mTOR pathway candidate genes and physical activity interaction on breast cancer risk in black women from the women's circle of health study.

BACKGROUND: Physical activity has been shown to affect the mammalian target of rapamycin (mTOR) signaling pathway and consequently breast carcinogenesis. Given that Black women in the USA are less physically active, it is not well understood whether there are gene-environment interactions between mTOR pathway genes and physical activity in relation to breast cancer risk in Black women. METHODS: The study included 1398 Black women (567 incident breast cancer cases and 831 controls) from the Women's Circle of Health Study (WCHS). We examined interactions between 43 candidate single-nucleotide polymorphisms (SNPs) in 20 mTOR pathway genes with levels of vigorous physical activity in relation to breast cancer risk overall and by ER-defined subtypes using Wald test with 2-way interaction term and multivariable logistic regression. RESULTS: AKT1 rs10138227 (C > T) and AKT1 rs1130214 (C > A) were only associated with a decreased risk of ER + breast cancer among women with vigorous physical activity (odds ratio [OR] = 0.15, 95% confidence interval (CI) 0.04, 0.56, for each copy of the T allele, p-interaction = 0.007 and OR = 0.51, 95% CI 0.27, 0.96, for each copy of the A allele, p-interaction = 0.045, respectively). MTOR rs2295080 (G > T) was only associated with an increased risk of ER + breast cancer among women with vigorous physical activity (OR = 2.24, 95% CI 1.16, 4.34, for each copy of the G allele; p-interaction = 0.043). EIF4E rs141689493 (G > A) was only associated with an increased risk of ER- breast cancer among women with vigorous physical activity (OR = 20.54, 95% CI 2.29, 184.17, for each copy of the A allele; p-interaction = 0.003). These interactions became non-significant after correction for multiple testing (FDR-adjusted p-value > 0.05). CONCLUSION: Our findings suggest that mTOR genetic variants may interact with physical activity in relation to breast cancer risk in Black women. Future studies should confirm these findings.

mTOR pathway candidate genes and obesity interaction on breast cancer risk in black women from the Women's Circle of Health Study.

BACKGROUND: Obesity is known to stimulate the mammalian target of rapamycin (mTOR) signaling pathway and both obesity and the mTOR signaling pathway are implicated in breast carcinogenesis. We investigated potential gene-environment interactions between mTOR pathway genes and obesity in relation to breast cancer risk among Black women. METHODS: The study included 1,655 Black women (821 incident breast cancer cases and 834 controls) from the Women's Circle of Health Study (WCHS). Obesity measures including body mass index (BMI); central obesity i.e., waist circumference (WC) and waist/hip ratio (WHR); and body fat distribution (fat mass, fat mass index and percent body fat) were obtained by trained research staff. We examined the associations of 43 candidate single-nucleotide polymorphisms (SNPs) in 20 mTOR pathway genes with breast cancer risk using multivariable logistic regression. We next examined interactions between these SNPs and measures of obesity using Wald test with 2-way interaction term. RESULTS: The variant allele of BRAF (rs114729114 C > T) was associated with an increase in overall breast cancer risk [odds ratio (OR) = 1.81, 95% confidence interval (CI) 1.10-2.99, for each copy of the T allele] and the risk of estrogen receptor (ER)-defined subtypes (ER+ tumors: OR = 1.83, 95% CI 1.04,3.29, for each copy of the T allele; ER- tumors OR = 2.14, 95% CI 1.03,4.45, for each copy of the T allele). Genetic variants in AKT, AKT1, PGF, PRKAG2, RAPTOR, TSC2 showed suggestive associations with overall breast cancer risk and the risk of, ER+ and ER- tumors (range of p-values = 0.040-0.097). We also found interactions of several of the SNPs with BMI, WHR, WC, fat mass, fat mass index and percent body fat in relation to breast cancer risk. These associations and interactions, however, became nonsignificant after correction for multiple testing (FDR-adjusted p-value > 0.05). CONCLUSION: We found associations between mTOR genetic variants and breast cancer risk as well as gene and body fatness interactions in relation to breast cancer risk. However, these associations and interactions became nonsignificant after correction for multiple testing. Future studies with larger sample sizes are required to confirm and validate these findings.

mTOR pathway candidate genes and energy intake interaction on breast cancer risk in Black women from the Women's Circle of Health Study.

