Second primary cancer risks according to race and ethnicity among U.S. breast cancer survivors.

Breast cancer survivors have an increased risk of developing second primary cancers, yet risks by race and ethnicity have not been comprehensively described. We evaluated second primary cancer risks among 717,335 women diagnosed with first primary breast cancer (aged 20-84 years and survived ≥1-year) in the SEER registries using standardized incidence ratios (SIRs; observed/expected). SIRs were estimated by race and ethnicity compared with the racial- and ethnic-matched general population, and further stratified by clinical characteristics of the index breast cancer. Poisson regression was used to test for heterogeneity by race and ethnicity. SIRs for second primary cancer differed by race and ethnicity with the highest risks observed among non-Hispanic/Latina Asian American, Native Hawaiian, or other Pacific Islander (AANHPI), non-Hispanic/Latina Black (Black), and Hispanic/Latina (Latina) survivors and attenuated risk among non-Hispanic/Latina White (White) survivors (SIRAANHPI = 1.49, 95% CI = 1.44-1.54; SIRBlack = 1.41, 95% CI = 1.37-1.45; SIRLatina = 1.45, 95% CI = 1.41-1.49; SIRWhite = 1.09, 95% CI = 1.08-1.10; p-heterogeneity<.001). SIRs were particularly elevated among AANHPI, Black, and Latina survivors diagnosed with an index breast cancer before age 50 (SIRs range = 1.88-2.19) or with estrogen receptor-negative tumors (SIRs range = 1.60-1.94). Heterogeneity by race and ethnicity was observed for 16/27 site-specific second cancers (all p-heterogeneity's < .05) with markedly elevated risks among AANHPI, Black, and Latina survivors for acute myeloid and acute non-lymphocytic leukemia (SIRs range = 2.68-3.15) and cancers of the contralateral breast (SIRs range = 2.60-3.01) and salivary gland (SIRs range = 2.03-3.96). We observed striking racial and ethnic differences in second cancer risk among breast cancer survivors. Additional research is needed to inform targeted approaches for early detection strategies and treatment to reduce these racial and ethnic disparities.

Racial disparities in initiation of chemotherapy among breast cancer patients with discretionary treatment indication in the state of Georgia.

PURPOSE: The majority of breast cancer patients are diagnosed with early-stage estrogen receptor (ER) positive disease. Despite effective treatments for these cancers, Black women have higher mortality than White women. We investigated demographic and clinical factors associated with receipt of chemotherapy among those with a discretionary indication who are at risk for overtreatment. METHODS: Using Georgia Cancer Registry data, we identified females diagnosed with ER positive breast cancer who had a discretionary indication for chemotherapy (2010-2017). We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) associating patient demographic and clinical characteristics with chemotherapy initiation overall, and comparing non-Hispanic Black (NHB) with non-Hispanic White (NHW) women within strata of patient factors. RESULTS: We identified 11,993 ER positive breast cancer patients with a discretionary indication for chemotherapy. NHB patients were more likely to initiate chemotherapy compared with NHW women (OR = 1.41, 95% CI: 1.28, 1.56). Race differences in chemotherapy initiation were pronounced among those who did not receive Oncotype DX testing (OR = 1.47, 95% CI: 1.31, 1.65) and among those residing in high socioeconomic status neighborhoods (OR = 2.48, 95% CI: 1.70, 3.61). However, we observed equitable chemotherapy receipt among patients who received Oncotype DX testing (OR = 0.90, 95% CI: 0.71, 1.14), were diagnosed with grade 1 disease (OR = 1.00, 95% CI: 0.74, 1.37), and those resided in rural areas (OR = 1.01, 95% CI: 0.76, 1.36). CONCLUSION: We observed racial disparities in the initiation of chemotherapy overall and by sociodemographic and clinical factors, and more equitable outcomes when clinical guidelines were followed.

The Population-level Effect of Adjuvant Therapies on Breast Cancer Recurrence: Application of the Trend-in-Trend Design.

