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Background: A high body mass index (BMI, kg/m 2 ) is associated with decreased risk of breast cancer before menopause, but increased risk after menopause. Exactly when this reversal occurs in relation to menopause is unclear. Locating that change point could provide insight into the role of adiposity in breast cancer etiology., Methods: We examined the association between BMI and breast cancer risk in the Premenopausal Breast Cancer Collaborative Group, from age 45 up to breast cancer diagnosis, loss to follow-up, death, or age 55, whichever came first. Analyses included 609,880 women in 16 prospective studies, including 9956 who developed breast cancer before age 55. We fitted three BMI hazard ratio (HR) models over age-time: constant, linear, or nonlinear (via splines), applying piecewise exponential additive mixed models, with age as the primary time scale. We divided person-time into four strata: premenopause; postmenopause due to natural menopause; postmenopause because of interventional loss of ovarian function (bilateral oophorectomy (BO) or chemotherapy); postmenopause due to hysterectomy without BO. Sensitivity analyses included stratifying by BMI in young adulthood, or excluding women using menopausal hormone therapy., Results: The constant BMI HR model provided the best fit for all four menopausal status groups. Under this model, the estimated association between a five-unit increment in BMI and breast cancer risk was HR=0.87 (95% CI: 0.85, 0.89) before menopause, HR=1.00 (95% CI: 0.96, 1.04) after natural menopause, HR=0.99 (95% CI: 0.93, 1.05) after interventional loss of ovarian function, and HR=0.88 (95% CI: 0.76, 1.02) after hysterectomy without BO., Conclusion: The BMI breast cancer HRs remained less than or near one during the 45-55 year age range indicating that the transition to a positive association between BMI and risk occurs after age 55., Competing Interests: Declaration of Competing Interest none., (Published by Elsevier Ltd.)

Purpose: There is strong evidence that leisure-time physical activity is protective against postmenopausal breast cancer risk but the association with premenopausal breast cancer is less clear. The purpose of this study was to examine the association of physical activity with the risk of developing premenopausal breast cancer., Methods: We pooled individual-level data on self-reported leisure-time physical activity across 19 cohort studies comprising 547,601 premenopausal women, with 10,231 incident cases of breast cancer. Multivariable Cox regression was used to estimate hazard ratios (HRs) and 95% CIs for associations of leisure-time physical activity with breast cancer incidence. HRs for high versus low levels of activity were based on a comparison of risk at the 90th versus 10th percentiles of activity. We assessed the linearity of the relationship and examined subtype-specific associations and effect modification across strata of breast cancer risk factors, including adiposity., Results: Over a median 11.5 years of follow-up (IQR, 8.0-16.1 years), high versus low levels of leisure-time physical activity were associated with a 6% (HR, 0.94 [95% CI, 0.89 to 0.99]) and a 10% (HR, 0.90 [95% CI, 0.85 to 0.95]) reduction in breast cancer risk, before and after adjustment for BMI, respectively. Tests of nonlinearity suggested an approximately linear relationship ( P nonlinearity = .94). The inverse association was particularly strong for human epidermal growth factor receptor 2-enriched breast cancer (HR, 0.57 [95% CI, 0.39 to 0.84]; P het = .07). Associations did not vary significantly across strata of breast cancer risk factors, including subgroups of adiposity., Conclusion: This large, pooled analysis of cohort studies adds to evidence that engagement in higher levels of leisure-time physical activity may lead to reduced premenopausal breast cancer risk.

Background: To support mammography screening decision making, we developed a competing-risk model to estimate 5-year breast cancer risk and 10-year nonbreast cancer death for women aged 55 years and older using Nurses' Health Study data and examined model performance in the Black Women's Health Study (BWHS). Here, we examine model performance in predicting 10-year outcomes in the BWHS, Women's Health Initiative-Extension Study (WHI-ES), and Multiethnic Cohort (MEC) and compare model performance to existing breast cancer prediction models., Methods: We used competing-risk regression and Royston and Altman methods for validating survival models to calculate our model's calibration and discrimination (C index) in BWHS (n = 17 380), WHI-ES (n = 106 894), and MEC (n = 49 668). The Nurses' Health Study development cohort (n = 48 102) regression coefficients were applied to the validation cohorts. We compared our model's performance with breast cancer risk assessment tool (Gail) and International Breast Cancer Intervention Study (IBIS) models by computing breast cancer risk estimates and C statistics., Results: When predicting 10-year breast cancer risk, our model's C index was 0.569 in BWHS, 0.572 in WHI-ES, and 0.576 in MEC. The Gail model's C statistic was 0.554 in BWHS, 0.564 in WHI-ES, and 0.551 in MEC; IBIS's C statistic was 0.547 in BWHS, 0.552 in WHI-ES, and 0.562 in MEC. The Gail model underpredicted breast cancer risk in WHI-ES; IBIS underpredicted breast cancer risk in WHI-ES and in MEC but overpredicted breast cancer risk in BWHS. Our model calibrated well. Our model's C index for predicting 10-year nonbreast cancer death was 0.760 in WHI-ES and 0.763 in MEC., Conclusions: Our competing-risk model performs as well as existing breast cancer prediction models in diverse cohorts and predicts nonbreast cancer death. We are developing a website to disseminate our model., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Previous work in European ancestry populations has shown that adding a polygenic risk score (PRS) to breast cancer risk prediction models based on epidemiologic factors results in better discriminatory performance as measured by the AUC (area under the curve). Following publication of the first PRS to perform well in women of African ancestry (AA-PRS), we conducted an external validation of the AA-PRS and then evaluated the addition of the AA-PRS to a risk calculator for incident breast cancer in Black women based on epidemiologic factors (BWHS model)., Methods: Data from the Black Women's Health Study, an ongoing prospective cohort study of 59,000 US Black women followed by biennial questionnaire since 1995, were used to calculate AUCs and 95% confidence intervals (CIs) for discriminatory accuracy of the BWHS model, the AA-PRS alone, and a new model that combined them. Analyses were based on data from 922 women with invasive breast cancer and 1844 age-matched controls., Results: AUCs were 0.577 (95% CI 0.556-0.598) for the BWHS model and 0.584 (95% CI 0.563-0.605) for the AA-PRS. For a model that combined estimates from the questionnaire-based BWHS model with the PRS, the AUC increased to 0.623 (95% CI 0.603-0.644)., Conclusions: This combined model represents a step forward for personalized breast cancer preventive care for US Black women, as its performance metrics are similar to those from models in other populations. Use of this new model may mitigate exacerbation of breast cancer disparities if and when it becomes feasible to include a PRS in routine health care decision-making., (© 2023. The Author(s).)

Mammography enables early detection of breast cancer, a critical factor in improving treatment outcomes and breast cancer mortality. Yet, not all women benefit equally, and striking racial disparities in breast cancer mortality persist, with Black women 40% more likely to die from breast cancer compared with non-Hispanic White women. The current issue of Cancer Epidemiology, Biomarkers & Prevention presents three informative reports revealing racial and ethnic variations in mammography's performance in risk stratification, detection, and surveillance. The performance dynamics of mammography across different racial and ethnic groups highlight the urgency for additional research and innovative interventions to ensure equitable breast cancer control. We emphasize a pressing need for a comprehensive evaluation of multilevel influences on the performance and implementation of mammography in racially and ethnically diverse populations, complemented by equally urgent efforts to address factors influencing the risk of aggressive tumor subtypes and timely and effective treatment delivery. See related articles by Kerlikowske et al., p. 1524, Hubbard et al., p. 1531, Nyante et al., p. 1542., (©2023 American Association for Cancer Research.)

Purpose: Women with preeclampsia are more likely to deliver preterm. Reports of inverse associations between preeclampsia and breast cancer risk, and positive associations between preterm birth and breast cancer risk are difficult to reconcile. We investigated the co-occurrence of preeclampsia/gestational hypertension with preterm birth and breast cancer risk using data from the Premenopausal Breast Cancer Collaborative Group., Methods: Across 6 cohorts, 3096 premenopausal breast cancers were diagnosed among 184,866 parous women. We estimated multivariable hazard ratios (HR) and 95% confidence intervals (CI) for premenopausal breast cancer risk using Cox proportional hazards regression., Results: Overall, preterm birth was not associated (HR 1.02, 95% CI 0.92, 1.14), and preeclampsia was inversely associated (HR 0.86, 95% CI 0.76, 0.99), with premenopausal breast cancer risk. In stratified analyses using data from 3 cohorts, preterm birth associations with breast cancer risk were modified by hypertensive conditions in first pregnancies (P-interaction = 0.09). Preterm birth was positively associated with premenopausal breast cancer in strata of women with preeclampsia or gestational hypertension (HR 1.52, 95% CI: 1.06, 2.18), but not among women with normotensive pregnancy (HR = 1.09, 95% CI: 0.93, 1.28). When stratified by preterm birth, the inverse association with preeclampsia was more apparent, but not statistically different (P-interaction = 0.2), among women who did not deliver preterm (HR = 0.82, 95% CI 0.68, 1.00) than those who did (HR = 1.07, 95% CI 0.73, 1.56)., Conclusion: Findings support an overall inverse association of preeclampsia history with premenopausal breast cancer risk. Estimates for preterm birth and breast cancer may vary according to other conditions of pregnancy., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Guidelines recommend shared decision making (SDM) for mammography screening for women ≥ 75 and not screening women with < 10-year life expectancy. High-quality SDM requires consideration of women's breast cancer (BC) risk, life expectancy, and values but is hard to implement because no models simultaneously estimate older women's individualized BC risk and life expectancy., Methods: Using competing risk regression and data from 83,330 women > 55 years who completed the 2004 Nurses' Health Study (NHS) questionnaire, we developed (in 2/3 of the cohort, n = 55,533) a model to predict 10-year non-breast cancer (BC) death. We considered 60 mortality risk factors and used best-subsets regression, the Akaike information criterion, and c-index, to identify the best-fitting model. We examined model performance in the remaining 1/3 of the NHS cohort (n = 27,777) and among 17,380 Black Women's Health Study (BWHS) participants, ≥ 55 years, who completed the 2009 questionnaire. We then included the identified mortality predictors in a previously developed competing risk BC prediction model and examined model performance for predicting BC risk., Results: Mean age of NHS development cohort participants was 70.1 years (± 7.0); over 10 years, 3.1% developed BC, 0.3% died of BC, and 20.1% died of other causes; NHS validation cohort participants were similar. BWHS participants were younger (mean age 63.7 years [± 6.7]); over 10-years 3.1% developed BC, 0.4% died of BC, and 11.1% died of other causes. The final non-BC death prediction model included 21 variables (age; body mass index [BMI]; physical function [3 measures]; comorbidities [12]; alcohol; smoking; age at menopause; and mammography use). The final BC prediction model included age, BMI, alcohol and hormone use, family history, age at menopause, age at first birth/parity, and breast biopsy history. When risk factor regression coefficients were applied in the validation cohorts, the c-index for predicting 10-year non-BC death was 0.790 (0.784-0.796) in NHS and 0.768 (0.757-0.780) in BWHS; for predicting 5-year BC risk, the c-index was 0.612 (0.538-0.641) in NHS and 0.573 (0.536-0.611) in BWHS., Conclusions: We developed and validated a novel competing-risk model that predicts 10-year non-BC death and 5-year BC risk. Model risk estimates may help inform SDM around mammography screening., (© 2023. The Author(s).)