BACKGROUND: Excessive energy intake has been shown to affect the mammalian target of the rapamycin (mTOR) signaling pathway and breast cancer risk. It is not well understood whether there are gene-environment interactions between mTOR pathway genes and energy intake in relation to breast cancer risk. METHODS: The study included 1642 Black women (809 incident breast cancer cases and 833 controls) from the Women's Circle of Health Study (WCHS). We examined interactions between 43 candidate single-nucleotide polymorphisms (SNPs) in 20 mTOR pathway genes and quartiles of energy intake in relation to breast cancer risk overall and by ER- defined subtypes using Wald test with a 2-way interaction term. RESULTS: AKT1 rs10138227 (C > T) was only associated with a decreased overall breast cancer risk among women in quartile (Q)2 of energy intake, odds ratio (OR) = 0.60, 95% confidence interval (CI) 0.40, 0.91 (p-interaction = 0.042). Similar results were found in ER- tumors. AKT rs1130214 (C > A) was associated with decreased overall breast cancer risk in Q2 (OR = 0.63, 95% CI 0.44, 0.91) and Q3 (OR = 0.65, 95% CI 0.48, 0.89) (p-interaction = 0.026). HIF-1α C1772T rs11549465 (C > T) was associated with decreased overall breast cancer risk in Q4 (OR = 0.29, 95% CI 0.14, 0.59, p-interaction = 0.007); the results were similar in ER+ tumors. These interactions became non-significant after correction for multiple comparisons. CONCLUSION: Our findings suggest that mTOR genetic variants may interact with energy intake in relation to breast cancer risk, including the ER- subtype, in Black women. Future studies should confirm these findings.

Electronic Nicotine Delivery Systems (ENDS) use Among Members of a Community Engagement Program.

Electronic nicotine delivery systems (ENDS) are relatively new and ENDS use data from community engagement programs may help us understand usage patterns and facilitate targeted longitudinal studies. Community members in Florida, USA, were asked about ENDS use, tobacco use, and health history/concerns by Community Health Workers. Among 7253 members recruited during 2014 to 2021 into our HealthStreet program, 1177 had ever used ENDS; the proportion increased from 12 to 27% from 2014 to 2021 (adjusted odds ratio (aOR) 2.5; 95% CI 1.7-3.5; Ever versus never used ENDS). Ever tobacco use was strongly associated with ENDS use; 69% of ever users were current tobacco users. Demographic determinants (sex, age, race) and food insecurity were strongest predictors of ENDS use. Most who had ever used ENDS were aged 18-25 (aOR 5.9; 95% CI 4.6-7.6; vs. aged 60 + years), White (aOR 3.7; 95% CI 3.2-4.3; vs. Black/African American), male (aOR 1.5; 95% CI 1.3-1.7; vs. female), and recently food insecure (aOR 1.8; 95% CI 1.5-2.0; vs. not recently food insecure). Those with respiratory issues were more likely to have used ENDS compared to those without (aOR 2.0; 95% CI 1.6-2.6; aOR 1.3; 95% CI 1.1-1.5). Members concerned about hypertension were less likely to have used ENDS (aOR 0.7; 95% CI 0.5-0.9). In this relatively rural, micropolitan sample, tobacco use, socio-economic determinants, and certain health history/concerns were strongly associated with ENDS use. Community outreach approaches are needed to further understand these factors and implement interventions.

Association of injury after prescription opioid initiation with risk for opioid-related adverse events among older Medicare beneficiaries in the United States: A nested case-control study.

