. The longer the duration of OCP also further increases the risk of breast cancer anthracene . The work to date indicates that they influence breast cancer risk in different ways with menopause timing likely to be hormonally driven, whereas age at menarche might influence breast cancer risk indirectly through BMI. Increasing epidemiological evidence for these theories is emerging but functional studies are lacking.By contrast, childbearing trends are mirroring breast cancer incidence. Increasing numbers of women today remain nulliparous, women are having fewer children and a quarter of new mothers are delaying the start of childbearing , 36, 37.The studies reviewed herein show that age at menarche and timing of pregnancy have the greatest influence on breast cancer risk indicating that this early window of life is the most sensitive. The protection afforded by parity does not affect all women and unfortunately we have no way to identify those who are protected by childbearing. It is intriguing to postulate that the women with the potential to receive the protective effects of parity may be the same women who are most at risk of a carcinogenic insult. It may be that their mammary glands are more sensitive to developmental programming, be it protective or detrimental. The important questions remaining are can we predict who these women are, and can we use this information to develop preventive therapeutics? Through further functional validation of the genetic pathways involved in age at menarche, age at menopause and parity, the field may step a little closer to understanding these complex reproductive systems and their effects on breast cancer risk.The authors conceived and assisted in the writing of this review article.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


There has been tremendous progress in detection of breast cancer in postmenopausal women, resulting in two-thirds of women surviving more than 20 years after treatment. However, breast cancer remains the leading cause of cancer-related deaths in premenopausal women. Breast cancer is increasing in younger women due to changes in life-style as well as those at high risk as carriers of mutations in high-penetrance genes. Premenopausal women with breast cancer are more likely to be diagnosed with aggressive tumours and therefore have a lower survival rate. Mammography plays an important role in detecting breast cancer in postmenopausal women, but is considerably less sensitive in younger women. Imaging techniques, such as contrast-enhanced MRI improve sensitivity, but as with all imaging approaches, cannot differentiate between benign and malignant growths. Hence, current well-established detection methods are falling short of providing adequate safety, convenience, sensitivity and specificity for premenopausal women on a global level, necessitating the exploration of new methods. In order to detect and prevent the disease in high risk women as early as possible, methods that require more frequent monitoring need to be developed. The emergence of “omics” strategies over the last 20 years, enabling the characterisation and understanding of breast cancer at the molecular level, are providing the potential for long term, longitudinal monitoring of the disease. Tissue and serum biomarkers for breast cancer stratification, diagnosis and predictive outcome have emerged, but have not successfully translated into clinical screening for early detection of the disease. The use of breast-specific liquid biopsies, such as nipple aspirate fluid (NAF), a natural secretion produced by breast epithelial cells, can be collected non-invasively for biomarker profiling. As we move towards an age of active surveillance, home-based liquid biopsy collection kits are increasingly being applied and these could provide a paradigm shift where NAF biomarker profiling is used for routine breast health monitoring. The current status of established and newly emerging imaging techniques for early detection of breast cancer and the potential for alternative biomarker screening of liquid biopsies, particularly those applied to high-risk, premenopausal women, will be reviewed. Breast cancer is a global health problem affecting women, and to a lesser extent men, and constituted 25% of all cancers in 2012, with 883,000 cases each year in less developed and 794,000 cases in more developed regions of the world , 7, reprThe major risk factor is age and the majority of breast cancer cases occur in women after menopause. However, the correlation of risk with reproductive, environmental and lifestyle parameters, strongly indicate the origins of many breast cancers are concealed by a prolonged period of dormancy that only manifest in later life . LifestyThe emergence of genomic technologies in the last 20 years has had a major impact on understanding disease stratification in breast cancer, which is not only providing insights on how the disease progresses, but clinical direction in targeted treatment and prediction of outcome. There are currently 5 main phenotypes, Luminal A, Luminal B, Her2, basal-like and Claudin-low, but further stratification can be anticipated . At the Because of extensive epidemiological and etiological studies, it is becoming easier to identify those women who are at highest risk of breast