Background: Childhood adiposity is inversely associated with young adult percent dense breast volume (%DBV) and absolute dense breast volume (ADBV), which could contribute to its protective effect for breast cancer later in life. The objective of this study was to identify metabolites in childhood serum that may mediate the inverse association between childhood adiposity and young adult breast density., Methods: Longitudinal data from 182 female participants in the Dietary Intervention Study in Children (DISC) and the DISC 2006 (DISC06) Follow-Up Study were analyzed. Childhood adiposity was assessed by anthropometry at the DISC visit with serum available that occurred closest to menarche and expressed as a body mass index (BMI) z-score. Serum metabolites were measured by untargeted metabolomics using ultra-high-performance liquid chromatography-tandem mass spectrometry. %DBV and ADBV were measured by magnetic resonance imaging at the DISC06 visit when participants were 25-29 years old. Robust mixed effects linear regression was used to identify serum metabolites associated with childhood BMI z-scores and breast density, and the R package mediation was used to quantify mediation., Results: Of the 115 metabolites associated with BMI z-scores (FDR < 0.20), 4 were significantly associated with %DBV and 6 with ADBV before, though not after, adjustment for multiple comparisons. Mediation analysis identified 2 unnamed metabolites, X-16576 and X-24588, as potential mediators of the inverse association between childhood adiposity and dense breast volume. X-16576 mediated 14% (95% confidence interval (CI) = 0.002, 0.46; P = 0.04) of the association of childhood adiposity with %DBV and 11% (95% CI = 0.01, 0.26; P = 0.02) of its association with ADBV. X-24588 also mediated 7% (95% CI = 0.001, 0.18; P = 0.05) of the association of childhood adiposity with ADBV. None of the other metabolites examined contributed to mediation of the childhood adiposity-%DBV association, though there was some support for contributions of lysine, valine and 7-methylguanine to mediation of the inverse association of childhood adiposity with ADBV., Conclusions: Additional large longitudinal studies are needed to identify metabolites and other biomarkers that mediate the inverse association of childhood adiposity with breast density and possibly breast cancer risk., (© 2022. The Author(s).)

Purpose: Compared to white women, Black women have increased risk of developing hypertensive diseases of pregnancy (HDOP) and have a higher incidence of aggressive breast cancer subtypes. Few studies of HDOP and breast cancer risk have included large numbers of Black women. This study examined the relation of HDOP to incidence of breast cancer overall and by estrogen receptor (ER) status in Black women., Methods: We followed 42,982 parous women in the Black Women's Health Study, a nationwide prospective study of Black women. Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) to assess associations of self-reported HDOP, including preeclampsia and gestational hypertension, with breast cancer incidence overall and by ER subtype, adjusted for age and established breast cancer risk factors., Results: Over 20 years of follow-up, we identified 2376 incident breast cancer cases. History of HDOP (11.7%) was not associated with breast cancer risk overall (HR 0.98; 95% CI 0.87, 1.11). HRs for invasive ER+ and ER- breast cancer were 1.11 (95% CI 0.93, 1.34) and 0.81 (95% CI 0.61, 1.07), respectively., Conclusions: HDOP was not associated with risk of overall breast cancer in Black women. A suggestive inverse association with ER- breast cancer may reflect an anti-tumorigenic hormone profile in HDOP, but those results require confirmation in other studies., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Socioeconomic and health-related factors, including comorbid illness, may affect mammography screening rates and subsequently contribute to breast cancer outcomes. We explored the association between diabetes and mammography screening, and whether this association varied between racial, ethnic, and geographic groups. Methods: Cross-sectional data from the 2012, 2014, 2016, and 2018 Behavioral Risk Factor Surveillance System were used to fit logistic regression models assessing the association between diabetes and up-to-date mammography screening in 497,600 women, aged 50-74 years. Participants were considered exposed if they responded "yes" to "(Ever told) you have diabetes?" and up to date on screening if they responded "yes" to having a mammogram within the past 2 years. Models were adjusted for age, health status, socioeconomic, and access variables. Results: The majority of participants were White (79.6%), non-Hispanic (88.9%), and up to date on screening (78.8%). Overall, 16.8% reported having diabetes. In fully adjusted models, White women with diabetes were 12% more likely to be up to date on screening (odds ratio [OR]: 1.12, 95% confidence interval [CI]: 1.06-1.19) than those without diabetes. Black/African American women and those of Hispanic ethnicity with diabetes were more likely to report being up to date with mammography (OR Black : 1.28, 95% CI: 1.12-1.45; OR Hispanic : 1.19, 95% CI: 1.13-1.24) than those without. Patterns were similar across geographic regions. Conclusions: Women of ages 50-74 years with diabetes were more likely to be up to date on screening than women without diabetes. Chronic disease management may represent an opportunity to address cancer screening.

While excess weight is an established risk factor for postmenopausal breast cancer, consideration of maximum body mass index (maxBMI; BMI is calculated as weight (kg)/height (m)2) or BMI at a point in time relevant for breast carcinogenesis may offer new insights. We prospectively evaluated maxBMI and time-dependent BMI in relation to breast cancer incidence among 31,028 postmenopausal women in the Black Women's Health Study. During 1995-2015, a total of 1,384 diagnoses occurred, including 787 estrogen-receptor (ER)-positive (ER+) cases and 310 ER-negative (ER-) cases. BMI was assessed at baseline and 2, 4, 6, and 8 years before diagnosis. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Compared with women with BMI <25, those with BMI ≥35 had increased risk of ER+ breast cancer but not ER- breast cancer. For BMI assessed 2 years before diagnosis, the HRs for ER+ breast cancer associated with maxBMI ≥35 and time-dependent BMI ≥35 were 1.42 (95% confidence interval (CI): 1.10, 1.84) and 1.63 (95% CI: 1.25, 2.13), respectively. The corresponding HR for time-dependent BMI assessed 6 years before diagnosis was 1.95 (95% CI: 1.45, 2.62). These findings suggest strong associations of BMI with risk of ER+ breast cancer in postmenopausal women, regardless of timing of BMI assessment., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The history of gestational diabetes mellitus (GDM) has been associated with breast cancer risk in some studies, particularly in young women, but results of cohort studies are conflicting., Methods: We pooled data from 257 290 young (age <55 years) women from five cohorts. We used multivariable Cox proportional-hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between GDM history and risk of breast cancer, overall and by oestrogen receptor (ER) status, before age 55 years, adjusted for established breast cancer risk factors., Results: Five percent of women reported a history of GDM and 6842 women reported an incident breast-cancer diagnosis (median follow-up = 16 years; maximum = 24 years). Compared with parous women without GDM, women with a history of GDM were not at increased risk of young-onset breast cancer overall (HR = 0.90; 95% CI: 0.78, 1.03) or by ER status (HR = 0.96; 95% CI: 0.79, 1.16 for ER-positive; HR = 1.07; 95% CI: 0.78, 1.47 for ER-negative). Compared with nulliparous women, parous women with a history of GDM had a lower risk of breast cancer overall (HR = 0.79; 95% CI: 0.68, 0.91) and of ER-positive (HR = 0.82; 95% CI: 0.66, 1.02) but not ER-negative (HR = 1.09; 95% CI: 0.76, 1.54) invasive breast cancer. These results were consistent with the HRs comparing parous women without GDM to nulliparous women., Conclusions: Results of this analysis do not support the hypothesis that GDM is a risk factor for breast cancer in young women. Our findings suggest that the well-established protective effect of parity on risk of ER-positive breast cancer persists even for pregnancies complicated by GDM., (© The Author(s) 2021; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Purpose: Breast cancer risk prediction models are used to identify high-risk women for early detection, targeted interventions, and enrollment into prevention trials. We sought to develop and evaluate a risk prediction model for breast cancer in US Black women, suitable for use in primary care settings., Methods: Breast cancer relative risks and attributable risks were estimated using data from Black women in three US population-based case-control studies (3,468 breast cancer cases; 3,578 controls age 30-69 years) and combined with SEER age- and race-specific incidence rates, with incorporation of competing mortality, to develop an absolute risk model. The model was validated in prospective data among 51,798 participants of the Black Women's Health Study, including 1,515 who developed invasive breast cancer. A second risk prediction model was developed on the basis of estrogen receptor (ER)-specific relative risks and attributable risks. Model performance was assessed by calibration (expected/observed cases) and discriminatory accuracy (C-statistic)., Results: The expected/observed ratio was 1.01 (95% CI, 0.95 to 1.07). Age-adjusted C-statistics were 0.58 (95% CI, 0.56 to 0.59) overall and 0.63 (95% CI, 0.58 to 0.68) among women younger than 40 years. These measures were almost identical in the model based on estrogen receptor-specific relative risks and attributable risks., Conclusion: Discriminatory accuracy of the new model was similar to that of the most frequently used questionnaire-based breast cancer risk prediction models in White women, suggesting that effective risk stratification for Black women is now possible. This model may be especially valuable for risk stratification of young Black women, who are below the ages at which breast cancer screening is typically begun., Competing Interests: Tracy BattagliaResearch Funding: American Cancer Society, Patient Centered Outcomes Research Institute, NIH NCATs (Inst) Elisa V. BanderaConsulting or Advisory Role: PfizerNo other potential conflicts of interest were reported.