PURPOSE: Breast cancer has an average 10-year relative survival reaching 84%. This favorable survival is due, in part, to the introduction of biomarker-guided therapies. We estimated the population-level effect of the introduction of two adjuvant therapies-tamoxifen and trastuzumab-on recurrence using the trend-in-trend pharmacoepidemiologic study design. METHODS: We ascertained data on women diagnosed with nonmetastatic breast cancer who were registered in the Danish Breast Cancer Group clinical database. We used the trend-in-trend design to estimate the population-level effect of the introduction of (1) tamoxifen for postmenopausal women with estrogen receptor (ER)-positive breast cancer in 1982, (2) tamoxifen for premenopausal women diagnosed with ER-positive breast cancer in 1999, and (3) trastuzumab for women <60 years diagnosed with human epidermal growth factor receptor 2-positive breast cancer in 2007. RESULTS: For the population-level effect of the introduction of tamoxifen among premenopausal women diagnosed with ER-positive breast cancer in 1999, the risk of recurrence decreased by nearly one-half (OR = 0.52), consistent with evidence from clinical trials; however, the estimate was imprecise (95% confidence interval [CI] = 0.25, 1.85). We observed an imprecise association between tamoxifen use and recurrence from the time it was introduced in 1982 (OR = 1.24 95% CI = 0.46, 5.11), inconsistent with prior knowledge from clinical trials. For the introduction of trastuzumab in 2007, the estimate was also consistent with trial evidence, though imprecise (OR = 0.51; 95% CI = 0.21, 22.4). CONCLUSIONS: We demonstrated how novel pharmacoepidemiologic analytic designs can be used to evaluate the routine clinical care and effectiveness of therapeutic advancements in a population-based setting while considering some limitations of the approach.

A Comparison of Three Area-Level Indices of Neighborhood Deprivation and Socioeconomic Status and their Applicability to Breast Cancer Mortality.

Neighborhood deprivation indices are widely used in research, but the performance of these indices has rarely been directly compared in the same analysis. We examined the Area Deprivation Index, Neighborhood Deprivation Index, and Yost index, and compared their associations with breast cancer mortality. Indices were constructed for Georgia census block groups using 2011-2015 American Community Survey data. Pearson correlation coefficients and percent agreement were calculated. Associations between each index and breast cancer mortality were estimated among 36,795 women diagnosed with breast cancer using Cox proportional hazards regression. The indices were strongly correlated (absolute value of correlation coefficients > 0.77), exhibited moderate (41.4%) agreement, and were similarly associated with a 36% increase in breast cancer mortality. The similar associations with breast cancer mortality suggest the indices measure the same underlying construct, despite only moderate agreement. By understanding their correlations, agreement, and associations with health outcomes, researchers can choose the most appropriate index for analysis.

The obesity-breast cancer link: a multidisciplinary perspective.

Obesity, exceptionally prevalent in the USA, promotes the incidence and progression of numerous cancer types including breast cancer. Complex, interacting metabolic and immune dysregulation marks the development of both breast cancer and obesity. Obesity promotes chronic low-grade inflammation, particularly in white adipose tissue, which drives immune dysfunction marked by increased pro-inflammatory cytokine production, alternative macrophage activation, and reduced T cell function. Breast tissue is predominantly composed of white adipose, and developing breast cancer readily and directly interacts with cells and signals from adipose remodeled by obesity. This review discusses the biological mechanisms through which obesity promotes breast cancer, the role of obesity in breast cancer health disparities, and dietary interventions to mitigate the adverse effects of obesity on breast cancer. We detail the intersection of obesity and breast cancer, with an emphasis on the shared and unique patterns of immune dysregulation in these disease processes. We have highlighted key areas of breast cancer biology exacerbated by obesity, including incidence, progression, and therapeutic response. We posit that interception of obesity-driven breast cancer will require interventions that limit protumor signaling from obese adipose tissue and that consider genetic, structural, and social determinants of the obesity-breast cancer link. Finally, we detail the evidence for various dietary interventions to offset obesity effects in clinical and preclinical studies of breast cancer. In light of the strong associations between obesity and breast cancer and the rising rates of obesity in many parts of the world, the development of effective, safe, well-tolerated, and equitable interventions to limit the burden of obesity on breast cancer are urgently needed.