cancer. Unfortunately, none of these measures can predict when breast cancer will occur. Regular screening for the appearance of breast cancer, which is recommended for women reaching menopause, is even more critical in high risk women during their reproductive years. There are various screening modalities, each with advantages and disadvantages Table , making Self-examination encourages women to be involved in active surveillance of their own breast health, increasing awareness of changes, both natural and abnormal. It provides an effective way for early detection of up to 50% tumours and improves discovery of other breast-related diseases without involving specialist equipment or professional health care assistance . HoweverMammography is by far the most common approach for screening breast cancer. In Europe, women aged 50–70 are invited for breast screening every 2–3 years, while in US annual mammograms are recommended from 50 to 74 years equating to nearly 39 million images in 2014. Women who have an increased risk of developing breast cancer, but are too young to join national screening programs, are offered annual screening using mammography and magnetic resonance imaging (MRI) based on a risk–benefit decision. Sensitivity of mammography can vary from almost 100–40% dependent on tissue composition , 24, andThe continuing development of mammography, including digitisation with improved resolution , has strengthened its position as the Gold standard for screening but still requires the presence of a substantial mass in the breast for a diagnosis , 33. ManOne of the challenges for imaging methods is breast tissue density, which is higher in younger women, making their mammograms harder to interpret, whereas postmenopausal women with extensive fatty breast tissue or ductal atrophy are more likely to have an accurate diagnosis . Breast Digital breast tomosynthesis (DBT) is a relatively new screening approach, which uses an X-ray beam in an arc around the breast to provide a 3D reconstruction of the tissue. In a comparison of DBT with digital mammography for 2666 breast lesions, the former had improved performance  compared to the latter  , but wasContrast-enhanced MRI, by comparison is not limited by breast density, nor does it use ionising radiation. In a review of 11 studies comparing MRI with digital mammography, the former achieved 94% sensitivity, but identified few cases of cancer in addition to those discovered by digital mammography alone . FurtherThere have been extensive studies to identify breast cancer biomarkers, but with varying degrees of success. Genomics has already stratified the disease to identify high risk individuals and histopathological approaches are used to determine ER, PR and HER2 expression, helping to direct clinical intervention. Indeed, microarray-based technologies for routine prognostic screening of multigene signatures  for developing a screening diagnostic are those readily accessible and in close proximity to the disease area, such as saliva for oral cancers or urine for bladder or renal cancer Table . In thisThere have been a number of proteomics studies on milk purely from a functional perspective, unrelated to cancer, with a recent study identifying up to 1600 proteins , 55. Col+/Na+ ratios while Type I cysts are more strongly related with breast cancer  (SOD-1) in NAF was decreased in breast cancer patients compared to healthy individuals . SOD-1 iThe expression of anti-oxidant oncogene DJ-1 mRNA is increased in ductal carcinoma tissues but the opposite effect was observed at the protein level, where expression is decreased and contrarily was elevated in blood of breast cancer patients. A study on NAF collected from 136 patients identified high levels of DJ-1 protein in NAF from breast cancer patients, but low levels in benign papilloma cases .NAF samples collected from non-cancer and cancer women for cytokine profiling found no difference in anti-inflammatory cytokines , pro-inflammatory cytokines (IL-2 and interferon-γ), immuno-modulatory interleukins  or chemokines . However, NAFs from cancer patients with high levels of aluminium in the breast microenvironment, had higher concentrations of pro-inflammatory cytokines , and C–C (MCP-1 and MIP-1α) and CXC-type chemokines (IL-8) compared to those cancer patients with low aluminium levels. This indicated a significant correlation between pro-inflammatory cytokines (IL-6), monocyte/macrophage chemo-attractant chemokines (MIP-1α and MCP-1), oxidative stress and aluminium content in cancerous NAFs .Cancer cells contain high levels of transferrin (TF) and ferritin (FTN), as well as higher expression of TF receptors compared to normal cells, suggesting proteins involved in Fe metabolism play important role in the proliferation of breast cancer cells . A studyPlasminogen activator inhibitor-1 (PAI-1), normally found in plasma, promotes breast cancer invasion and metastasis by directly inhibiting proteases, suggesting that excessive plasmin proteolysis may inhibit the assembly of tumour blood vessels, modulation of cell adhesion and the stimulation of cell proliferation . SignifiC-reactive protein (CRP) is already a developed serum biomarker for metastasis of various cancers including advanced stages of breast cancer . Elevate1-acid glycoprotein, were observed to be changed in