CD163+ macrophages in the triple-negative breast tumor microenvironment are associated with improved survival in the Women's Circle of Health Study and the Women's Circle of Health Follow-Up Study.

BACKGROUND: Tumor-associated macrophages (TAMs) are a prominent immune subpopulation in the tumor microenvironment that could potentially serve as therapeutic targets for breast cancer. Thus, it is important to characterize this cell population across different tumor subtypes including patterns of association with demographic and prognostic factors, and breast cancer outcomes. METHODS: We investigated CD163+ macrophages in relation to clinicopathologic variables and breast cancer outcomes in the Women's Circle of Health Study and Women's Circle of Health Follow-up Study populations of predominantly Black women with breast cancer. We evaluated 611 invasive breast tumor samples (507 from Black women, 104 from White women) with immunohistochemical staining of tissue microarray slides followed by digital image analysis. Multivariable Cox proportional hazards models were used to estimate hazard ratios for overall survival (OS) and breast cancer-specific survival (BCSS) for 546 cases with available survival data (median follow-up time 9.68 years (IQR: 7.43-12.33). RESULTS: Women with triple-negative breast cancer showed significantly improved OS in relation to increased levels of tumor-infiltrating CD163+ macrophages in age-adjusted (Q3 vs. Q1: HR = 0.36; 95% CI 0.16-0.83) and fully adjusted models (Q3 vs. Q1: HR = 0.30; 95% CI 0.12-0.73). A similar, but non-statistically significant, association was observed for BCSS. Macrophage infiltration in luminal and HER2+ tumors was not associated with OS or BCSS. In a multivariate regression model that adjusted for age, subtype, grade, and tumor size, there was no significant difference in CD163+ macrophage density between Black and White women (RR = 0.88; 95% CI 0.71-1.10). CONCLUSIONS: In contrast to previous studies, we observed that higher densities of CD163+ macrophages are independently associated with improved OS and BCSS in women with invasive triple-negative breast cancer. Trial registration Not applicable.

Comparing patient-reported outcomes and lifestyle factors before and after the COVID-19 pandemic among Black and Hispanic breast cancer survivors in New Jersey.

PURPOSE: The impact of the COVID-19 pandemic restrictions in the US since March 2020 on cancer survivorship among Black and Hispanic breast cancer (BC) survivors remains largely unknown. We aimed to evaluate associations of the pandemic with participant characteristics, patient-reported outcomes (PROs), and lifestyle factors among Black and Hispanic BC survivors in the Women's Circle of Health Follow-Up Study and the New Jersey BC Survivors Study. METHODS: We included 447 Black (npre = 364 and npost = 83) and 182 Hispanic (npre = 102 and npost = 80) BC survivors who completed a home interview approximately 24 months post-diagnosis between 2017 and 2023. The onset of the pandemic was defined as March 2020. The association of the pandemic with binary outcomes was estimated using robust Poisson regression models. RESULTS: Hispanic and Black BC survivors recruited after the onset of the pandemic reported higher socioeconomic status and fewer comorbidities. Black women in the post-pandemic group reported a higher prevalence of clinically significant sleep disturbance (prevalence ratio (PR) 1.43, 95% CI 1.23, 1.68), lower sleep efficiency, and lower functional well-being, compared to the pre-pandemic group. Hispanic women were less likely to report low health-related quality of life (vs. high; PR 0.62, 95% CI 0.45, 0.85) after the onset of the pandemic. CONCLUSIONS: Ongoing research is crucial to untangle the impact of the pandemic on racial and ethnic minorities participating in cancer survivorship research, as well as PROs and lifestyle factors. IMPLICATIONS FOR CANCER SURVIVORS: This study highlights the importance of considering the impact of the pandemic in all aspects of research, including the interpretation of findings.

Neighborhood Disadvantage, African Genetic Ancestry, Cancer Subtype, and Mortality Among Breast Cancer Survivors.