Total Energy Intake: Implications for Epidemiologic Analyses.

In 1986, Willett and Stampfer (Am J Epidemiol. 1986;124(1):17-27) propelled the nutritional epidemiology field forward by publishing a commentary emphasizing the importance of analyzing diet in relation to total energy intake in epidemiologic analyses of diet and disease, detailing the value of accounting for body size, physical activity, and metabolic efficiency in diet-disease analyses via energy intake adjustment. Their publication has since been cited over 2,886 times and has inarguably advanced methodology for studying diet-disease associations, with most nutritional epidemiology studies standardly including some form of energy adjustment. However, there remains debate regarding the best scenarios and methods for energy adjustment. The goals of this commentary are to provide an updated review on factors that account for interindividual differences in energy intake, provide a balanced discussion regarding the considerations for or against adjustment for energy intake, and provide an updated examination of the commonly employed methods for the analysis of nutrient-disease associations. The principles of energy adjustment continue to be relevant nearly 25 years later, as it remains a critical method to account for potentially confounding interindividual variations in body size and physical activity.

Census Tracts Are Not Neighborhoods: Addressing Spatial Misalignment in Studies Examining the Impact of Historical Redlining on Present-day Health Outcomes.

BACKGROUND: Research examining the effects of historical redlining on present-day health outcomes is often complicated by the misalignment of contemporary census boundaries with the neighborhood boundaries drawn by the US Home Owners' Loan Corporation (HOLC) in the 1930s. Previous studies have used different approaches to assign historical HOLC grades to contemporary geographies, but how well they capture redlining exposure is unknown. METHODS: Our analysis included 7711 residences identified in the Multiple Listing Service database in Atlanta, Georgia (2017-2022). We evaluated the classification of HOLC grade assignment (A, B, C, D, or ungraded) when assigning exposure under four area-level approaches (centroid, majority land area, weighted score, and highest HOLC) compared with using complete address data (gold standard). We additionally compared approaches across three 2020 census geographies (tract, block group, and block). RESULTS: When comparing the use of census tracts to complete address data, sensitivity was highest for the weighted score approach, which correctly identified 77% of residences in truly A-D graded neighborhoods as compared with the majority land area (44%), centroid (54%), and highest HOLC (59%) approaches. Regarding specificity, the majority land area approach best-classified residences in truly ungraded neighborhoods (93%) as compared with the weighted score (65%), centroid (81%), and highest HOLC (54%) approaches. Classification improved regardless of approach when using census block compared with the census tract. CONCLUSIONS: Misclassification of historical redlining exposure is inevitable when using contemporary census geographies rather than complete address data. This study provides a framework for assessing spatial misalignment and selecting an approach for classification.

Drivers of racial, regional, and socioeconomic disparities in late-stage breast cancer mortality.

BACKGROUND: The authors identified tumor, treatment, and patient characteristics that may contribute to differences in breast cancer (BC) mortality by race, rurality, and area-level socioeconomic status (SES) among women diagnosed with stage IIIB-IV BC in Georgia. METHODS: Using the Georgia Cancer Registry, 3084 patients with stage IIIB-IV primary BC (2013-2017) were identified. Cox proportional hazards regression was used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) comparing mortality among non-Hispanic Black (NHB) versus non-Hispanic White (NHW), residents of rural versus urban neighborhoods, and residents of low- versus high-SES neighborhoods by tumor, treatment, and patient characteristics. The mediating effects of specific characteristics on the association between race and BC mortality were estimated. RESULTS: Among the study population, 41% were NHB, 21% resided in rural counties, and 72% resided in low SES neighborhoods. The authors observed mortality disparities by race (HR, 1.27; 95% CI, 1.13, 1.41) and rurality (HR, 1.14; 95% CI, 1.00, 1.30), but not by SES (HR, 1.04; 95% CI, 0.91, 1.19). In the stratified analyses, racial disparities were the most pronounced among women with HER2 overexpressing tumors (HR, 2.30; 95% CI, 1.53, 3.45). Residing in a rural county was associated with increased mortality among uninsured women (HR, 2.25; 95% CI, 1.31, 3.86), and the most pronounced SES disparities were among younger women (<40 years: HR, 1.46; 95% CI, 0.88, 2.42). CONCLUSIONS: There is considerable variation in racial, regional, and socioeconomic disparities in late-stage BC mortality by tumor, treatment, and patient characteristics.