cancer NAF samples. Further validation by ELISA, indicated that expression of these proteins correlated with pre-/postmenopausal status and cancer stage. Pawlik et al. [Proteomics approaches for characterising NAF has previously been reviewed by Mannello et al. , since wk et al.  used Isok et al. . Recentlk et al. . The mosk et al. , identifk et al. . A compak et al. . While mk et al. . Indeed,k et al. . The difOne of the major causes of death among women throughout the world is breast cancer. Despite tremendous progress in understanding the causes and advances in treatment regimens, the options for women at high risk of breast cancer are limited to drastic surgical intervention, because current methods for regular screening have significant limitations. Identifying biomarkers indicative of the earliest stages of malignancy has great potential, but so far it has not been fully explored. Cancer associated tissues are not readily accessible on a regular basis and plasma dilutes biomarkers once released from the diseased area. There would be huge benefits in analysing a biofluid collected from healthy volunteers and breast cancer patients that directly originates from the affected organ source. In this respect, NAF-based biomarkers offer great potential for developing an innovative non-invasive, patient-led screening strategy. NAF has multiple advantages as a liquid biopsy for detection of breast cancer: (1) premenopausal women, for whom current diagnostic modalities are limiting, are more likely to produce NAF than postmenopausal women where ductal atrophy is prevalent, (2) NAF production is non-invasive and causes less discomfort compared to other breast cancer screening procedures –126, (3)In a study of matched pairs of NAF samples by multiple reaction monitoring mass spectrometry (MRM MS), significant differences in prolactin inducible protein were observed between the diseased breast and the contralateral healthy breast Fig. . With an


We conducted a meta-analysis of observational studies to examine the hypothesized association between breast cancer and antihypertensive drug (AHT) use. Fixed- or random- effect models were used to calculate pooled risk ratios (RRs) and 95% confidence intervals (CIs) for all AHTs and individual classes . Twenty-one studies with 3,116,266 participants were included. Overall, AHT use was not significantly associated with breast cancer risk , and no consistent association was found for specific AHT classes with pooled RRs of 1.02 (95% CI: 0.96-1.09) for BBs, 1.07 (95% CI: 0.99-1.16) for CCBs, 0.99 (95% CI: 0.93-1.05) for ACEi/ARBs, and 1.05 (95% CI: 0.99-1.12) for diuretics. When stratified by duration of use, there was a significantly reduced breast cancer risk for ACEi/ARB use ≥10 years . Although there was no significant association between AHT use and breast cancer risk, there was a possible beneficial effect was found for long-term ACEi/ARB. Large, randomized controlled trials with long-term follow-up are needed to further test the effect of these medications on breast cancer risk. Hypertension is a highly prevalent condition worldwide, affecting more than one billion individuals and causing 9.4 million deaths annually . AntihypBreast cancer is the most common form of cancer and the second leading cause of cancer-related death among women worldwide . There hThus, given the widespread use of AHTs and the continued uncertainty regarding their effects on breast cancer incidence, we carried out a comprehensive meta-analysis to determine if there is an association of AHT use, including overall and different classes, with breast cancer risk based on all available observational studies.A total of 1,875 potentially eligible studies were identified during the initial search. After removing the duplicates and reviewing the titles or abstracts, 1,836 studies were deemed ineligible. Among the 39 articles for full-text review, 21 were further excluded for the following reasons: review or meta-analysis –35; confA list of details abstracted from the 21 included studies is provided in Table Pheterogeneity = 0.001, I2 = 55.3%; Figure Pheterogeneity = 0.133, I2 = 31.2%) or prospective studies .Twenty-one epidemiologic studies (twelve retrospective and nine prospective) presented results on use versus nonuse of AHTs and breast cancer risk. The pooled RR was 1.02 (95% CI: 0.98-1.06), with moderate heterogeneity among studies  for retrospective studies and 0.97  for prospective studies. Combining the retrospective and prospective data, the pooled RR was 1.02 (95% CI: 0.96-1.09) with low heterogeneity among all the studies  was found among all the studies. Random-effects pooled analysis suggested that CCB use was not associated with breast cancer risk  but not among prospective studies .Six retrospective studies and seven prospective studies were included in the analysis for breast cancer risk among CCB users. Low heterogeneity  for overall studies, 1.03  for retrospective studies, and 0.92  for prospective studies.Thirteen studies (seven retrospective and six prospective) examined the role of ACEi/ARB use on breast cancer risk. The results are shown in Figure Pheterogeneity = 0.004, I2 =58.2%). No significant link was found in retrospective studies  or prospective studies .Eleven studies provided information on diuretics use Figure . CompareWhen stratifying by geographic region, we did not found any association between AHT use and breast cancer risk. There was also no association observed in either study quality score stratum. Stratification by time period of drug use  showed that exposure to any class of AHT did not alter breast cancer risk. However, in examining duration effects of medication use, a reduced risk of breast cancer was found for ACEi/ARB use for 10 years or longer  but not in those observed for 5-10 years or fewer than 5 years. No statistically significant associations were seen for the other drug categories Tables  and 3.Further, we performed a subgroup analysis based on AHT subclasses. With respect to CCBs dihydropyridine and nondihydropyridines CCB use were assessed separately, but neither was associated with breast cancer risk. Similarly, analyses by specific ACEi/ARB type did not reveal any statistically significant association. However, in evaluating risks according to diuretic subclasses, a borderline elevated risk of breast cancer was observed among users of thiazides diuretics  but not other diuretic subtypes  or CCBs .To confirm the robustness of our results, we carried out several sensitivity analyses. First, we excluded four studies , 15, 23 P = 0.827 for AHTs, P = 0.396 for BBs, P = 0.127 for CCBs, P = 0.587 for ACEi/ARBs, and P = 0.734 for diuretics).There was no evidence of publication bias with regard to use of overall AHTs or individual classes in relation to breast cancer risk according to Begg’s funnel plot and Egger’s regression test , and the transcription factors NF-κB and CREB [Although our results provided no evidence of an overall association between ACEi/ARB use and breast cancer risk, a potentially intriguing finding is the decreased risk for longer duration of ACEi/ARB use (≥10 years). This finding is consistent with a prior Seattle-Puget Sound case-control study, which identified a borderline significant risk reduction for lobular breast cancers among women using ACEis for 10 years or longer  . Furtherand CREB –60. ACEiand CREB . In addiand CREB .Preclinical studies have shown that antagonism of β-adrenergic receptor signaling by BBs may inhibit multiple cellular processes involved in breast cancer initiation and progression, including cell proliferation, angiogenesis, and tumor immune responses . While aWith respect to diuretics, we did not observe an increased risk of breast cancer associated with overall diuretic use. Moreover, no trend of increasing risk with increasing duration of use was observed. Of note though, our subgroup analyses did show that use of thiazide diuretics but not other diuretic subclasses was significantly associated with an increased risk of breast cancer. To interpret the difference by drug subtype is challenging. One possible explanation is that thiazide diuretic use may increase insulin resistance , which hEven though most of the included studies in this meta-analysis were of high quality as evidenced by high Newcastle-Ottawa quality assessment scores, we acknowledge that there were some limitations, and thus, the results should be interpreted with caution. First, this was a meta-analysis of observational studies, which are inherently prone to several types of bias . For exaIn conclusion, the results of our study suggest a possible beneficial effect of long-term ACEi/ARB use on breast cancer risk. Considering potential biases and confounders in this meta-analysis of observational studies, large clinical trials with long-term follow-up are needed to fully assess the effect of these medications on breast cancer risk.A comprehensive, computerized literature search was independently performed by two investigators (Q.R. and H.B.N.) in PubMed and EMBASE databases from January 1966 through July 2016. The following text and/or medical subject heading terms were used: “antihypertensive drug” or “calcium channel blockers” or “beta blockers” or “angiotensin-converting enzyme inhibitors” or “angiotensin receptor blockers” or “diuretics” combined with “breast cancer” or “breast neoplasm.” In addition, the reference lists of reviews and retrieved articles were manually searched to identify additional relevant articles. No language restrictions were imposed. The present study was performed in accordance with the guidelines proposed by the Meta-analysis of Observational Studies in Epidemiology group .Studies were eligible for this meta-analysis if they fulfilled the following inclusion criteria: (1) published as an original article; (2) used a case-control or cohort design; (3) the exposure of interest was AHT intake, including the following five classes: ACEi, ARB, CCB, BB, or diuretics; (4) outcome was primary breast cancer occurrence; and (5) reported relative risk (RR), odds ratio (OR), or hazard ratio (HR) with corresponding 95% confidence intervals (CIs) or sufficient data to calculate them. When multiple studies reported the same data, results from the publication including the largest number of participants were used. We did not consider conference abstracts for inclusion.From each included study, the following information were recorded: first author’s surname, publication year, study design, geographical location, study period, duration of follow-up evaluation in cohort studies, participant age, numbers of cases and