Importance: Racial disparities in breast cancer (BC) survival arise from multilevel causes, which may exert influence at different stages of BC progression. Clarifying the importance of genetic and social factors could help prioritize interventions. Objective: To jointly examine associations between African genetic ancestry, social environment, and mortality from any cause and BC in Black BC survivors. Design, Setting, and Participants: This population-based cohort study enrolled self-identified Black women aged 20 to 75 years with histologically confirmed BC from June 2005 to May 2019 and followed them up until death or censoring in September 2021. Participants lived in 10 New Jersey counties. Data were analyzed between December 2022 and April 2023. Exposures: A neighborhood socioeconomic status (nSES) index composed of census tract measures (education, income, wealth, employment status, and occupation) was linked to residential addresses at diagnosis. Percentage African ancestry was estimated using the ADMIXTURE program. Main Outcomes and Measures: Sequentially adjusted (age adjusted: age and interview year; fully adjusted: age adjusted with individual SES, lifestyle factors, and comorbidities) logistic regression models were fit to estimate associations with tumor subtypes (estrogen receptor-negative [ER-] vs estrogen receptor-positive [ER+]; triple-negative breast cancer [TNBC] vs luminal A), and Cox models were fit for associations with all-cause mortality (ACM) and breast cancer-specific mortality (BCSM). Models for BCSM were fit using Fine-Gray competing risks models, and robust standard errors were used to account for census tract-level clustering. Results: Among 1575 participants, median (IQR) African ancestry was 85% (76%-90%), and median (IQR) age was 55 (46-63) years. A 10-percentage point increase in African ancestry was associated with higher odds of ER- vs ER+ (adjusted odds ratio [aOR], 1.08; 95% CI, 0.98-1.18) and TNBC vs luminal (aOR, 1.15; 95% CI, 1.02-1.31) tumors, but not with ACM or BCSM. A 1-IQR increase in nSES was associated with lower ACM (adjusted hazard ratio [aHR], 0.76; 95% CI, 0.63-0.93), and the HR for BCSM was less than 1 but not statistically significant (aHR, 0.81; 95% CI, 0.62-1.04) in age-adjusted models, but associations attenuated following further adjustment for potential mediators (individual SES, lifestyles, comorbidities). Conclusions and Relevance: In this cohort study of Black female BC survivors, higher African ancestry was associated with aggressive tumor subtypes. Compared with genetic ancestry, mediating pathways related to social environments may be more important for survival in these patients.

A framework for assessing interactions for risk stratification models: the example of ovarian cancer.

Generally, risk stratification models for cancer use effect estimates from risk/protective factor analyses that have not assessed potential interactions between these exposures. We have developed a 4-criterion framework for assessing interactions that includes statistical, qualitative, biological, and practical approaches. We present the application of this framework in an ovarian cancer setting because this is an important step in developing more accurate risk stratification models. Using data from 9 case-control studies in the Ovarian Cancer Association Consortium, we conducted a comprehensive analysis of interactions among 15 unequivocal risk and protective factors for ovarian cancer (including 14 non-genetic factors and a 36-variant polygenic score) with age and menopausal status. Pairwise interactions between the risk/protective factors were also assessed. We found that menopausal status modifies the association among endometriosis, first-degree family history of ovarian cancer, breastfeeding, and depot-medroxyprogesterone acetate use and disease risk, highlighting the importance of understanding multiplicative interactions when developing risk prediction models.

Sociodemographic and Health Correlates of Multiple Health Behavior Adherence among Cancer Survivors: A Latent Class Analysis.

The study aimed to (a) assess current levels of adherence to the National Comprehensive Cancer Network's multiple health behavior guidelines and (b) identify characteristics of cancer survivors associated with different adherence levels. Cancer survivors (N = 661) were identified through the state registry and completed questionnaires. Latent class analysis (LCA) was used to identify patterns of adherence. Associations between predictors with the latent classes were reported as risk ratios. LCA identified three classes: lower- (39.6%), moderate- (52.0%), and high-risk lifestyle (8.3%). Participants in the lower-risk lifestyle class had the highest probability of meeting most of the multiple health behavior guidelines compared to participants in the high-risk lifestyle class. Characteristics associated with membership in the moderate-risk lifestyle class included self-identifying as a race other than Asian/Asian American, being never married, having some college education, and having been diagnosed with later stage colorectal or lung cancer. Those in the high-risk lifestyle class were more likely to be male, never married, have a high school diploma or less, diagnosed with colorectal or lung cancer, and diagnosed with pulmonary comorbidities. Study findings can be used to inform development of future interventions to promote multiple health behavior adherence among higher risk cancer survivors.