Neighborhood characteristics and breast tumor methylation: using epigenomics to explore cancer outcome disparities.

BACKGROUND: Social exposures may drive epigenetic alterations that affect racial disparities in breast cancer outcomes. This study examined the association between neighborhood-level factors and DNA methylation in non-Hispanic Black and White women diagnosed with breast cancer. METHODS: Genome-wide DNA methylation was measured using the EPIC array in the tumor tissue of 96 women. Linear regression models were used to examine the association between nine neighborhood-level factors and methylation, regressing ß values for each cytosine-phosphate guanine dinucleotide (CpG) site on neighborhood-level factors while adjusting for covariates. Neighborhood data were obtained from the Opportunity Atlas. We used a false discovery rate (FDR) threshold < 0.05, and for CpGs below this threshold, we examined interactions with race. We employed multivariable Cox proportional-hazards models to estimate whether aberrant methylation was associated with all-cause mortality. RESULTS: 26 of the CpG sites were associated with job density or college education (FDR < 0.05). Further exploration of these 26 CpG sites revealed no interactions by race, but a single probe in TMEM204 was associated with all-cause mortality. CONCLUSION: We identified novel associations between neighborhood-level factors and the breast tumor DNA methylome. Our data are the first to show that dysregulation in neighborhood associated CpG sites may be associated with all-cause mortality. Neighborhood-level factors may contribute to differential tumor methylation in genes related to tumor progression and metastasis. This contributes to the increasing body of evidence that area-level factors (such as neighborhood characteristics) may play an important role in cancer disparities through modulation of the breast tumor epigenome.

Have Paved Trails and Protected Bike Lanes Led to More Bicycling in Atlanta?: A Generalized Synthetic-Control Analysis.

BACKGROUND: Bicycling is an important form of physical activity in populations. Research assessing the effect of infrastructure on bicycling with high-resolution smartphone data is emerging in several places, but it remains limited in low-bicycling US settings, including the Southeastern US. The Atlanta area has been expanding its bicycle infrastructure, including off-street paved trails such as the Atlanta BeltLine and some protected bike lanes. METHODS: Using the generalized synthetic-control method, we estimated effects of five groups of off-street paved trails and protected bike lanes on bicycle ridership in their corresponding areas. To measure bicycling, we used 2 years (October 1, 2016 to September 30, 2018) of monthly Strava data in Atlanta's urban core along with data from 15 on-the-ground counters to adjust for spatiotemporal variation in app use. RESULTS: Considering all infrastructure as one joint intervention, an estimated 1.10 (95% confidence interval [CI]: 0.99, 1.18) times more bicycle-distance was ridden than would have been expected in the same areas had the infrastructure not been built, when defining treatment areas by the narrower of two definitions (defined in text). The Atlanta BeltLine Westside Trail and Proctor Creek Greenway had especially strong effect estimates, e.g., ratios of 1.45 (95% CI: 1.12, 1.86) and 1.55 (1.10, 2.14) under each treatment-area definition, respectively. We estimated that other infrastructure had weaker positive or no effects on bicycle-distance ridden. CONCLUSIONS: This study advances research on the topic because of its setting in the US Southeast, simultaneous assessment of several infrastructure groups, and data-driven approach to estimating effects. See video abstract at, http://links.lww.com/EDE/B936.

Time to Surgical Treatment and Facility Characteristics as Potential Drivers of Racial Disparities in Breast Cancer Mortality.