Background: Research on psychosocial stress and risk of breast cancer has produced conflicting results. Few studies have assessed this relation by breast cancer subtype or specifically among Black women, who experience unique chronic stressors., Methods: We used prospective data from the Black Women's Health Study, an ongoing cohort study of 59,000 US Black women, to assess neighborhood- and individual-level psychosocial factors in relation to risk of breast cancer. We used factor analysis to derive two neighborhood score variables after linking participant addresses to US Census data (2000 and 2010) on education, employment, income and poverty, female-headed households, and Black race for all households in each residential block group. We used Cox proportional hazards regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) adjusted for established breast cancer risk factors., Results: During follow-up from 1995 to 2017, there were 2167 incident invasive breast cancer cases (1259 estrogen receptor positive (ER +); 687 ER negative (ER-)). For ER- breast cancer, HRs were 1.26 (95% CI 1.00-1.58) for women living in the highest quartile of neighborhood disadvantage relative to women in the lowest quartile, and 1.24 (95% CI 0.98-1.57) for lowest versus highest quartile of neighborhood socioeconomic status (SES). For ER+ breast cancer, living in the lowest quartile of neighborhood SES was associated with a reduced risk of ER+ breast cancer (HR = 0.83, 95% CI 0.70-0.98). With respect to individual-level factors, childhood sexual abuse (sexual assault ≥ 4 times vs. no abuse: HR = 1.35, 95% CI 1.01-1.79) and marital status (married/living together vs. single: HR = 1.29, 95% CI 1.08-1.53) were associated with higher risk of ER+, but not ER- breast cancer., Conclusion: Neighborhood disadvantage and lower neighborhood SES were associated with an approximately 25% increased risk of ER- breast cancer in this large cohort of Black women, even after control for multiple behaviors and lifestyle factors. Further research is need to understand the underlying reasons for these associations. Possible contributing factors are biologic responses to the chronic stress/distress experienced by individuals who reside in neighborhoods characterized by high levels of noise, crime and unemployment or the direct effects of environmental toxins., (© 2021. The Author(s).)

Purpose: The prevalence of germline pathogenic variants (PVs) in established breast cancer predisposition genes in women in the general population over age 65 years is not well-defined. However, testing guidelines suggest that women diagnosed with breast cancer over age 65 years might have < 2.5% likelihood of a PV in a high-penetrance gene. This study aimed to establish the frequency of PVs and remaining risks of breast cancer for each gene in women over age 65 years., Methods: A total of 26,707 women over age 65 years from population-based studies (51.5% with breast cancer and 48.5% unaffected) were tested for PVs in germline predisposition gene. Frequencies of PVs and associations between PVs in each gene and breast cancer were assessed, and remaining lifetime breast cancer risks were estimated for non-Hispanic White women with PVs., Results: The frequency of PVs in predisposition genes was 3.18% for women with breast cancer and 1.48% for unaffected women over age 65 years. PVs in BRCA1 , BRCA2 , and PALB2 were found in 3.42% of women diagnosed with estrogen receptor (ER)-negative, 1.0% with ER-positive, and 3.01% with triple-negative breast cancer. Frequencies of PVs were lower among women with no first-degree relatives with breast cancer. PVs in CHEK2 , PALB2 , BRCA2 , and BRCA1 were associated with increased risks (odds ratio = 2.9-4.0) of breast cancer. Remaining lifetime risks of breast cancer were ≥ 15% for those with PVs in BRCA1 , BRCA2 , and PALB2 ., Conclusion: This study suggests that all women diagnosed with triple-negative breast cancer or ER-negative breast cancer should receive genetic testing and that women over age 65 years with BRCA1 and BRCA2 PVs and perhaps with PALB2 and CHEK2 PVs should be considered for magnetic resonance imaging screening., Competing Interests: Jeffrey N. WeitzelSpeakers' Bureau: AstraZeneca Amal YussufEmployment: Ambry Genetics Celine M. VachonStock and Other Ownership Interests: Exact SciencesResearch Funding: GRAILPatents, Royalties, Other Intellectual Property: Breast Density softwareTravel, Accommodations, Expenses: GRAIL Tina PesaranEmployment: Ambry Genetics/Konica MinoltaTravel, Accommodations, Expenses: Ambry Genetics/Konica Minolta Irene M. OngEmployment: Propeller HealthStock and Other Ownership Interests: AyrFlo Rachid KaramEmployment: Ambry GeneticsResearch Funding: Ambry GeneticsTravel, Accommodations, Expenses: Ambry Genetics Holly LaDucaEmployment: Ambry GeneticsStock and Other Ownership Interests: Ambry Genetics Jill S. DolinskyEmployment: Ambry Genetics Elizabeth ChaoEmployment: Ambry Genetics Eric C. PolleyResearch Funding: GRAIL Susan M. DomchekHonoraria: AstraZeneca, Clovis Oncology, Bristol Myers SquibbResearch Funding: AstraZeneca, Clovis OncologyOpen Payments Link: https://openpaymentsdata.cms.gov/physician/917904 Fergus J. CouchConsulting or Advisory Role: AstraZenecaSpeakers' Bureau: Ambry Genetics, QiagenResearch Funding: GRAILTravel, Accommodations, Expenses: GRAIL, QiagenOther Relationship: Ambry GeneticsNo other potential conflicts of interest were reported.

Hair relaxers and leave-in conditioners and oils, commonly used by Black/African American women, may contain estrogens or estrogen-disrupting compounds. Thus, their use may contribute to breast cancer risk. Results of the few previous studies on this topic are inconsistent. We assessed the relation of hair relaxer and leave-in conditioner use to breast cancer incidence in the Black Women's Health Study, a nationwide prospective study of Black women. Among 50 543 women followed from 1997 to 2017, 2311 incident breast cancers occurred. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression for breast cancer overall and by estrogen receptor (ER) status. For heavy use (≥15 years of use for ≥7 times/year) of hair relaxers relative to never/light use (<4 years, no more than 1-2 times/year), the multivariable HR for breast cancer overall was 1.13 (95%CI: 0.96-1.33). Duration, frequency, age at first use and number of scalp burns were not associated with overall breast cancer risk. For heavy use of hair relaxers containing lye, the corresponding HR for ER+ breast cancer was 1.32 (95% CI: 0.97, 1.80); there was no association for non-lye products. There was no association of conditioner use and breast cancer. Results of this study were largely null, but there was some evidence that heavy use of lye-containing hair relaxers may be associated with increased risk of ER+ breast cancer. Consistent results from several studies are needed before it can be concluded that use of certain hair relaxers impacts breast cancer development., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Purpose: We evaluated the association of percent mammographic density (PMD), absolute dense area (DA), and non-dense area (NDA) with risk of "intrinsic" molecular breast cancer (BC) subtypes., Methods: We pooled 3492 invasive BC and 10,148 controls across six studies with density measures from prediagnostic, digitized film-screen mammograms. We classified BC tumors into subtypes [63% Luminal A, 21% Luminal B, 5% HER2 expressing, and 11% as triple negative (TN)] using information on estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and tumor grade. We used polytomous logistic regression to calculate odds ratio (OR) and 95% confidence intervals (CI) for density measures (per SD) across the subtypes compared to controls, adjusting for age, body mass index and study, and examined differences by age group., Results: All density measures were similarly associated with BC risk across subtypes. Significant interaction of PMD by age (P = 0.001) was observed for Luminal A tumors, with stronger effect sizes seen for younger women < 45 years (OR = 1.69 per SD PMD) relative to women of older ages (OR = 1.53, ages 65-74, OR = 1.44 ages 75 +). Similar but opposite trends were seen for NDA by age for risk of Luminal A: risk for women: < 45 years (OR = 0.71 per SD NDA) was lower than older women (OR = 0.83 and OR = 0.84 for ages 65-74 and 75 + , respectively) (P < 0.001). Although not significant, similar patterns of associations were seen by age for TN cancers., Conclusions: Mammographic density measures were associated with risk of all "intrinsic" molecular subtypes. However, findings of significant interactions between age and density measures may have implications for subtype-specific risk models.

Background: Air pollution contains numerous carcinogens and endocrine disruptors which may be relevant for breast cancer. Previous research has predominantly been conducted in White women; however, Black women may have higher air pollution exposure due to geographic and residential factors., Objective: We evaluated the association between air pollution and breast cancer risk in a large prospective population of Black women., Methods: We estimated annual average ambient levels of particulate matter <2.5 μm (PM 2.5 ), nitrogen dioxide (NO 2 ) and ozone (O 3 ) at the 1995 residence of 41,317 participants in the Black Women's Health Study who resided in 56 metropolitan areas across the United States. Cox proportional hazards regression was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for an interquartile range (IQR) increase in each pollutant. We evaluated whether the association varied by menopausal status, estrogen receptor (ER) status of the tumor and geographic region of residence., Results: With follow-up through 2015 (mean = 18.3 years), 2146 incident cases of breast cancer were confirmed. Higher exposure to NO 2 or O 3 was not associated with a higher risk of breast cancer. For PM 2.5 , although we observed no association overall, there was evidence of modification by geographic region for both ER- (p for heterogeneity = 0.01) and premenopausal breast cancer (p for heterogeneity = 0.01). Among women living in the Midwest, an IQR increase in PM 2.5 (2.87 μg/m 3 ), was associated with a higher risk of ER- (HR = 1.53, 95% CI: 1.07-2.19) and premenopausal breast cancer (HR = 1.32, 95% CI: 1.03-1.71). In contrast, among women living in the South, PM 2.5 was inversely associated with both ER- (HR = 0.74, 95% CI: 0.56-0.97) and premenopausal breast cancer risk (HR = 0.75, 95% CI: 0.62-0.91)., Discussion: Overall, we observed no association between air pollution and increased breast cancer risk among Black women, except perhaps among women living in the Midwestern US., (Published by Elsevier Inc.)