participants, type of medication exposure, assessment method of exposure and breast cancer, and adjustments for confounders. We extracted the risk estimates that reflected the greatest degree of control for potential confounders from each eligible study.The Newcastle-Ottawa scale was used to assess the quality of individual studies. In brief, a maximum of 9 points was assigned to each study: 4 for selection, 2 for comparability, and 3 for outcomes. A final score >6 was regarded as high quality. Data extraction and quality assessment were performed by two independent investigators (Q.R. and H.B.N.). Any disagreement was settled by discussion.Q and I2 statistics. For Cochran’s Q statistic, results were defined as heterogeneous for P values less than 0.10; I2 values of 25%, 50%, and 75% represented cut-off points for low, moderate, and high heterogeneity, respectively [We used RRs as common measures of the association between AHT use and breast cancer risk across studies. For one study  that strectively .We estimated the associations between overall AHT use as well as specific classes  and breast cancer risk. For six studies , 27, 52 P value less than 0.05 was considered statistically significant unless otherwise specified.Potential publication bias was examined using Begg’s funnel plots  and Egge


While the guidelines for breast cancer screening in average-risk women are well established, screening in high-risk women is not as clear. For women with BRCA1 or BRCA2 mutations, current guidelines recommend screening by clinical breast examination and mammography starting at age 30. For certain high-risk women, additional screening with magnetic resonance imaging (MRI) is encouraged. This review focuses on differentiating imaging modalities used for screening women at high-risk for breast cancer over the age of 50 by discussing the different imaging techniques, cost versus benefit, detection rates, and impact on survival. While mammography is the only imaging modality proven to reduce mortality from breast cancer, MRI is more sensitive in identifying cancers. MRI can often identify smaller malignancies at a greater resolution at an earlier stage. The use of MRI would be more cost effective as there would be less need for invasive therapeutic procedures. Research thus far has not identified an age-specific preference in imaging modality. There are no guidelines for high-risk women that specify screening with respect to age . More research is needed before screening guidelines in different age groups with various risk factors can be established. Breast cancer is the most common cancer in women independent of race or ethnicity. In 2012, approximately 1.4 million invasive cancers were diagnosed. Of those diagnosed, 224,147 women (16%) and 2,125 men (0.15%) in the United States were diagnosed with breast cancer. In the same year, 582,607 cancer deaths were reported and of those deaths, 41,150 women (7%) and 405 men (0.07%) in the United States died from breast cancer [For average-risk women, less than 15% lifetime risk of breast cancer using the Gail and Claus models, the United States Preventative Services Task Force (USPSTF) recommends that women who are 50 to 74 years old to get a mammogram every two years -4. MammoManagement of women who are considered high-risk for the development of breast cancer is controversial, especially in women who carry a BRCA1 or BRCA2 mutation as they can develop cancers at an earlier age . This isOur review focuses on differentiating imaging modalities used for screening women at high-risk for breast cancer over the age of 50 who have not already developed a malignancy, through a discussion of the different imaging techniques, cost versus benefit, detection rates, and impact on survival.For women over the age of 50 with a high-risk for breast cancer, such as having BRCA mutations, a family history of breast cancer, an early menstrual period, or late or no pregnancies, there is currently no uniform screening guidelines with respect to specific age and risk factors , 6. AccoAlthough currently there is evidence and recommendations for the addition of MRI to mammography for younger high-risk patients, there has been insufficient evidence looking at the screening accuracy of patients over the age of 50. It is known that breast density tends to decrease with age, and the sensitivity of mammography increases as breast density decreases. In 2014, Phi. et al. performed a meta-analysis on individual patient data to evaluate whether there was a significant difference in sensitivity for patients less than 50 years compared to patients over 50 years. The results of the study showed that the sensitivity of MRI with mammography was significantly greater than mammography alone for patients over 50 years (P < 0.001). The study also showed that there was no significant difference in sensitivity when using MRI with mammography on patients less than 50 years old compared to patients over 50 years (P = 0.79). The study was based on six major high-risk screening trials  and meta-analyses that mammography improves cancer mortality in the general population, but there is currently no evidence that it reduces mortality in high-risk breast cancer patients . TherefoAlthough MRI alone has shown to have high sensitivity for detecting breast cancers, it is