BACKGROUND: Black women are more likely to die of breast cancer than White women. This study evaluated the contribution of time to primary surgical management and surgical facility characteristics to racial disparities in breast cancer mortality among both Black and White women. METHODS: The study identified 2224 Black and 3787 White women with a diagnosis with stages I to III breast cancer (2010-2014). Outcomes included time to surgical treatment (> 30 days from diagnosis) and breast cancer mortality. Odds ratios (ORs) and 95% confidence intervals (CIs) associating surgical facility characteristics with surgical delay were computed, and Cox proportional hazards regression was used to compute hazard ratios (HRs) and 95% CIs associating delay and facility characteristics with breast cancer mortality. RESULTS: Black women were two times more likely to have a surgical delay (OR, 2.15; 95% CI, 1.92-2.41) than White women. Racial disparity in surgical delay was least pronounced among women treated at a non-profit facility (OR, 1.95; 95% CI, 1.70-2.25). The estimated mortality rate for Black women was two times that for White women (HR, 2.00; 95% CI, 1.83-2.46). Racial disparities in breast cancer mortality were least pronounced among women who experienced no surgical delay (HR, 1.81; 95% CI, 1.28-2.56), received surgery at a government facility (HR, 1.31; 95% CI, 0.76-2.27), or underwent treatment at a Commission on Cancer-accredited facility (HR, 1.82; 95% CI, 1.38-2.40). CONCLUSIONS: Black women were more likely to experience a surgical delay and breast cancer death. Persistent racial disparities in breast cancer mortality were observed across facility characteristics except for government facilities.

Joint associations of physical activity and body mass index with the risk of established excess body fatness-related cancers among postmenopausal women.

PURPOSE: Excess body fatness and physical activity independently influence the risk of several types of cancer. However, few studies have examined whether physical activity mitigates the excess risk associated with higher body mass index (BMI). METHODS: We examined the individual and joint associations between BMI (kg/m2) and leisure-time moderate-to-vigorous physical activity (MVPA, MET-hours/week) with the risk of three established excess body fatness-related cancers (breast, colon, and endometrial) among 43,795 postmenopausal women in the Cancer Prevention Study II (CPS-II) Nutrition Cohort (1992/1993-2015). Further exclusions for women without an intact uterus resulted in 31,805 women for endometrial cancer analyses. Multivariable Cox proportional hazards regression was used to calculate hazard ratio (HR) and 95% confidence intervals (CIs) with interaction terms to assess multiplicative interaction. The relative excess risk due to interaction (RERI) was calculated to assess additive interaction. RESULTS: BMI and MVPA were individually associated with breast and endometrial cancer risk, but only BMI was associated with colon cancer risk. In joint analyses, increasing levels of MVPA did not lower the risk of these cancers among obese women. For example, compared to the common referent (BMI 18.5- < 25 kg/m2, MVPA > 0- < 7.5 MET-hours/week), BMI ≥ 30 kg/m2 was associated with a higher risk of breast cancer among women with low MVPA (> 0-< 7.5 MET-hours/week: HR = 1.42, 95% CI: 1.22 - 1.67) and high MVPA (≥ 15 MET-hours/week: HR = 1.53, 95% CI: 1.25 - 1.87; RERI = 0.20, 95% CI: -0.14, 0.54, multiplicative Pinteraction = 0.64). CONCLUSION: Our results do not support the hypothesis that leisure-time physical activity mitigates the excess risk associated with higher BMI for risk of breast, endometrial, or colon cancer among postmenopausal women.

At-risk-measure Sampling in Case-Control Studies with Aggregated Data.

Transient exposures are difficult to measure in epidemiologic studies, especially when both the status of being at risk for an outcome and the exposure change over time and space, as when measuring built-environment risk on transportation injury. Contemporary "big data" generated by mobile sensors can improve measurement of transient exposures. Exposure information generated by these devices typically only samples the experience of the target cohort, so a case-control framework may be useful. However, for anonymity, the data may not be available by individual, precluding a case-crossover approach. We present a method called at-risk-measure sampling. Its goal is to estimate the denominator of an incidence rate ratio (exposed to unexposed measure of the at-risk experience) given an aggregated summary of the at-risk measure from a cohort. Rather than sampling individuals or locations, the method samples the measure of the at-risk experience. Specifically, the method as presented samples person-distance and person-events summarized by location. It is illustrated with data from a mobile app used to record bicycling. The method extends an established case-control sampling principle: sample the at-risk experience of a cohort study such that the sampled exposure distribution approximates that of the cohort. It is distinct from density sampling in that the sample remains in the form of the at-risk measure, which may be continuous, such as person-time or person-distance. This aspect may be both logistically and statistically efficient if such a sample is already available, for example from big-data sources like aggregated mobile-sensor data.