Association of Cigarette Smoking and Alcohol Consumption With Subsequent Mortality Among Black Breast Cancer Survivors in New Jersey.

Importance: There are limited data about how lifestyle factors are associated with breast cancer prognosis among Black or African American women because most of the evidence is based on studies of White breast cancer survivors. Objective: To examine the association of prediagnostic cigarette smoking and alcohol consumption with all-cause mortality and breast cancer-specific mortality in a cohort of Black breast cancer survivors. Design, Setting, and Participants: This population-based cohort study included 1926 Black or African American breast cancer survivors who received a diagnosis from June 6, 2005, to May 21, 2019, identified in 10 counties in New Jersey through rapid case ascertainment by the New Jersey State Cancer Registry. Statistical analysis was conducted from January 1, 2021, to August 1, 2022. Exposures: Information on prediagnostic cigarette smoking, alcohol consumption, and additional covariates was collected during in-person interviews. The covariates examined included smoking status at the time of breast cancer diagnosis (currently smoking at the time of breast cancer diagnosis, formerly smoking, or never smoking), smoking duration (number of years smoking), smoking intensity (cigarettes smoked per day), number of pack-years of smoking, and regular alcohol consumption the year before diagnosis (categorized as nondrinkers, ≤3 drinks per week, or >3 drinks per week). Main Outcomes and Measures: Primary outcomes included breast cancer-specific mortality and all-cause mortality. Results: Among the 1926 women in the study, the mean (SD) age at breast cancer diagnosis was 54.4 (10.8) years. During 13 464 person-years of follow-up (median follow-up, 6.7 years [range, 0.5-16.0 years]), there were 337 deaths, of which 187 (55.5%) were breast cancer related. Compared with never smokers, current smokers at the time of breast cancer diagnosis had a 52% increased risk for all-cause mortality (hazard ratio [HR], 1.52; 95% CI, 1.15-2.02), which was most pronounced for those with 10 or more pack-years of smoking (HR, 1.84; 95% CI, 1.34-2.53). Similar findings were observed for breast cancer-specific mortality (current smokers vs never smokers: HR, 1.27; 95% CI, 0.87-1.85), although they were not statistically significant. There was no statistically significant association between alcohol consumption and all-cause mortality (>3 drinks per week vs nondrinkers: HR, 1.05; 95% CI, 0.73-1.51) or breast cancer-specific mortality (>3 drinks per week vs nondrinkers: HR, 1.06; 95% CI, 0.67-1.67). Conclusions and Relevance: This population-based cohort study of Black breast cancer survivors suggests that current smoking at the time of diagnosis was associated with an increased risk of all-cause mortality, particularly among women with greater pack-years of smoking.

Spirituality and financial toxicity among Hispanic breast cancer survivors in New Jersey.

OBJECTIVE: Cancer survivors often incur significant out-of-pocket costs; this can result in financial toxicity, defined as the adverse financial impact of cancer due to direct or indirect costs related to the disease. There has been little research on whether spirituality is associated with the experience of financial toxicity. In this study, we tested the hypothesis that spirituality would be inversely associated with financial toxicity. METHODS: We evaluated these associations in a cross-sectional study of Hispanic breast cancer survivors (n = 102) identified through the New Jersey State Cancer Registry. Participants completed the FACIT-Sp-12, which has two spirituality subscales (meaning/peace; faith). Financial toxicity was assessed using the 11-item COST measure; lower scores suggest worse toxicity. In multivariable linear regression analyses, we examined the associations between spirituality scores and financial toxicity, adjusting for age, race, education, household income, and insurance status. RESULTS: The spirituality total score (ß = 0.49, 95% confidence interval (CI): 0.17, 0.8), meaning/peace subscale score (ß = 0.71, 95% CI: 0.12, 1.31), and faith (ß = 0.71, 95% CI: 0.2, 1.21) subscale score were all inversely associated with financial toxicity. CONCLUSIONS: Spirituality may be an important factor in ameliorating the detrimental effects of financial toxicity among Hispanic breast cancer survivors and should be considered in interventions for financial toxicity in this population.

Cancer Education Interventions in Adolescents: A Systematic Review of Scope and Content.