limited by its lower specificity and thus increased false-positive rates. The increased false-positive rate increases the rate of recalls  and biopsies , 9. AlthWhile across breast cancer patients collectively, MRI and mammography combined have proven to be the most sensitive imaging modality for high-risk patients; different risk types may benefit from different imaging modalities. There are different types of high-risk patients, including BRCA mutations, radiation history, personal cancer history, history of lobular carcinoma in situ (LCIS), etc. Each risk type may benefit from a different surveillance program based on the type of breast cancer they are more likely to develop. For example, patients with a history of chest irradiation, such as Hodgkin lymphoma survivors, are at a high-risk for breast cancer; however, unlike BRCA patients, irradiated patients are more likely to have breast cancers with calcifications that are more easily found on mammography . FurtherIn patients with a personal history of breast cancer, post-treatment changes tend to distort the architecture and increase the density of the breast, therefore, limiting the effectiveness of mammography. In 2010, Brennan, et al., performed a retrospective study looking at 144 patients with a personal history of breast cancer. In the study, patients were screened with MRI, and 17 malignancies were detected. Ten of the 17 malignancies were mammographically occult, meaning it cannot be detected via mammogram. This study did not discuss the impact on survival but did state that the cancers detected via MRI were all minimal cancers ; therefore, it can be inferred that early detection of early stage cancer would decrease the mortality rate .Regarding patients with a history of LCIS, there has been no consensus on the effectiveness of MRI in this patient group. While the ACS guidelines state that there is insufficient evidence for this patient group to recommend either for or against MRI screening, the National Comprehensive Cancer Network (NCCN) guidelines advise MRI as an adjunct to mammography. A study by Sung, et al. in 2013 have found that MRI has increased detection rates in LCIS patients up to 4.5% compared to mammography, and detected early T1 (tumor size ≤ 2 cm) invasive cancers that were found to be mammographically occult. Again, detection of early cancers with MRI indicate possible cure in these patients .Cost-effectiveness of medical interventions and screening modalities can be quantified using several different parameters. For breast cancer, some parameters include cost per breast cancer detected, cost per breast cancer death averted, and cost per quality-adjusted life year (QALY) . When diThe Magnetic Resonance Imaging Breast Screening Study (MAR-IBS) looked at the cost effectiveness of moderately high-risk patients, those with a 50% likelihood of BRCA1 or BRCA2 Table .The study estimated the incremental cost of adding MRI to mammography to be $40,911 per cancer detected . Taneja,One of the major limitations of most studies that have compared MRI with mammography is that they have not been able to show evidence of decreased mortality. To date, only mammography has been validated as the imaging modality that has an impact on decreasing mortality.There have been few studies that have looked at long-term follow-up of high-risk patients following surveillance with MRI. The Dutch MRI trial (30) found that four of the 42 mutations carriers diagnosed with invasive breast cancer died of the disease, and one had developed metastatic disease. The study reported an 84% distant disease-free survival at six years and an annual mortality rate of 1.2%. In the Passaperuma, et al. 2012 study with an eight-year follow-up, there was only one distant recurrence and death occurrence out of 54 mutation carriers diagnosed with breast cancer, which was equivalent to a 0.5% mortality rate for invasive cancers .Surrogate markers for breast cancer mortality are currently tumor size and nodal status, which in addition to metastasis determine tumor stage . TherefoMammography has long been the standard of preventative care for breast cancer screening in average-risk patients. When considering high-risk patients, research has identified the use of MRI as a more sensitive screening tool. Current guidelines are established for using MRI in younger high-risk patients but do not specifically clarify screening protocol for high-risk patients of older age and with different risk factors. MRI in combination with mammography has increased sensitivity in cancer detection for younger high-risk women. In addition, the use of MRI with mammography has proven to be the most cost-effective choice for high-risk women.For older women, there has been insufficient evidence to support the use of MRI with mammography. This could be explained in part by decreased breast density with age allowing for equal detection rates with mammography alone. The most sensitive imaging modality may also vary with risk type depending on calcification, tissue architecture, and breast density. It is often unclear which imaging modality is the appropriate screening for high-risk women given the difference in age and risk factors. More research is needed to establish guidelines for screening high-risk women with regard to different ages and risk factors.