Receipt of Guideline-Concordant Care Does Not Explain Breast Cancer Mortality Disparities by Race in Metropolitan Atlanta.

BACKGROUND: Racial disparities in breast cancer mortality in the United States are well documented. Non-Hispanic Black (NHB) women are more likely to die of their disease than their non-Hispanic White (NHW) counterparts. The disparity is most pronounced among women diagnosed with prognostically favorable tumors, which may result in part from variations in their receipt of guideline care. In this study, we sought to estimate the effect of guideline-concordant care (GCC) on prognosis, and to evaluate whether receipt of GCC modified racial disparities in breast cancer mortality. PATIENTS AND METHODS: Using the Georgia Cancer Registry, we identified 2,784 NHB and 4,262 NHW women diagnosed with a stage I-III first primary breast cancer in the metropolitan Atlanta area, Georgia, between 2010 and 2014. Women were included if they received surgery and information on their breast tumor characteristics was available; all others were excluded. Receipt of recommended therapies (chemotherapy, radiotherapy, endocrine therapy, and anti-HER2 therapy) as indicated was considered GCC. We used Cox proportional hazards models to estimate the impact of receiving GCC on breast cancer mortality overall and by race, with multivariable adjusted hazard ratios (HRs). RESULTS: We found that NHB and NHW women were almost equally likely to receive GCC (65% vs 63%, respectively). Failure to receive GCC was associated with an increase in the hazard of breast cancer mortality (HR, 1.74; 95% CI, 1.37-2.20). However, racial disparities in breast cancer mortality persisted despite whether GCC was received (HRGCC: 2.17 [95% CI, 1.61-2.92]; HRnon-GCC: 1.81 [95% CI, 1.28-2.91] ). CONCLUSIONS: Although receipt of GCC is important for breast cancer outcomes, racial disparities in breast cancer mortality did not diminish with receipt of GCC; differences in mortality between Black and White patients persisted across the strata of GCC.

Detection of crown-like structures in breast adipose tissue and clinical outcomes among African-American and White women with breast cancer.

BACKGROUND: Crown-like structures in breast adipose tissue (CLS-B), composed of necrotic adipocytes encircled by macrophages, are associated with obesity and hypothesized to worsen breast cancer prognosis; however, data are sparse, particularly in multi-racial populations. METHODS: We assessed specimens for CLS-B from 174 African-American and 168 White women with stage I-III breast cancer treated by mastectomy. Benign breast tissue from an uninvolved quadrant was immunohistochemically stained for CD68 to determine CLS-B presence and density (per cm2 of adipose tissue). Demographic and lifestyle factors, collected via medical record review, were analyzed for associations with CLS-B using logistic regression. Multivariable Cox proportional hazards models were used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between CLS-B and overall (OS) or progression-free (PFS) survival. RESULTS: Detection of any CLS-B was similar between African-American (32%) and White (29%) patients with no evidence of an association between race and CLS-B in multivariable models (OR = 0.82, 95% CI = 0.49-1.36). Detection of CLS-B was associated with obesity (OR = 4.73, 95% CI = 2.48-9.01) and age ≥ 60 years at diagnosis (OR = 1.78, 95% CI = 0.99-3.21). There was some evidence of associations with parity and current smoking status. Detection of CLS-B was not associated with OS (HR = 1.02, 95% CI = 0.55-1.87) or PFS (HR = 0.99, 95% CI = 0.59-1.67). CONCLUSIONS: Our results show a strong, positive association between BMI and CLS-B in non-tumor tissue similar to previous findings. Detection of CLS-B did not vary by race and was not associated with worse OS or PFS.