Given the long induction time of many cancers and the fact that modifiable risk factors (e.g., cigarette smoking) including preventive factors (e.g., human papillomavirus [HPV] vaccination, healthy dietary and physical activity patterns) are influenced in adolescence, educating adolescents about cancer causation and risk reduction may have a large impact on reducing the cancer burden. We conducted a systematic review of literature evaluating the impact of cancer education interventions on adolescent knowledge of cancer risk reduction. We searched for articles published from 2000 to 2019 and identified 33 studies meeting our criteria. Given the methodological heterogeneity across studies, we briefly assessed effectiveness but focused on examining the design of the intervention and study. The majority of studies took place outside of the United States (67%). Most studies solely addressed skin or cervical cancer (67%) with only 18% (n = 6) discussing multiple cancers. The majority of interventions were a single-session (55%), did not involve a control or comparison group (67%), and were evaluated using a pre-test and a single post-test (61%); some studies administered multiple post-tests. Few studies (12%) investigated adolescents' knowledge of lifestyle and environmental risk factors at both the individual and community level. Most studies (94%) reported improvement in knowledge following an intervention. Our review revealed wide methodological variation and a deficit in research evaluating interventions that address multiple cancer types and risk factors. Future research should robustly test whether comprehensive cancer education for adolescents can reduce the cancer burden, particularly in communities with major cancer health disparities.

Multilevel Factors for Adiposity Change in a Population-Based Prospective Study of Black Breast Cancer Survivors.

PURPOSE: Unfavorable weight change after breast cancer diagnosis increases the risk of mortality, but individual and neighborhood risk factors affecting postdiagnosis weight and body fat changes are unclear among Black women, who have higher rates of obesity and mortality than any other racial/ethnic group. METHODS: Adiposity changes during the period approximately 10 months-24 months after diagnosis were evaluated among 785 women diagnosed between 2012 and 2018 and enrolled in the Women's Circle of Health Follow-Up Study, a population-based prospective cohort of Black breast cancer survivors in New Jersey. Multilevel factors for weight and fat mass change (with gain or loss defined as a relative difference of 3% or more, and considering whether changes were intentional or unintentional) were estimated using multivariable polytomous logistic regressions and multilevel models. RESULTS: Adiposity gain was prevalent: 28% and 47% gained weight and body fat, respectively, despite a high baseline prevalence of overweight or obesity (86%). Risk factors for fat mass gain included receiving chemotherapy (relative risk ratio: 1.59, 95% CI, 1.08 to 2.33) and residing in neighborhoods with a greater density of fast-food restaurants (relative risk ratio comparing highest with lowest tertile: 2.18, 95% CI, 1.38 to 3.46); findings were similar for weight gain. Only 9% of women had intentional weight loss, and multilevel risk factors differed vastly from unintentional loss. CONCLUSION: Both individual and neighborhood factors were associated with adiposity change among Black breast cancer survivors. Residential environment characteristics may offer clinically meaningful information to identify cancer survivors at higher risk for unfavorable weight change and to address barriers to postdiagnosis weight management.

Cancer Risk Reduction Through Education of Adolescents: Development of a Tailored Cancer Risk-Reduction Educational Tool.

Growing evidence links adolescent exposures to cancer risk later in life, particularly for common cancers like breast. The adolescent time period is also important for cancer risk reduction as many individual lifestyle behaviors are initiated including smoking and alcohol use. We developed a cancer risk-reduction educational tool tailored for adolescents that focused on five modifiable cancer risk factors. To contextualize risk factors in adolescents' social and physical environments, the intervention also focused on structural barriers to individual- and community-level change, with an emphasis on environmental justice or the fair treatment and meaningful involvement of all people regardless of race, color, national origin, or income with respect to the development, implementation, and enforcement of environmental laws, regulations, and policies. The educational tool consisted of a 50-min module that included an introduction to cancer biology including genetic susceptibility and environmental interactions, cancer burden in the local community, and risk reduction strategies. The module also included an interactive activity in which adolescent students identify cancer risk factors and brainstorm strategies for risk reduction at both the individual and community level. We administered the module to 12 classes of over 280 high school and college students in New York City. Cancer risk reduction strategies identified by the students included family- or peer-level strategies such as team physical activity and community-level action including improving parks and taxing sugary foods. We developed a novel and interactive cancer risk-reduction education tool focused on multiple cancers that can be adopted by other communities and educational institutions.