Background: Population-based estimates of the risk of breast cancer associated with germline pathogenic variants in cancer-predisposition genes are critically needed for risk assessment and management in women with inherited pathogenic variants., Methods: In a population-based case-control study, we performed sequencing using a custom multigene amplicon-based panel to identify germline pathogenic variants in 28 cancer-predisposition genes among 32,247 women with breast cancer (case patients) and 32,544 unaffected women (controls) from population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Associations between pathogenic variants in each gene and the risk of breast cancer were assessed., Results: Pathogenic variants in 12 established breast cancer-predisposition genes were detected in 5.03% of case patients and in 1.63% of controls. Pathogenic variants in BRCA1 and BRCA2 were associated with a high risk of breast cancer, with odds ratios of 7.62 (95% confidence interval [CI], 5.33 to 11.27) and 5.23 (95% CI, 4.09 to 6.77), respectively. Pathogenic variants in PALB2 were associated with a moderate risk (odds ratio, 3.83; 95% CI, 2.68 to 5.63). Pathogenic variants in BARD1 , RAD51C , and RAD51D were associated with increased risks of estrogen receptor-negative breast cancer and triple-negative breast cancer, whereas pathogenic variants in ATM , CDH1 , and CHEK2 were associated with an increased risk of estrogen receptor-positive breast cancer. Pathogenic variants in 16 candidate breast cancer-predisposition genes, including the c.657&#95;661del5 founder pathogenic variant in NBN , were not associated with an increased risk of breast cancer., Conclusions: This study provides estimates of the prevalence and risk of breast cancer associated with pathogenic variants in known breast cancer-predisposition genes in the U.S. population. These estimates can inform cancer testing and screening and improve clinical management strategies for women in the general population with inherited pathogenic variants in these genes. (Funded by the National Institutes of Health and the Breast Cancer Research Foundation.)., (Copyright © 2021 Massachusetts Medical Society.)

Background: The risks of breast cancer in African American (AA) women associated with inherited mutations in breast cancer predisposition genes are not well defined. Thus, whether multigene germline hereditary cancer testing panels are applicable to this population is unknown. We assessed associations between mutations in panel-based genes and breast cancer risk in 5054 AA women with breast cancer and 4993 unaffected AA women drawn from 10 epidemiologic studies., Methods: Germline DNA samples were sequenced for mutations in 23 cancer predisposition genes using a QIAseq multiplex amplicon panel. Prevalence of mutations and odds ratios (ORs) for associations with breast cancer risk were estimated with adjustment for study design, age, and family history of breast cancer., Results: Pathogenic mutations were identified in 10.3% of women with estrogen receptor (ER)-negative breast cancer, 5.2% of women with ER-positive breast cancer, and 2.3% of unaffected women. Mutations in BRCA1, BRCA2, and PALB2 were associated with high risks of breast cancer (OR = 47.55, 95% confidence interval [CI] = 10.43 to >100; OR = 7.25, 95% CI = 4.07 to 14.12; OR = 8.54, 95% CI = 3.67 to 24.95, respectively). RAD51D mutations were associated with high risk of ER-negative disease (OR = 7.82, 95% CI = 1.61 to 57.42). Moderate risks were observed for CHEK2, ATM, ERCC3, and FANCC mutations with ER-positive cancer, and RECQL mutations with all breast cancer., Conclusions: The study identifies genes that predispose to breast cancer in the AA population, demonstrates the validity of current breast cancer testing panels for use in AA women, and provides a basis for increased referral of AA patients for cancer genetic testing., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The size distribution of adipocytes in fat tissue provides important information about metabolic status and overall health of patients. Histological measurements of biopsied adipose tissue can reveal cardiovascular and/or cancer risks, to complement typical prognosis parameters such as body mass index, hypertension or diabetes. Yet, current methods for adipocyte quantification are problematic and insufficient. Methods such as hand-tracing are tedious and time-consuming, ellipse approximation lacks precision, and fully automated methods have not proven reliable. A semi-automated method fills the gap in goal-directed computational algorithms, specifically for high-throughput adipocyte quantification. Here, we design and develop a tool, AdipoCyze, which incorporates a novel semi-automated tracing algorithm, along with benchmark methods, and use breast histological images from the Komen for the Cure Foundation to assess utility. Speed and precision of the new approach are superior to conventional methods and accuracy is comparable, suggesting a viable option to quantify adipocytes, while increasing user flexibility. This platform is the first to provide multiple methods of quantification in a single tool. Widespread laboratory and clinical use of this program may enhance productivity and performance, and yield insight into patient metabolism, which may help evaluate risks for breast cancer progression in patients with comorbidities of obesity., Abbreviations: BMI: body mass index.

Background: Use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been hypothesized to be associated with reduced risk of breast cancer; however, results of epidemiological studies have been mixed. Few studies have investigated these associations among African American women., Methods: To assess the relation of aspirin use to risk of breast cancer in African American women, we conducted a prospective analysis within the Black Women's Health Study, an ongoing nationwide cohort study of 59,000 African American women. On baseline and follow-up questionnaires, women reported regular use of aspirin (defined as use at least 3 days per week) and years of use. During follow-up from 1995 through 2017, 1919 invasive breast cancers occurred, including 1112 ER+, 569 ER-, and 284 triple-negative (TN) tumors. We used age-stratified Cox proportional hazards regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations of aspirin use with risk of ER+, ER-, and TN breast cancer, adjusted for established breast cancer risk factors., Results: Overall, the HR for current regular use of aspirin relative to non-use was 0.92 (95% CI 0.81, 1.04). For ER+, ER-, and TN breast cancer, corresponding HRs were 0.98 (0.84, 1.15), 0.81 (0.64, 1.04), and 0.70 (0.49, 0.99), respectively., Conclusions: Our findings with regard to ER- and TN breast cancer are consistent with hypothesized inflammatory mechanisms of ER- and TN breast cancer, rather than hormone-dependent pathways. Aspirin may represent a potential opportunity for chemoprevention of ER- and TN breast cancer.

Early-adulthood body size is strongly inversely associated with risk of premenopausal breast cancer. It is unclear whether subsequent changes in weight affect risk. We pooled individual-level data from 17 prospective studies to investigate the association of weight change with premenopausal breast cancer risk, considering strata of initial weight, timing of weight change, other breast cancer risk factors and breast cancer subtype. Hazard ratios (HR) and 95% confidence intervals (CI) were obtained using Cox regression. Among 628,463 women, 10,886 were diagnosed with breast cancer before menopause. Models adjusted for initial weight at ages 18-24 years and other breast cancer risk factors showed that weight gain from ages 18-24 to 35-44 or to 45-54 years was inversely associated with breast cancer overall (e.g., HR per 5 kg to ages 45-54: 0.96, 95% CI: 0.95-0.98) and with oestrogen-receptor(ER)-positive breast cancer (HR per 5 kg to ages 45-54: 0.96, 95% CI: 0.94-0.98). Weight gain from ages 25-34 was inversely associated with ER-positive breast cancer only and weight gain from ages 35-44 was not associated with risk. None of these weight gains were associated with ER-negative breast cancer. Weight loss was not consistently associated with overall or ER-specific risk after adjusting for initial weight. Weight increase from early-adulthood to ages 45-54 years is associated with a reduced premenopausal breast cancer risk independently of early-adulthood weight. Biological explanations are needed to account for these two separate factors., (© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Dioxins are persistent organic pollutants generated from industrial combustion processes such as waste incineration. To date, results from epidemiologic studies of dioxin exposure and breast cancer risk have been mixed., Objectives: To prospectively examine the association between ambient dioxin exposure using a nationwide spatial database of industrial dioxin-emitting facilities and invasive breast cancer risk in the Nurses' Health Study II (NHSII)., Methods: NHSII includes female registered nurses in the US who have completed self-administered biennial questionnaires since 1989. Incident invasive breast cancer diagnoses were self-reported and confirmed by medical record review. Dioxin exposure was estimated based on residential proximity, duration of residence, and emissions from facilities located within 3, 5, and 10 km around geocoded residential addresses updated throughout follow-up. Cox regression models adjusted for breast cancer risk factors were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs)., Results: From 1989 to 2013, 3840 invasive breast cancer cases occurred among 112,397 participants. There was no association between residential proximity to any dioxin facilities (all facilities combined) and breast cancer risk overall. However, women who resided within 10 km of any municipal solid waste incinerator (MSWI) compared to none had increased breast cancer risk (adjusted HR = 1.15, 95% CI: 1.03, 1.28), with stronger associations noted for women who lived within 5 km (adjusted HR = 1.25, 95% CI: 1.04, 1.52). Positive associations were also observed for longer duration of residence and higher dioxin emissions from MSWIs within 3, 5, and 10 km. There were no clear differences in patterns of association for ER + vs. ER-breast cancer or by menopausal status., Discussion: Results from this study support positive associations between dioxin exposure from MSWIs and invasive breast cancer risk., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Gestational diabetes mellitus (GDM) has been hypothesized to increase breast cancer risk, but results from the few prior epidemiologic studies are conflicting, and no studies have examined the association in African American women., Methods: We analyzed data from the prospective Black Women's Health Study to evaluate associations of history of GDM with breast cancer risk among 41,767 parous African American women, adjusting for potential confounders. HRs and 95% confidence intervals (CI) were estimated from multivariable Cox proportional hazards regression models., Results: There was no evidence of an association between history of GDM and risk of invasive breast cancer, overall or by estrogen receptor status., Conclusions: Results of this study do not support the hypothesis that GDM is an important risk factor for breast cancer in African American women overall., Impact: On the basis of these data, breast cancer risk is not increased among African American women with a history of GDM compared with parous women without a history of GDM., (©2020 American Association for Cancer Research.)