Obesity-associated methylation in breast tumors: a possible link to disparate outcomes?

PURPOSE: As a primary risk factor and modifier of breast cancer incidence and prognosis, obesity may contribute to race disparities in breast cancer outcomes. This study examined association between obesity and DNA methylation in non-Hispanic Black and White women diagnosed with breast cancer. METHODS: Genome-wide DNA methylation was measured in the breast cancer tumor tissue of 96 women using the EPIC array. To examine the association between obesity and tumor methylation, linear regression models were used-regressing methylation ß value for each cytosine and guanine (CpG) site on body mass index adjusting for covariates. Significance was set at false discovery rate (FDR) < 0.05. In the top 20 CpG sites, we explored the interactions with race and estrogen receptor (ER) status. We used multivariable Cox-proportional hazard models to examine whether methylation in the top 20 sites was associated with all-cause mortality. RESULTS: While none of the CpG sites passed the FDR threshold for significance, among the top 20 CpG sites, we observed interactions with race (TOMM20) and ER status (PSMB1, QSOX1 and PHF1). The same CpG sites in TOMM20, PSMB1, and QSOX1 were associated with all-cause mortality. CONCLUSIONS: We identified novel interactions between obesity-associated methylation and both race and ER status in genes that have been associated with tumor regulation. Our data suggest that dysregulation in two sites may associate with all-cause mortality.

The American Cancer Society Cancer Prevention Study-3 FFQ Has Reasonable Validity and Reproducibility for Food Groups and a Diet Quality Score.

BACKGROUND: FFQs are commonly used to assess dietary intake and it is important to evaluate their performance in the target population. OBJECTIVE: We evaluated the reproducibility and relative validity of the Cancer Prevention Study-3 (CPS-3) FFQ in estimating usual intake of 63 food groups and diet quality in accordance with the American Cancer Society dietary guidelines for cancer prevention. METHODS: A subset of participants from the CPS-3 (433 women, 244 men), 31-70 y of age, were included in a cross-sectional diet assessment substudy (2015-2016). Reproducibility was assessed by comparing estimates from repeat FFQs, approximately 1 y apart, using Spearman correlation coefficient (rs) and Pearson correlation coefficient (rp) correlations for food groups and diet quality, respectively. Validity was assessed similarly by comparing FFQ estimates with estimates from ≤6 interviewer-administered 24-h dietary recall (24HR). Analyses were stratified by sex and race/ethnicity. RESULTS: Reproducibility correlations for repeated FFQs were > 0.50 for 83-97% of food groups analyzed across strata of sex and race. Although participants tended to overreport plant foods (e.g., fruits and legumes) and underreport refined grains and sugar-sweetened beverages, the median energy-adjusted, deattenuated Spearman correlations comparing the second FFQ to the 24HR were 0.50 and 0.52 among men and women (range: 0.05-0.82), respectively, suggesting that ranking was preserved for most food groups. Validity was highest for coffee, alcohol, and total dairy, and lowest for pasta and regular-fat yogurt. Median validity across food groups varied by race/ethnicity and was highest among whites (rs = 0.54) followed by Hispanics (rs = 0.49) and African Americans (rs = 0.45). The diet quality score had good validity in all subgroups examined, but was higher among men (rp = 0.69) than women (rp = 0.61), and lower among whites (rp = 0.62) than Hispanics (rp = 0.64) or African Americans (rp = 0.73). CONCLUSIONS: This study indicates good reproducibility and validity of the CPS-3 FFQ for most major food groups and the diet quality score in all sex and race/ethnicity groups examined.

Prediagnosis aspirin use, DNA methylation, and mortality after breast cancer: A population-based study.