Recreational Physical Activity and Outcomes After Breast Cancer in Women at High Familial Risk.

Background: Recreational physical activity (RPA) is associated with improved survival after breast cancer (BC) in average-risk women, but evidence is limited for women who are at increased familial risk because of a BC family history or BRCA1 and BRCA2 pathogenic variants (BRCA1/2 PVs). Methods: We estimated associations of RPA (self-reported average hours per week within 3 years of BC diagnosis) with all-cause mortality and second BC events (recurrence or new primary) after first invasive BC in women in the Prospective Family Study Cohort (n = 4610, diagnosed 1993-2011, aged 22-79 years at diagnosis). We fitted Cox proportional hazards regression models adjusted for age at diagnosis, demographics, and lifestyle factors. We tested for multiplicative interactions (Wald test statistic for cross-product terms) and additive interactions (relative excess risk due to interaction) by age at diagnosis, body mass index, estrogen receptor status, stage at diagnosis, BRCA1/2 PVs, and familial risk score estimated from multigenerational pedigree data. Statistical tests were 2-sided. Results: We observed 1212 deaths and 473 second BC events over a median follow-up from study enrollment of 11.0 and 10.5 years, respectively. After adjusting for covariates, RPA (any vs none) was associated with lower all-cause mortality of 16.1% (95% confidence interval [CI] = 2.4% to 27.9%) overall, 11.8% (95% CI = -3.6% to 24.9%) in women without BRCA1/2 PVs, and 47.5% (95% CI = 17.4% to 66.6%) in women with BRCA1/2 PVs (RPA*BRCA1/2 multiplicative interaction P = .005; relative excess risk due to interaction = 0.87, 95% CI = 0.01 to 1.74). RPA was not associated with risk of second BC events. Conclusion: Findings support that RPA is associated with lower all-cause mortality in women with BC, particularly in women with BRCA1/2 PVs.

Generalizability of Polygenic Risk Scores for Breast Cancer Among Women With European, African, and Latinx Ancestry.

Importance: Multiple polygenic risk scores (PRSs) for breast cancer have been developed from large research consortia; however, their generalizability to diverse clinical settings is unknown. Objective: To examine the performance of previously developed breast cancer PRSs in a clinical setting for women of European, African, and Latinx ancestry. Design, Setting, and Participants: This cohort study using the Electronic Medical Records and Genomics (eMERGE) network data set included 39 591 women from 9 contributing medical centers in the US that had electronic medical records (EMR) linked to genotype data. Breast cancer cases and controls were identified through a validated EMR phenotyping algorithm. Main Outcomes and Measures: Multivariable logistic regression was used to assess the association between breast cancer risk and 7 previously developed PRSs, adjusting for age, study site, breast cancer family history, and first 3 ancestry informative principal components. Results: This study included 39 591 women: 33 594 with European, 3801 with African, and 2196 with Latinx ancestry. The mean (SD) age at breast cancer diagnosis was 60.7 (13.0), 58.8 (12.5), and 60.1 (13.0) years for women with European, African, and Latinx ancestry, respectively. PRSs derived from women with European ancestry were associated with breast cancer risk in women with European ancestry (highest odds ratio [OR] per 1-SD increase, 1.46; 95% CI, 1.41-1.51), women with Latinx ancestry (highest OR, 1.31; 95% CI, 1.09-1.58), and women with African ancestry (OR, 1.19; 95% CI, 1.05-1.35). For women with European ancestry, this association with breast cancer risk was largest in the extremes of the PRS distribution, with ORs ranging from 2.19 (95% CI, 1.84-2.53) to 2.48 (95% CI, 1.89-3.25) for the 3 different PRSs examined for those in the highest 1% of the PRS compared with those in the middle quantile. Among women with Latinx and African ancestries at the extremes of the PRS distribution, there were no statistically significant associations. Conclusions and Relevance: This cohort study found that PRS models derived from women with European ancestry for breast cancer risk generalized well for women with European, Latinx, and African ancestries across different clinical settings, although the effect sizes for women with African ancestry were smaller, likely because of differences in risk allele frequencies and linkage disequilibrium patterns. These results highlight the need to improve representation of diverse population groups, particularly women with African ancestry, in genomic research cohorts.