Background: The V measure captures grayscale intensity variation on a mammogram and is positively associated with breast cancer risk, independent of percent mammographic density (PMD), an established marker of breast cancer risk. We examined whether anthropometrics are associated with V, independent of PMD., Methods: The analysis included 1,700 premenopausal and 1,947 postmenopausal women without breast cancer within the Nurses' Health Study (NHS) and NHSII. Participants recalled their body fatness at ages 5, 10, and 20 years using a 9-level pictogram (level 1: most lean) and reported weight at age 18 years, current adult weight, and adult height. V was estimated by calculating standard deviation of pixels on screening mammograms. Linear mixed models were used to estimate beta coefficients (ß) and 95% confidence intervals (CI) for the relationships between anthropometric measures and V, adjusting for confounders and PMD., Results: V and PMD were positively correlated (Spearman r = 0.60). Higher average body fatness at ages 5 to 10 years (level ≥ 4.5 vs. 1) was significantly associated with lower V in premenopausal (ß = -0.32; 95% CI, -0.48 to -0.16) and postmenopausal (ß = -0.24; 95% CI, -0.37 to -0.10) women, independent of current body mass index (BMI) and PMD. Similar inverse associations were observed with average body fatness at ages 10 to 20 years and BMI at age 18 years. Current BMI was inversely associated with V, but the associations were largely attenuated after adjustment for PMD. Height was not associated with V., Conclusions: Our data suggest that early-life body fatness may reflect lifelong impact on breast tissue architecture beyond breast density. However, further studies are needed to confirm the results., Impact: This study highlights strong inverse associations of early-life adiposity with mammographic image intensity variation., (©2019 American Association for Cancer Research.)

Background: Compared to U.S. white women, African American women are more likely to die from ductal carcinoma in situ (DCIS). Elucidation of risk factors for DCIS in African American women may provide opportunities for risk reduction., Methods: We used data from three epidemiologic studies in the African American Breast Cancer Epidemiology and Risk Consortium to study risk factors for estrogen receptor (ER) positive DCIS (488 cases; 13,830 controls). Results were compared to associations observed for ER+ invasive breast cancer (n = 2,099)., Results: First degree family history of breast cancer was associated with increased risk of ER+ DCIS [odds ratio (OR): 1.69, 95% confidence interval (CI): 1.31, 2.17]. Oral contraceptive use within the past 10 years (vs. never) was also associated with increased risk (OR: 1.43, 95%CI: 1.03, 1.97), as was late age at first birth (≥25 years vs. <20 years) (OR: 1.26, 95%CI: 0.96, 1.67). Risk was reduced in women with older age at menarche (≥15 years vs. <11 years) (OR: 0.62, 95%CI: 0.42, 0.93) and higher body mass index (BMI) in early adulthood (≥25 vs. <20 kg/m 2 at age 18 or 21) (OR: 0.75, 95%CI: 0.55, 1.01). There was a positive association of recent BMI with risk in postmenopausal women only. In general, associations of risk factors for ER+ DCIS were similar in magnitude and direction to those for invasive ER+ breast cancer., Conclusions: Our findings suggest that most risk factors for invasive ER+ breast cancer are also associated with increased risk of ER+ DCIS among African American women., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: Epidemiologic evidence supports an association between high mammographic density and increased breast cancer risk yet etiologic mechanisms remain largely unknown. Mixed evidence exists as to whether circulating lipid levels influence mammographic density and breast cancer risk. Therefore, we examined these associations in the Nurses' Health Study (NHS) and Nurses' Health Study II (NHSII), two large prospective cohorts with information on PMD and circulating lipid measures, long follow-up, and breast cancer risk factor and outcome data., Methods: We conducted a nested case-control study among women in the NHS and NHSII. Percent mammographic density (PMD) was measured using Cumulus software, a computer-assisted method, on digitized film mammograms. Cross-sectional associations between circulating lipids [total cholesterol (n = 1,502), high-density lipoprotein (HDL-C; n = 579), and triglycerides (n = 655)] and PMD were evaluated among controls. All analyses were stratified by menopausal status at time of mammogram. Relative risks for breast cancer by lipid and PMD measures were estimated among postmenopausal women in the full nested case-control study (cases/controls for cholesterol, HDL-C, and triglycerides were 937/975, 416/449, and 506/537, respectively)., Results: There were no significant associations between circulating lipid levels and PMD among healthy women, irrespective of menopausal status. The association between PMD and breast cancer risk among postmenopausal women was not modified by circulating lipid levels (p interaction = 0.83, 0.80, and 0.34 for total cholesterol, HDL-C, and triglycerides, respectively)., Conclusion: Overall, no association was observed between lipid levels and PMD, and there was no evidence that lipid levels modified the association between PMD and breast cancer risk.

Background: Obesity and elevated breast density are common risk factors for breast cancer, and their effects may vary by estrogen receptor (ER) subtype. However, their joint effects on ER subtype-specific risk are unknown. Understanding this relationship could enhance risk stratification for screening and prevention. Thus, we assessed the association between breast density and ER subtype according to body mass index (BMI) and menopausal status., Methods: We conducted a case-control study nested within two mammography screening cohorts, the Mayo Mammography Health Study and the San Francisco Bay Area Breast Cancer SPORE/San Francisco Mammography Registry. Our pooled analysis contained 1538 ER-positive and 285 ER-negative invasive breast cancer cases and 4720 controls matched on age, menopausal status at time of mammogram, and year of mammogram. Percent density was measured on digitized film mammograms using computer-assisted techniques. We used polytomous logistic regression to evaluate the association between percent density and ER subtype by BMI subgroup (normal/underweight, < 25 kg/m 2 versus overweight/obese, ≥ 25 kg/m 2 ). We used Wald chi-squared tests to assess for interactions between percent density and BMI. Our analysis was stratified by menopausal status and hormone therapy usage at the time of index mammogram., Results: Percent density was associated with increased risk of overall breast cancer regardless of menopausal status or BMI. However, when analyzing breast cancer across ER subtype, we found a statistically significant (p = 0.008) interaction between percent density and BMI in premenopausal women only. Specifically, elevated percent density was associated with a higher risk of ER-negative than ER-positive cancer in overweight/obese premenopausal women [OR per standard deviation increment 2.17 (95% CI 1.50-3.16) vs 1.33 (95% CI 1.11-1.61) respectively, P heterogeneity  = 0.01]. In postmenopausal women, elevated percent density was associated with similar risk of ER-positive and ER-negative cancers, and no substantive differences were seen after accounting for BMI or hormone therapy usage., Conclusions: The combination of overweight/obesity and elevated breast density in premenopausal women is associated with a higher risk of ER-negative compared with ER-positive cancer. Eighteen percent of premenopausal women in the USA have elevated BMI and breast density and may benefit from lifestyle modifications involving weight loss and exercise.

Background: Parity is widely recognized as protective for breast cancer, but breast cancer risk may be increased shortly after childbirth. Whether this risk varies with breastfeeding, family history of breast cancer, or specific tumor subtype has rarely been evaluated., Objective: To characterize breast cancer risk in relation to recent childbirth., Design: Pooled analysis of individual-level data from 15 prospective cohort studies., Setting: The international Premenopausal Breast Cancer Collaborative Group., Participants: Women younger than 55 years., Measurements: During 9.6 million person-years of follow-up, 18 826 incident cases of breast cancer were diagnosed. Hazard ratios (HRs) and 95% CIs for breast cancer were calculated using Cox proportional hazards regression., Results: Compared with nulliparous women, parous women had an HR for breast cancer that peaked about 5 years after birth (HR, 1.80 [95% CI, 1.63 to 1.99]) before decreasing to 0.77 (CI, 0.67 to 0.88) after 34 years. The association crossed over from positive to negative about 24 years after birth. The overall pattern was driven by estrogen receptor (ER)-positive breast cancer; no crossover was seen for ER-negative cancer. Increases in breast cancer risk after childbirth were pronounced when combined with a family history of breast cancer and were greater for women who were older at first birth or who had more births. Breastfeeding did not modify overall risk patterns., Limitations: Breast cancer diagnoses during pregnancy were not uniformly distinguishable from early postpartum diagnoses. Data on human epidermal growth factor receptor 2 (HER2) oncogene overexpression were limited., Conclusion: Compared with nulliparous women, parous women have an increased risk for breast cancer for more than 20 years after childbirth. Health care providers should consider recent childbirth a risk factor for breast cancer in young women., Primary Funding Source: The Avon Foundation, the National Institute of Environmental Health Sciences, Breast Cancer Now and the UK National Health Service, and the Institute of Cancer Research.

Purpose: The purpose of the study was to investigate the association between pre- or perinatal factors and breast cancer risk among African American women., Methods: Participants in the Black Women's Health Study, a prospective cohort of 59,000 African American women, reported birth weight, preterm birth, twin or triplet status, maternal age at birth, birth order, and having been breastfed during infancy at various times during follow-up from 1997 to 2015. Numbers of incident cases ranged from 312 for breastfed analyses to 1,583 for twin or triplet analyses. Using multivariable Cox proportional hazards regression, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between each factor and breast cancer risk overall and by estrogen receptor (ER) status., Results: Compared to birth weights of 5 lbs. 8 oz.-8 lbs. 13 oz., low (< 5 lbs. 8 oz.) and high (> 8 lbs. 13 oz.) birth weights were associated with increased breast cancer risk; HRs (95% CI) were 1.19 (0.98-1.44) and 1.26 (0.97-1.63), respectively. Associations were similar by ER status. Having been born to a mother aged ≥ 35 years versus < 20 years was associated with risk of ER+ (HR 1.59, 95% CI 1.10-2.29), but not ER- breast cancer. Other perinatal factors were not associated with breast cancer., Conclusion: African American women with a low or high birth weight or born to older mothers may have increased breast cancer risk. Trends towards delayed child birth and higher birth weights, coupled with disproportionately high rates of low birth weight among African Americans, may contribute to increases in breast cancer incidence.