BACKGROUND: The authors hypothesized that epigenetic changes may help to clarify the underlying biologic mechanism linking aspirin use to breast cancer prognosis. To the authors' knowledge, this is the first epidemiologic study to examine whether global methylation and/or tumor promoter methylation of breast cancer-related genes interact with aspirin use to impact mortality after breast cancer. METHODS: Prediagnosis aspirin use was assessed through in-person interviews within a population-based cohort of 1508 women diagnosed with a first primary breast cancer in 1996 and 1997. Global methylation in peripheral blood was assessed by long interspersed elements-1 (LINE-1) and the luminometric methylation assay. Promoter methylation of 13 breast cancer-related genes was measured in tumor by methylation-specific polymerase chain reaction and the MethyLight assay. Vital status was determined by the National Death Index through December 31, 2014 (N = 202/476 breast cancer-specific/all-cause deaths identified among 1266 women with any methylation assessment and complete aspirin data). Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs, and the likelihood ratio test was used to evaluate multiplicative interactions. RESULTS: All-cause mortality was elevated among aspirin users who had methylated promotor of BRCA1 (HR, 1.67; 95% CI, 1.26-2.22), but not among those with unmethylated promoter of BRCA1 (HR, 0.99; 95% CI, 0.67-1.45; P for interaction ≤.05). Decreased breast cancer-specific mortality was observed among aspirin users who had unmethylated promotor of BRCA1 and PR and global hypermethylation of LINE-1 (HR, 0.60, 0.78, and 0.63, respectively; P for interaction ≤.05), although the 95% CIs included the null. CONCLUSIONS: The current study suggests that the LINE-1 global methylation and promoter methylation of BRCA1 and PR in tumor may interact with aspirin use to influence mortality after breast cancer.

Disadvantaged neighborhoods and racial disparity in breast cancer outcomes: the biological link.

Neighborhoods encompass complex environments comprised of unique economic, physical, and social characteristics that have a profound impact on the residing individual's health and, collectively, on the community's wellbeing. Neighborhood disadvantage (ND) is one of several factors that prominently contributes to racial breast cancer (BC) health disparities in American women. African American (AA) women develop more aggressive breast cancer features, such as triple-negative receptor status and more advanced histologic grade and tumor stage, and suffer worse clinical outcomes than European American (EA) women. While the adverse effects of neighborhood disadvantage on health, including increased risk of cancer and decreased longevity, have recently come into focus, the specific molecular mechanisms by which neighborhood disadvantage increases BC risk and worsens BC outcomes (survivorship, recurrence, mortality) are not fully elucidated. This review illuminates the probable biological links between neighborhood disadvantage and predominantly BC risk, with an emphasis on stress reactivity and inflammation, epigenetics and telomere length in response to adverse neighborhood conditions.

Reproductive characteristics are associated with gene-specific promoter methylation status in breast cancer.

BACKGROUND: Reproductive characteristics are well-established risk factors for breast cancer, but the underlying mechanisms are not fully resolved. We hypothesized that altered DNA methylation, measured in tumor tissue, could act in concert with reproductive factors to impact breast carcinogenesis. METHODS: Among a population-based sample of women newly diagnosed with first primary breast cancer, reproductive history was assessed using a life-course calendar approach in an interviewer-administered questionnaire. Methylation-specific polymerase chain reaction and Methyl Light assays were used to assess gene promotor methylation status (methylated vs. unmethylated) for 13 breast cancer-related genes in archived breast tumor tissue. We used case-case unconditional logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for associations with age at menarche and parity (among 855 women), and age at first birth and lactation (among a subset of 736 parous women) in association with methylation status. RESULTS: Age at first birth > 27 years, compared with < 23 years, was associated with lower odds of methylation of CDH1 (OR = 0.44, 95% CI = 0.20-0.99) and TWIST1 (OR = 0.48, 95% CI = 0.28-0.82), and higher odds of methylation of BRCA1 (OR = 1.63, 95% CI = 1.14-2.35). Any vs. no lactation was associated with higher odds of methylation of the PGR gene promoter (OR = 1.59, 95% CI = 1.01-2.49). No associations were noted for parity and methylation in any of the genes assayed. CONCLUSIONS: Our findings indicate that age at first birth, lactation and, perhaps age at menarche, are associated with gene promoter methylation in breast cancer, and should be confirmed in larger studies with robust gene coverage.