Association of Body Mass Index, Central Obesity, and Body Composition With Mortality Among Black Breast Cancer Survivors.

IMPORTANCE: Obesity disproportionately affects Black women, who also have a higher risk of death after a breast cancer diagnosis compared with women of other racial/ethnic groups. However, few studies have evaluated the association of measures of adiposity with mortality among Black breast cancer survivors. OBJECTIVE: To assess the association of measures of adiposity with survival after a breast cancer diagnosis among Black women. DESIGN, SETTING, AND PARTICIPANTS: This prospective population-based cohort study comprised 1891 women with stage 0 to IV breast cancer who self-identified as African American or Black and were ages 20 to 75 years. The New Jersey State Cancer Registry was used to identify women living in 10 counties in New Jersey who were recruited from March 1, 2006, to February 29, 2020, and followed up until September 2, 2020. EXPOSURES: Measures of adiposity, including body mass index, body fat distribution (waist circumference and waist-to-hip ratio), and body composition (percent body fat and fat mass index), were collected during in-person interviews at approximately 10 months after breast cancer diagnosis. MAIN OUTCOMES AND MEASURES: All-cause and breast cancer-specific mortality. RESULTS: Among 1891 women, the mean (SD) age at breast cancer diagnosis was 54.5 (10.8) years. During a median follow-up of 5.9 years (range, 0.5-14.8 years), 286 deaths were identified; of those, 175 deaths (61.2%) were associated with breast cancer. A total of 1060 women (56.1%) had obesity, and 1291 women (68.3%) had central obesity. Higher adiposity, particularly higher waist-to-hip ratio, was associated with worse survival. Women in the highest quartile of waist-to-hip ratio had a 61% increased risk of dying from any cause (hazard ratio [HR], 1.61; 95% CI, 1.12-2.33) and a 68% increased risk of breast cancer death (HR, 1.68; 95% CI, 1.04-2.71) compared with women in the lowest quartile. The risks of all-cause and breast cancer-specific death were similarly high among women in the highest quartile for waist circumference (HR, 1.74 [95% CI, 1.26-2.41] and 1.64 [95% CI, 1.08-2.48], respectively), percent body fat (HR, 1.53 [95% CI, 1.09-2.15] and 1.81 [95% CI, 1.17-2.80]), and fat mass index (HR, 1.57 [95% CI, 1.11-2.22] and 1.74 [95% CI, 1.10-2.75]); however, the risk was less substantial for body mass index (HR, 1.26 [95% CI, 0.89-1.79] and 1.33 [95% CI, 0.84-2.10]). In analyses stratified by estrogen receptor status, menopausal status, and age, a higher waist-to-hip ratio was associated with a higher risk of all-cause death among women who had estrogen receptor-negative tumors (HR, 2.24; 95% CI, 1.14-4.41), women who were postmenopausal (HR, 2.15; 95% CI, 1.28-3.61), and women who were 60 years or older at diagnosis (HR per 0.10-U increase, 1.76; 95% CI, 1.37-2.26). CONCLUSIONS AND RELEVANCE: In this population-based cohort study, central obesity and higher adiposity were associated with higher all-cause and breast cancer-specific mortality among Black breast cancer survivors. Simple measures of body fat distribution and body composition were found to be useful tools for identifying Black women with a higher risk of death after a breast cancer diagnosis.

Cases in Precision Medicine: The Role of Polygenic Risk Scores in Breast Cancer Risk Assessment.

Polygenic risk scores (PRSs) have been consistently associated with elevated breast cancer risk in cohort studies and are associated with risk in both women with and those without a family history of breast cancer. However, before clinical implementation, several issues must be addressed, including understanding the potential clinical utility and optimal method to communicate personalized screening recommendations that incorporate the PRS. Several trials are under way to answer some of these questions and facilitate clinical implementation. Because these PRSs have been developed in women of European ancestry, it is important to understand the limitations of their predictive ability in other ancestral groups. Finally, the value of the PRS will lie in considering it along with other clinical, familial, and rare genetic factors that are currently used in personalized risk assessment of breast cancer.

Associations of prenatal exposure to polycyclic aromatic hydrocarbons with pubertal timing and body composition in adolescent girls: Implications for breast cancer risk.