Importance: The association between increasing body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) and risk of breast cancer is unique in cancer epidemiology in that a crossover effect exists, with risk reduction before and risk increase after menopause. The inverse association with premenopausal breast cancer risk is poorly characterized but might be important in the understanding of breast cancer causation., Objective: To investigate the association of BMI with premenopausal breast cancer risk, in particular by age at BMI, attained age, risk factors for breast cancer, and tumor characteristics., Design, Setting, and Participants: This multicenter analysis used pooled individual-level data from 758 592 premenopausal women from 19 prospective cohorts to estimate hazard ratios (HRs) of premenopausal breast cancer in association with BMI from ages 18 through 54 years using Cox proportional hazards regression analysis. Median follow-up was 9.3 years (interquartile range, 4.9-13.5 years) per participant, with 13 082 incident cases of breast cancer. Participants were recruited from January 1, 1963, through December 31, 2013, and data were analyzed from September 1, 2013, through December 31, 2017., Exposures: Body mass index at ages 18 to 24, 25 to 34, 35 to 44, and 45 to 54 years., Main Outcomes and Measures: Invasive or in situ premenopausal breast cancer., Results: Among the 758 592 premenopausal women (median age, 40.6 years; interquartile range, 35.2-45.5 years) included in the analysis, inverse linear associations of BMI with breast cancer risk were found that were stronger for BMI at ages 18 to 24 years (HR per 5 kg/m2 [5.0-U] difference, 0.77; 95% CI, 0.73-0.80) than for BMI at ages 45 to 54 years (HR per 5.0-U difference, 0.88; 95% CI, 0.86-0.91). The inverse associations were observed even among nonoverweight women. There was a 4.2-fold risk gradient between the highest and lowest BMI categories (BMI≥35.0 vs <17.0) at ages 18 to 24 years (HR, 0.24; 95% CI, 0.14-0.40). Hazard ratios did not appreciably vary by attained age or between strata of other breast cancer risk factors. Associations were stronger for estrogen receptor-positive and/or progesterone receptor-positive than for hormone receptor-negative breast cancer for BMI at every age group (eg, for BMI at age 18 to 24 years: HR per 5.0-U difference for estrogen receptor-positive and progesterone receptor-positive tumors, 0.76 [95% CI, 0.70-0.81] vs hormone receptor-negative tumors, 0.85 [95% CI: 0.76-0.95]); BMI at ages 25 to 54 years was not consistently associated with triple-negative or hormone receptor-negative breast cancer overall., Conclusions and Relevance: The results of this study suggest that increased adiposity is associated with a reduced risk of premenopausal breast cancer at a greater magnitude than previously shown and across the entire distribution of BMI. The strongest associations of risk were observed for BMI in early adulthood. Understanding the biological mechanisms underlying these associations could have important preventive potential.

In a prospective cohort study of the health effects associated with prenatal Diethylstilbestrol (DES) exposure, DES was associated with an increased breast cancer risk after 40 years of age. It is unknown whether it is associated with greater mammographic density, which strongly predicts breast cancer risk. A cohort of DES-exposed and unexposed women was assembled at the Mayo Clinic in 1975, and followed through 2012 as part of the National Cancer Institute's DES follow-up study. Mammographic density from 3,637 mammograms for 332 (222 DES-exposed, 110 unexposed) women in this cohort screened at the Mayo Clinic, Rochester between 1996 and 2015 was determined clinically using the Breast Imaging Reporting and Data System (BI-RADS). Any effect of prenatal DES exposure on mammographic density was estimated using repeated measures logistic regression. There was no association between prenatal DES exposure and high mammographic density for either premenopausal [Odds ratios (OR) = 0.92 (95% Confidence Interval (CI): 0.50, 1.7] or postmenopausal women (OR = 0.90; 95% CI: 0.54, 1.5). Among premenopausal women, associations differed by body mass index (BMI), with ORs of 1.47 (0.70, 3.1) for women with BMI above the median and 0.53 (0.23, 1.3) for those with BMI below the median (p interaction  = 0.05). Overall, however, prenatal DES exposure was not associated with high mammographic density in this sample of DES Study participants. Consequently, this study does not provide evidence that high mammographic density is involved with the influence of DES on breast cancer risk., (© 2018 UICC.)

Background: Though mammographic density (MD) has been proposed as an intermediate marker of breast cancer risk, few studies have examined whether the associations between breast cancer risk factors and risk are mediated by MD, particularly by tumor characteristics., Methods: Our study population included 3392 cases (1105 premenopausal) and 8882 (3192 premenopausal) controls from four case-control studies. For established risk factors, we estimated the percent of the total risk factor association with breast cancer that was mediated by percent MD (secondarily, by dense area and non-dense area) for invasive breast cancer as well as for subtypes defined by the estrogen receptor (ER+/ER-), progesterone receptor (PR+/PR-), and HER2 (HER2+/HER2-). Analyses were conducted separately in pre- and postmenopausal women., Results: Positive associations between prior breast biopsy and risk of invasive breast cancer as well as all subtypes were partially mediated by percent MD in pre- and postmenopausal women (percent mediated = 11-27%, p ≤ 0.02). In postmenopausal women, nulliparity and hormone therapy use were positively associated with invasive, ER+ , PR+ , and HER2- breast cancer; percent MD partially mediated these associations (percent mediated ≥ 31%, p ≤ 0.02). Further, among postmenopausal women, percent MD partially mediated the positive association between later age at first birth and invasive as well as ER+ breast cancer (percent mediated = 16%, p ≤ 0.05)., Conclusion: Percent MD partially mediated the associations between breast biopsy, nulliparity, age at first birth, and hormone therapy with risk of breast cancer, particularly among postmenopausal women, suggesting that these risk factors at least partially influence breast cancer risk through changes in breast tissue composition.

Prior research suggests that several endogenous hormones in premenopausal women are associated with breast cancer risk; however, few studies have evaluated associations of endogenous hormones with mammographic density (MD) in premenopausal women. We conducted a cross-sectional study of plasma hormone levels in relation to MD among 634 cancer-free premenopausal women in the Nurses' Health Study II. We measured percent MD from screening mammograms using a computer-assisted method. We assayed estradiol, estrone, and estrone sulfate in blood samples timed in early follicular and mid-luteal phases of the menstrual cycle as well as testosterone, androstenedione, progesterone, dehydroepiandrosterone (DHEA), DHEA sulfate, sex hormone-binding globulin (SHBG), and anti-Müllerian hormone in luteal or untimed samples. We used multivariable linear regression to quantify the association of %MD with quartiles of each hormone, adjusting for age, body mass index, and breast cancer risk factors. Women in the highest quartile of follicular estradiol levels had significantly greater %MD compared to those in the lowest quartile [difference, 6.7 percentage points; 95% confidence interval (CI) 2.2, 11.3; p-trend < 0.001]. Similar associations were observed for follicular free estradiol but not luteal-phase estradiol. Also, women in the top (vs. bottom) quartile of free testosterone had significantly lower %MD (difference, - 4.7; 95% CI - 8.7, - 0.8; p-trend = 0.04). Higher SHBG was significantly associated with higher percent MD (difference, 4.8; 95% CI 1.1, 8.6; p-trend = 0.002). Percent MD was not strongly associated with other measured hormones. Results were similar in analyses that excluded women with anovulatory cycles. Our findings suggest that follicular estradiol and SHBG may play an important role in premenopausal percent MD.

Background: Findings from a recent prospective cohort study in California suggested increased risk of breast cancer associated with higher exposure to certain carcinogenic and estrogen-disrupting hazardous air pollutants (HAPs). However, to date, no nationwide studies have evaluated these possible associations. Our objective was to examine the impacts of mammary carcinogen and estrogen disrupting HAPs on risk of invasive breast cancer in a nationwide cohort., Methods: We assigned HAPs from the US Environmental Protection Agency's 2002 National Air Toxics Assessment to 109,239 members of the nationwide, prospective Nurses' Health Study II (NHSII). Risk of overall invasive, estrogen receptor (ER)-positive (ER+), and ER-negative (ER-) breast cancer with increasing quartiles of exposure were assessed in time-varying multivariable proportional hazards models, adjusted for traditional breast cancer risk factors., Results: A total of 3321 invasive cases occurred (2160 ER+, 558 ER-) during follow-up 1989-2011. Overall, there was no consistent pattern of elevated risk of the HAPs with risk of breast cancer. Suggestive elevations were only seen with increasing 1,2-dibromo-3-chloropropane exposures (multivariable adjusted HR of overall breast cancer = 1.12, 95% CI: 0.98-1.29; ER+ breast cancer HR = 1.09; 95% CI: 0.92, 1.30; ER- breast cancer HR = 1.14; 95% CI: 0.81, 1.61; each in the top exposure quartile compared to the lowest)., Conclusions: Exposures to HAPs during adulthood were not consistently associated with an increased risk of overall or estrogen-receptor subtypes of invasive breast cancer in this nationwide cohort of women.

Purpose: Consumption of alcoholic beverages during adolescence and early adulthood has been consistently associated with higher breast cancer risk. The influence of alcohol consumption early in life on mammographic breast density, a marker of breast cancer risk, is inconclusive. This study examined associations of alcohol consumption across the life course with premenopausal mammographic density., Methods: The study population included 1211 premenopausal women in the Nurses' Health Study II without cancer, who recalled their alcohol consumption at age 15 through enrollment in 1989 (baseline), and had mammograms available. Recent alcohol consumption was updated over follow-up. Percent and absolute measures of mammographic density were quantified on digitized film mammograms. Generalized linear regression was used to assess associations., Results: There were no notable differences in any of the three density measures for alcohol consumption at any age (15-17, 18-22, 23-30, and 31-mammogram). Neither alcohol consumption before first pregnancy nor after first pregnancy was significantly associated with any of the three density measures., Conclusions: Moderate alcohol consumption during different age intervals during adolescence and early adulthood was not associated with mammographic density in premenopausal women.

Adult height has been positively associated with breast cancer risk. The timing of pubertal growth-as measured by age at menarche and age at attained height-may also influence risk. We evaluated associations of adult height, age at attained height, and age at menarche with incidence of invasive breast cancer in 55,687 African American women in the prospective Black Women's Health Study. Over 20 years, 1,826 invasive breast cancers [1,015 estrogen receptor (ER) positive; 542 ER negative] accrued. We used multivariable Cox proportional hazards regression to estimate hazards ratios (HRs) and 95% confidence intervals (CIs) for associations with breast cancer overall and by ER status, mutually adjusted for the three factors of interest. Adult height was associated with increased risk of ER+ breast cancer (HR for ≥70 inches vs ≤63 inches: 1.44; 95% CI: 1.09, 1.89) but not ER- (corresponding HR: 1.16; 95% CI: 0.78, 1.71) (p heterogeneity = 0.34). HRs for attained height before age 13 versus age >17 were 1.30 (95% CI: 0.96, 1.76) for ER+ and 1.25 (95% CI: 0.80, 1.96) for ER- breast cancer. Results for age at menarche (≤11 vs ≥14 years) were similar for ER+ and ER- breast cancer (HR for breast cancer overall: 1.30; 95% CI: 1.12, 1.50). We confirmed height as a strong risk factor for ER+ breast cancer in African American women and identified early age at attained height as a risk factor for both ER+ and ER- breast cancer, albeit without statistical significance of the latter associations. While adult height and timing of pubertal growth are inter-related, our findings suggest that they may be independent risk factors for breast cancer., (© 2017 UICC.)