BACKGROUND: While animal data support an association between prenatal exposure to endocrine disrupting chemicals (EDCs) and altered mammary gland development and tumorigenesis, epidemiologic studies have only considered a few classes of EDCs in association with pubertal growth and development in girls. Polycyclic aromatic hydrocarbons (PAH) are a class of EDCs that have not been rigorously evaluated in terms of prenatal exposure and pubertal growth and development in girls. OBJECTIVE: In a New York City birth cohort of Black and Hispanic girls (n = 196; recruited 1998-2006), we examined associations of prenatal PAH exposure with self-reported age at growth spurt onset, breast development onset and menarche, and clinical measures of adolescent body composition including body mass index, waist-to-hip ratio, and body fat measured at ages 11-20 years. METHODS: We measured prenatal exposure to PAH using personal air monitoring data collected from backpacks worn by mothers during the third trimester of pregnancy (data available for all 196 girls) and biomarkers of benzo[α]pyrene-DNA adducts in umbilical cord blood (data available for 106 girls). We examined associations of prenatal PAH with the timing of pubertal milestones and adolescent body composition (11-20 years) using multivariable linear regression models adjusted for race/ethnicity, household public assistance status at birth, and age at outcome assessment. We also fit models further adjusted for potential mediators, including birthweight and childhood body size (BMI-for-age z-score measured at 6-8 years). RESULTS: Girls in the highest versus lowest tertile of ambient exposure to PAH, based on a summary measure of eight carcinogenic higher-molecular weight non-volatile PAH compounds (Σ8 PAH), had a 0.90 year delay in growth spurt onset (95% confidence interval (CI) = 0.25, 1.55; n = 196), a 0.35 year delay in breast development onset (95% CI = -0.26, 0.95; n = 193), and a 0.59 year delay in menarche (95% CI = 0.06, 1.11; n = 191) in models adjusted for race/ethnicity and household public assistance at birth. The statistically significant associations for age at growth spurt onset and menarche were not impacted by adjustment for birthweight or childhood body size. No differences in BMI-for-age z-score, waist-to-hip ratio, or percent body fat were found between girls in the highest versus lowest tertile of ambient Σ8 PAH. Results were similar when we evaluated benzo[α]pyrene-DNA adduct levels. DISCUSSION: Our results suggest that prenatal exposure to PAH might delay pubertal milestones in girls, but findings need to be replicated in other cohorts using prospectively collected data on pubertal outcomes.

Comparing 5-Year and Lifetime Risks of Breast Cancer using the Prospective Family Study Cohort.

BACKGROUND: Clinical guidelines often use predicted lifetime risk from birth to define criteria for making decisions regarding breast cancer screening rather than thresholds based on absolute 5-year risk from current age. METHODS: We used the Prospective Family Cohort Study of 14 657 women without breast cancer at baseline in which, during a median follow-up of 10 years, 482 women were diagnosed with invasive breast cancer. We examined the performances of the International Breast Cancer Intervention Study (IBIS) and Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) risk models when using the alternative thresholds by comparing predictions based on 5-year risk with those based on lifetime risk from birth and remaining lifetime risk. All statistical tests were 2-sided. RESULTS: Using IBIS, the areas under the receiver-operating characteristic curves were 0.66 (95% confidence interval = 0.63 to 0.68) and 0.56 (95% confidence interval = 0.54 to 0.59) for 5-year and lifetime risks, respectively (Pdiff < .001). For equivalent sensitivities, the 5-year incidence almost always had higher specificities than lifetime risk from birth. For women aged 20-39 years, 5-year risk performed better than lifetime risk from birth. For women aged 40 years or older, receiver-operating characteristic curves were similar for 5-year and lifetime IBIS risk from birth. Classifications based on remaining lifetime risk were inferior to 5-year risk estimates. Results were similar using BOADICEA. CONCLUSIONS: Our analysis shows that risk stratification using clinical models will likely be more accurate when based on predicted 5-year risk compared with risks based on predicted lifetime and remaining lifetime, particularly for women aged 20-39 years.

Integrative genomic analysis implicates ERCC6 and its interaction with ERCC8 in susceptibility to breast cancer.

Up to 30% of all breast cancer cases may be inherited and up to 85% of those may be due to segregation of susceptibility genes with low and moderate risk [odds ratios (OR) ≤ 3] for (mostly peri- and post-menopausal) breast cancer. The majority of low/moderate-risk genes, particularly those with minor allele frequencies (MAF) of < 30%, have not been identified and/or validated due to limitations of conventional association testing approaches, which include the agnostic nature of Genome Wide Association Studies (GWAS). To overcome these limitations, we used a hypothesis-driven integrative genomics approach to test the association of breast cancer with candidate genes by analyzing multi-omics data. Our candidate-gene association analyses of GWAS datasets suggested an increased risk of breast cancer with ERCC6 (main effect: 1.29 ≤ OR ≤ 2.91, 0.005 ≤ p ≤ 0.04, 11.8 ≤ MAF ≤ 40.9%), and implicated its interaction with ERCC8 (joint effect: 3.03 ≤ OR ≤ 5.31, 0.01 ≤ pinteraction ≤ 0.03). We found significant upregulation of ERCC6 (p = 7.95 × 10-6) and ERCC8 (p = 4.67 × 10-6) in breast cancer and similar frequencies of ERCC6 (1.8%) and ERCC8 (0.3%) mutations in breast tumors to known breast cancer susceptibility genes such as BLM (1.9%) and LSP1 (0.3%). Our integrative genomics approach suggests that ERCC6 may be a previously unreported low- to moderate-risk breast cancer susceptibility gene, which may also interact with ERCC8.

Environmental exposures and breast cancer risk in the context of underlying susceptibility: A systematic review of the epidemiological literature.

BACKGROUND: The evidence evaluating environmental chemical exposures (ECE) and breast cancer (BC) risk is heterogeneous which may stem in part as few studies measure ECE during key BC windows of susceptibility (WOS). Another possibility may be that most BC studies are skewed towards individuals at average risk, which may limit the ability to detect signals from ECE. OBJECTIVES: We reviewed the literature on ECE and BC focusing on three types of studies or subgroup analyses based on higher absolute BC risk: BC family history (Type 1); early onset BC (Type 2); and/or genetic susceptibility (Type 3). METHODS: We systematically searched the PubMed database to identify epidemiologic studies examining ECE and BC risk published through June 1, 2019. RESULTS: We identified 100 publications in 56 unique epidemiologic studies. Of these 56 studies, only 2 (3.6%) were enriched with BC family history and only 11% of studies (6/56) were specifically enriched with early onset cases. 80% of the publications from these 8 enriched studies (Type 1: 8/10 publications; Type 2: 8/10 publications) supported a statistically significant association between ECE and BC risk including studies of PAH, indoor cooking, NO2, DDT; PCBs, PFOSA; metals; personal care products; and occupational exposure to industrial dyes. 74% of Type 3 publications (20/27) supported statistically significant associations for PAHs, traffic-related air pollution, PCBs, phthalates, and PFOSAs in subgroups of women with greater genetic susceptibility due to variants in carcinogen metabolism, DNA repair, oxidative stress, cellular apoptosis and tumor suppressor genes. DISCUSSION: Studies enriched for women at higher BC risk through family history, younger age of onset and/or genetic susceptibility consistently support an association between an ECE and BC risk. In addition to measuring exposures during WOS, designing studies that are enriched with women at higher absolute risk are necessary to robustly measure the role of ECE on BC risk.

Considerations When Using Breast Cancer Risk Models for Women with Negative BRCA1/BRCA2 Mutation Results.

The performance of breast cancer risk models for women with a family history but negative BRCA1 and/or BRCA2 mutation test results is uncertain. We calculated the cumulative 10-year invasive breast cancer risk at cohort entry for 14 657 unaffected women (96.1% had an affected relative) not known to carry BRCA1 or BRCA2 mutations at baseline using three pedigree-based models (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm, BRCAPRO, and International Breast Cancer Intervention Study). During follow-up, 482 women were diagnosed with invasive breast cancer. Mutation testing was conducted independent of incident cancers. All models underpredicted risk by 26.3%-56.7% for women who tested negative but whose relatives had not been tested (n = 1363; 63 breast cancers). Although replication studies with larger sample sizes are needed, until these models are recalibrated for women who test negative and have no relatives tested, caution should be used when considering changing the breast cancer risk management intensity of such women based on risk estimates from these models.