Background: High mammographic density is a strong, well-established breast cancer risk factor. Three studies conducted in various smaller geographic settings reported inconsistent findings between air pollution and mammographic density. We assessed whether particulate matter (PM) exposures (PM 2.5 , PM 2.5-10 , and PM 10 ) and distance to roadways were associated with mammographic density among women residing across the United States., Methods: The Nurses' Health Studies are prospective cohorts for whom a subset has screening mammograms from the 1990s (interquartile range 1990-1999). PM was estimated using spatio-temporal models linked to residential addresses. Among 3258 women (average age at mammogram 52.7 years), we performed multivariable linear regression to assess associations between square-root-transformed mammographic density and PM within 1 and 3 years before the mammogram. For linear regression estimates of PM in relation to untransformed mammographic density outcomes, bootstrapped robust standard errors are used to calculate 95% confidence intervals (CIs). Analyses were stratified by menopausal status and region of residence., Results: Recent PM and distance to roadways were not associated with mammographic density in premenopausal women (PM 2.5 within 3 years before mammogram β = 0.05, 95% CI -0.16, 0.27; PM 2.5-10 β = 0, 95%, CI -0.15, 0.16; PM 10 β = 0.02, 95% CI -0.10, 0.13) and postmenopausal women (PM 2.5 within 3 years before mammogram β = -0.05, 95% CI -0.27, 0.17; PM 2.5-10 β = -0.01, 95% CI -0.16, 0.14; PM 10 β = -0.02, 95% CI -0.13, 0.09). Largely null associations were observed within regions. Suggestive associations were observed among postmenopausal women in the Northeast (n = 745), where a 10-μg/m 3 increase in PM 2.5 within 3 years before the mammogram was associated with 3.4 percentage points higher percent mammographic density (95% CI -0.5, 7.3)., Conclusions: These findings do not support that recent PM or roadway exposures influence mammographic density. Although PM was largely not associated with mammographic density, we cannot rule out the role of PM during earlier exposure time windows and possible associations among northeastern postmenopausal women.

Background: Radon and its decay products, a source of ionizing radiation, are primarily inhaled and can deliver a radiation dose to breast tissue, where they may continue to decay and emit DNA damage-inducing particles. Few studies have examined the relationship between radon and breast cancer., Methods: The Nurses' Health Study II (NHSII) includes U.S. female registered nurses who completed biennial questionnaires since 1989. Self-reported breast cancer was confirmed from medical records. County-level radon exposures were linked with geocoded residential addresses updated throughout follow-up. Time-varying Cox regression models adjusted for established breast cancer risk factors were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs)., Results: From 1989 to 2013, 3966 invasive breast cancer cases occurred among 112,639 participants. Increasing radon exposure was not associated with breast cancer risk overall (adjusted HR comparing highest to lowest quintile = 1.06, 95% CI: 0.94, 1.21, p for trend = 0.30). However, women in the highest quintile of exposure (≥74.9 Bq/m 3 ) had a suggested elevated risk of ER-/PR- breast cancer compared to women in the lowest quintile (<27.0 Bq/m 3 ) (adjusted HR = 1.38, 95% CI: 0.97, 1.96, p for trend = 0.05). No association was observed for ER+/PR+ breast cancer., Conclusions: Although we did not find an association between radon exposure and risk of overall or ER+/PR+ breast cancer, we observed a suggestive association with risk of ER-/PR- breast cancer.

Breast cancer is a leading cancer diagnosis among premenopausal women around the world. Unlike rates in postmenopausal women, incidence rates of advanced breast cancer have increased in recent decades for premenopausal women. Progress in identifying contributors to breast cancer risk among premenopausal women has been constrained by the limited numbers of premenopausal breast cancer cases in individual studies and resulting low statistical power to subcategorize exposures or to study specific subtypes. The Premenopausal Breast Cancer Collaborative Group was established to facilitate cohort-based analyses of risk factors for premenopausal breast cancer by pooling individual-level data from studies participating in the United States National Cancer Institute Cohort Consortium. This article describes the Group, including the rationale for its initial aims related to pregnancy, obesity, and physical activity. We also describe the 20 cohort studies with data submitted to the Group by June 2016. The infrastructure developed for this work can be leveraged to support additional investigations. Cancer Epidemiol Biomarkers Prev; 26(9); 1360-9. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Purpose: We examined the associations of mammographic breast density with breast cancer risk by tumor aggressiveness and by menopausal status and current postmenopausal hormone therapy., Methods: This study included 2596 invasive breast cancer cases and 4059 controls selected from participants of four nested case-control studies within four established cohorts: the Mayo Mammography Health Study, the Nurses' Health Study, Nurses' Health Study II, and San Francisco Mammography Registry. Percent breast density (PD), absolute dense (DA), and non-dense areas (NDA) were assessed from digitized film-screen mammograms using a computer-assisted threshold technique and standardized across studies. We used polytomous logistic regression to quantify the associations of breast density with breast cancer risk by tumor aggressiveness (defined as presence of at least two of the following tumor characteristics: size ≥2 cm, grade 2/3, ER-negative status, or positive nodes), stratified by menopausal status and current hormone therapy., Results: Overall, the positive association of PD and borderline inverse association of NDA with breast cancer risk was stronger in aggressive vs. non-aggressive tumors (≥51 vs. 11-25% OR 2.50, 95% CI 1.94-3.22 vs. OR 2.03, 95% CI 1.70-2.43, p-heterogeneity = 0.03; NDA 4th vs. 2nd quartile OR 0.54, 95% CI 0.41-0.70 vs. OR 0.71, 95% CI 0.59-0.85, p-heterogeneity = 0.07). However, there were no differences in the association of DA with breast cancer by aggressive status. In the stratified analysis, there was also evidence of a stronger association of PD and NDA with aggressive tumors among postmenopausal women and, in particular, current estrogen+progesterone users (≥51 vs. 11-25% OR 3.24, 95% CI 1.75-6.00 vs. OR 1.93, 95% CI 1.25-2.98, p-heterogeneity = 0.01; NDA 4th vs. 2nd quartile OR 0.43, 95% CI 0.21-0.85 vs. OR 0.56, 95% CI 0.35-0.89, p-heterogeneity = 0.01), even though the interaction was not significant., Conclusion: Our findings suggest that associations of mammographic density with breast cancer risk differ by tumor aggressiveness. While there was no strong evidence that these associations differed by menopausal status or hormone therapy, they did appear more prominent among current estrogen+progesterone users.

Background: Animal and epidemiologic studies suggest that exposure to light at night (LAN) may disrupt circadian patterns and decrease nocturnal secretion of melatonin, which may disturb estrogen regulation, leading to increased breast cancer risk., Objectives: We examined the association between residential outdoor LAN and breast cancer incidence using data from the nationwide U.S.-based Nurses' Health Study II cohort., Methods: We followed 109,672 women from 1989 through 2013. Cumulative LAN exposure was estimated using time-varying satellite data for a composite of persistent nighttime illumination at ∼1 km 2 scale for each residence during follow-up. Incident invasive breast cancer cases were confirmed by medical record review. We used Cox proportional hazard models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for anthropometric, reproductive, lifestyle, and socioeconomic risk factors., Results: Over 2,187,425 person-years, we identified 3,549 incident breast cancer cases. Based on a fully adjusted model, the estimated HR for incident breast cancer with an interquartile range (IQR) (31.6 nW/cm 2 /sr) increase in cumulative average outdoor LAN was 1.05 (95% CI: 1.00, 1.11). An association between LAN and breast cancer appeared to be limited to women who were premenopausal at the time of a case [HR=1.07 (95% CI: 1.01, 1.14) based on 1,973 cases vs. HR=1.00 (95% CI: 0.91, 1.09) based on 1,172 cases in postmenopausal women; p -interaction=0.08]. The LAN-breast cancer association was observed only in past and current smokers at the end of follow-up [HR=1.00 (95% CI: 0.94, 1.07) based on 2,215 cases in never smokers; HR=1.10 (95% CI: 1.01, 1.19) based on 1,034 cases in past smokers vs. HR=1.21 (95% CI: 1.07, 1.37) for 300 cases in current smokers; p -interaction=0.08]., Conclusions: Although further work is required to confirm our results and to clarify potential mechanisms, our findings suggest that exposure to residential outdoor light at night may contribute to invasive breast cancer risk. https://doi.org/10.1289/EHP935.

Background: Given the disproportionately high incidence of early-onset breast cancer and aggressive subtypes, such as estrogen receptor (ER)-negative tumors, in African American (AA) women, elucidation of risk factors for early onset of specific subtypes of breast cancer is needed., Methods: We evaluated associations of reproductive, anthropometric, and other factors with incidence of invasive breast cancer by age at onset (<45, ≥45) in 57,708 AA women in the prospective Black Women's Health Study. From 1995 to 2013, we identified 529 invasive breast cancers among women <45 years of age (151 ER - , 219 ER + ) and 1,534 among women ≥45 years (385 ER - , 804 ER + ). We used multivariable Cox proportional hazards regression to estimate hazard ratios (HRs) for associations by age and ER status., Results: Higher parity, older age at first birth, never having breastfed, and abdominal adiposity were associated with increased risk of early-onset ER - breast cancer: HRs were 1.71 for ≥3 births versus one birth; 2.29 for first birth after age 25 versus <20 years; 0.61 for ever having breastfed versus never; and 1.64 for highest versus lowest tertile of waist-to-hip ratio. These factors were not associated with ER - cancer in older women or with ER + cancer regardless of age., Conclusions: Differences in risk factors by ER subtype were observed for breast cancer diagnosed before the age of 45 years., Impact: Etiological heterogeneity by tumor subtype in early-onset breast cancer, in combination with a higher prevalence of the risk factors in AA women, may explain, in part, racial disparities in breast cancer incidence. Cancer Epidemiol Biomarkers Prev; 26(2); 270-7. ©2016 AACR., Competing Interests: of Potential Conflicts of Interest The authors have no conflicts of interest to disclose., (©2016 American Association for Cancer Research.)

Background: Several studies have shown that mammographic texture features are associated with breast cancer risk independent of the contribution of breast density. Thus, texture features may provide novel information for risk stratification. We examined the association of a set of established texture features with breast cancer risk by tumor type and estrogen receptor (ER) status, accounting for breast density., Methods: This study combines five case-control studies including 1171 breast cancer cases and 1659 controls matched for age, date of mammogram, and study. Mammographic breast density and 46 breast texture features, including first- and second-order features, Fourier transform, and fractal dimension analysis, were evaluated from digitized film-screen mammograms. Logistic regression models evaluated each normalized feature with breast cancer after adjustment for age, body mass index, first-degree family history, percent density, and study., Results: Of the mammographic features analyzed, fractal dimension and second-order statistics features were significantly associated (p < 0.05) with breast cancer. Fractal dimensions for the thresholds equal to 10% and 15% (FD&#95;TH&#95;10 [corrected] and FD&#95;TH&#95;15) [corrected] were associated with an increased risk of breast cancer while thresholds from 60% to 85% (FD&#95;TH&#95;60 to FD&#95;TH&#95;85) [corrected] were associated with a decreased risk. Increasing the FD&#95;TH&#95;75 [corrected] and Energy feature values were associated with a decreased risk of breast cancer while increasing Entropy was associated with an increased [corrected] risk of breast cancer. For example, 1 standard deviation increase of FD&#95;TH&#95;75 [corrected] was associated with a 13% reduced risk of breast cancer (odds ratio = 0.87, 95% confidence interval 0.79-0.95). Overall, the direction of associations between features and ductal carcinoma in situ (DCIS) and invasive cancer, and estrogen receptor positive and negative cancer were similar., Conclusion: Mammographic features derived from film-screen mammograms are associated with breast cancer risk independent of percent mammographic density. Some texture features also demonstrated associations for specific tumor types. For future work, we plan to assess risk prediction combining mammographic density and features assessed on digital images.

Background: High mammographic density (MD) is a strong risk factor for breast cancer. However, it is unclear whether high MD is an intermediate phenotype or whether breast cancer risk factors influence breast cancer risk and MD independently., Methods: Our study population included 1290 invasive breast cancer cases and 3422 controls from the Nurses' Health Studies. We estimated the percent of the total association between the risk factor and breast cancer that was mediated by MD., Results: In both pre- and postmenopausal women, the association between history of biopsy-confirmed benign breast disease and risk was partially mediated by percent MD (percent mediated (PM) = 17 %, p < 0.01 and PM = 33 %, p = 0.04, respectively). In premenopausal women, the associations between early life body size (adolescent somatotype and BMI at age 18) and breast cancer risk were substantially mediated by percent MD (PM = 73 %, p = 0.05 and PM = 82 %, p = 0.04, respectively). In postmenopausal women, the proportion of the associations of childhood somatotype and adolescent somatotype that were mediated by percent MD were lower (PM = 26 %, p = 0.01 for both measures). Hormone therapy use at mammogram was significantly mediated by percent MD in postmenopausal women (PM = 22 %, p < 0.01). Associations with other risk factors, such as age at menarche or family history of breast cancer, were not mediated by percent MD., Conclusions: Percent MD partially mediated some of the associations between risk factors and breast cancer, though the magnitude varied by risk factor and menopausal status. These findings suggest that high MD may be an intermediate in some biological pathways for breast cancer development.

Background: Vitamin D deficiency, which has been linked to an increased risk of colorectal cancer, is particularly common among African Americans. Previous studies of vitamin D status and breast cancer risk, mostly conducted in white women, have had conflicting results. We examined the relationship between predicted vitamin D status and incidence of breast cancer in a cohort of 59,000 African American women., Methods: Participants in the Black Women's Health Study have been followed by biennial mail questionnaires since 1995, with self-reported diagnoses of cancer confirmed by hospital and cancer registry records. Repeated five-fold cross-validation with linear regression was used to derive the best 25-hydroxyvitamin D (25(OH)D) prediction model based on measured 25(OH)D in plasma specimens obtained from 2856 participants in 2013-2015 and questionnaire-based variables from the same time frame. In the full cohort, including 1454 cases of incident invasive breast cancer, Cox proportional hazards models were used to compute the incidence rate ratio (IRR) for each quartile of predicted vitamin D score relative to the highest quartile. Predicted vitamin D score for each two-year exposure period was a cumulative average of predicted scores from all exposure periods up to that time., Results: Twenty-two percent of women with measured 25(OH)D were categorized as "deficient" (<20 ng/mL) and another 25 % as "insufficient" (20-29 ng/mL). The prediction model explained 25 % of variation in measured 25(OH)D and the correlation coefficient for predicted versus observed 25(OH)D averaged across all cross-validation runs was 0.49 (SD 0.026). Breast cancer risk increased with decreasing quartile of predicted 25(OH)D, p for trend 0.015; the IRR for the lowest versus highest quartile was 1.23 (95 % confidence interval 1.04, 1.46)., Conclusions: In prospective data, African American women in the lowest quartile of cumulative predicted 25(OH)D were estimated to have a 23 % increased risk of breast cancer relative to those with relatively high levels. Preventing vitamin D deficiency may be an effective means of reducing breast cancer incidence in African American women.

Background: There is increasing concern that environmental exposures, such as air pollution, may be related to increasing rates of breast cancer; however, results from cohort studies have been mixed. We examined the association between particulate matter (PM) and measures of distance to roadway with the risk of incident breast cancer in the prospective nationwide Nurses' Health Study II (NHSII) cohort., Methods: Incident invasive breast cancer from 1993 to 2011 (N = 3,416) was assessed among 115,921 women in the NHSII cohort. Time-varying Cox proportional hazards models were used to calculate HRs and 95% confidence intervals (95% CI) for increases in ambient exposures to PM10, PM2.5-10, and PM2.5 and residential roadway proximity categories., Results: In multivariable adjusted models, there was little evidence of an increased risk of breast cancer (or any of the receptor-specific subtypes) overall or by menopausal status with PM exposure. There was, however, a suggestion of increased risks among women living <50 m of the largest road type (HR = 1.60; 95% CI, 0.80-3.21) or within <50 m of the two largest road types (1.14; 95% CI, 0.84-1.54) compared with women living farther (≥200 m) away., Conclusions: Among women in the NHSII, we found no statistically significant associations between particulate matter exposures and incidence of breast cancer overall, by menopausal status, or by hormone receptor subtype. There was, however, a suggestion that residential proximity to major roadways may be associated with increased risk., Impact: These results suggest no elevated breast cancer risk with increasing exposures to particulate matter air pollution, but that other traffic-related exposures may be important. Cancer Epidemiol Biomarkers Prev; 25(8); 1274-6. ©2016 AACR., (©2016 American Association for Cancer Research.)

Background: Bone mineral density (BMD) is a putative marker for lifetime exposure to estrogen. Studies that have explored whether BMD is a determinant of mammographic density (MD) have observed inconsistent results. Therefore,we examined this potential association in a sample of women (n = 1,516) from the clinical sub-cohort in the Mexican teachers’ cohort (n = 115,315)., Methods: We used multivariable linear regression to assess the association between quartiles of BMD and percent MD, as well as total dense and non-dense area of the breast, stratified by menopausal status. We also examined the associations by body mass index (BMI) (< 30 kg/m(2), ≥ 30 kg/m(2))., Results: Overall, there was no association between BMD and MD among premenopausal women. However, when we stratified by BMI, there was a modest inverse association between BMD and percent MD (difference between extreme quartiles = -2.8, 95 % CI -5.9, 0.27, p trend = 0.04) among women with BMI < 30 kg/m(2), but a positive association among obese women (comparable difference = 5.1, 95 % CI 0.02, 10.1, p trend = 0.03;p interaction < 0.01). Among postmenopausal women, BMD and percent MD were positively associated after adjustment for BMI (p trend < 0.01). Postmenopausal women in the highest two quartiles of BMD had 4–5 % point higher percent MD compared to women in the lowest quartile. The association did not differ by BMI in postmenopausal women (p interaction = 0.76)., Conclusion: Among obese premenopausal women as well as postmenopausal women, BMD was positively associated with percent MD. Among leaner premenopausal women, BMD and percent MD were modestly inversely associated. These findings support the hypothesis that cumulative exposure to estrogen (as measured by BMD) may influence MD.

Adolescence is hypothesized to be a time period of particular susceptibility to breast cancer risk factors. Red meat and fat intake during high school was positively associated with risk of breast cancer among premenopausal women in the Nurses' Health Study II (NHSII). High mammographic density is a strong predictor of breast cancer risk but there is limited research on dietary factors associated with breast density. To test the hypothesis that high intake of animal fat or red meat during adolescence is associated with mammographic density, we analyzed data from premenopausal women in the NHSII. Participants recalled adolescent diet on a high school food frequency questionnaire. We assessed absolute and percent mammographic density on digitized analog film mammograms for 687 premenopausal women with no history of cancer. We used generalized linear regression to quantify associations of adolescent animal fat and red meat intake with mammographic density, adjusting for age, body mass index, and other predictors of mammographic density. Adolescent animal fat intake was significantly positively associated with premenopausal mammographic density, with a mean percent density of 39.2 % in the lowest quartile of adolescent animal fat intake versus 43.1 % in the highest quartile (p trend: 0.03). A non-significant positive association was also observed for adolescent red meat intake (p trend: 0.14). These findings suggest that higher adolescent animal fat intake is weakly associated with percent mammographic density in premenopausal women.