BACKGROUND: Injury, prevalent and potentially associated with prescription opioid use among older adults, has been implicated as a warning sign of serious opioid-related adverse events (ORAEs) including opioid misuse, dependence, and poisoning, but this association has not been empirically tested. The study aims to examine the association between incident injury after prescription opioid initiation and subsequent risk of ORAEs and to assess whether the association differs by recency of injury among older patients. METHODS AND FINDINGS: This nested case-control study was conducted within a cohort of 126,752 individuals aged 65 years or older selected from a 5% sample of Medicare beneficiaries in the United States between 2011 and 2018. Cohort participants were newly prescribed opioid users with chronic noncancer pain who had no injury or ORAEs in the year before opioid initiation, had 30 days or more of observation, and had at least 1 additional opioid prescription dispensed during follow-up. We identified ORAE cases as patients who had an inpatient or outpatient encounter with diagnosis codes for opioid misuse, dependence, or poisoning. During a mean follow-up of 1.8 years, we identified 2,734 patients who were newly diagnosed with ORAEs and 10,936 controls matched on the year of cohort entry date and a disease risk score (DRS), a summary score derived from the probability of an ORAE outcome based on covariates measured prior to cohort entry and in the absence of injury. Multivariate conditional logistic regression was used to estimate ORAE risk associated with any and recency of injury, defined based on the primary diagnosis code of inpatient and outpatient encounters. Among the cases and controls, 68.0% (n = 1,859 for cases and n = 7,436 for controls) were women and the mean (SD) age was 74.5 (6.9) years. Overall, 54.0% (n = 1,475) of cases and 46.0% (n = 1,259) of controls experienced incident injury after opioid initiation. Patients with (versus without) injury after opioid therapy had higher risk of ORAEs after adjustment for time-varying confounders, including diagnosis of tobacco or alcohol use disorder, drug use disorder, chronic pain diagnosis, mental health disorder, pain-related comorbidities, frailty index, emergency department visit, skilled nursing facility stay, anticonvulsant use, and patterns of prescription opioid use (adjusted odds ratio [aOR] = 1.4; 95% confidence interval (CI) 1.2 to 1.5; P < 0.001). Increased risk of ORAEs was associated with current (≤30 days) injury (aOR = 2.8; 95% CI 2.3 to 3.4; P < 0.001), whereas risk of ORAEs was not significantly associated with recent (31 to 90 days; aOR = 0.93; 95% CI 0.73 to 1.17; P = 0.48), past (91 to 180 days; aOR = 1.08; 95% CI 0.88 to 1.33; P = 0.51), and remote (181 to 365 days; aOR = 0.88; 95% CI 0.73 to 1.1; P = 0.18) injury preceding the incident diagnosis of ORAE or matched date. Patients with injury and prescription opioid use versus those with neither in the month before the ORAE or matched date were at greater risk of ORAEs (aOR = 5.0; 95% CI 4.1 to 6.1; P < 0.001). Major limitations are that the study findings can only be generalized to older Medicare fee-for-service beneficiaries and that unknown or unmeasured confounders have the potential to bias the observed association toward or away from the null. CONCLUSIONS: In this study, we observed that incident diagnosis of injury following opioid initiation was associated with subsequent increased risk of ORAEs, and the risk was only significant among patients with injury in the month before the index date. Regular monitoring for injury may help identify older opioid users at high risk for ORAEs.

Associations between Genetic Variants and Blood Biomarkers of One-Carbon Metabolism in Postmenopausal Women from the Women's Health Initiative Observational Study.

BACKGROUND: Genetic variation in one-carbon metabolism may affect nutrient concentrations and biological functions. However, data on genetic variants associated with blood biomarkers of one-carbon metabolism in US postmenopausal women are limited, and whether these associations were affected by the nationwide folic acid (FA) fortification program is unclear. OBJECTIVES: We investigated associations between genetic variants and biomarkers of one-carbon metabolism using data from the Women's Health Initiative Observational Study. METHODS: In 1573 non-Hispanic White (NHW) and 282 Black/African American, American Indian/Alaska Native, Asian/Pacific Islander, and Hispanic/Latino women aged 50-79 y, 288 nonsynonymous and tagging single-nucleotide variants (SNVs) were genotyped. RBC folate, plasma folate, pyridoxal-5'-phosphate (PLP), vitamin B-12, homocysteine, and cysteine concentrations were determined in 12-h fasting blood. Multivariable linear regression tested associations per variant allele and for an aggregated genetic risk score. Effect modifications before, during, and after nationwide FA fortification were examined. RESULTS: After correction for multiple comparisons, among NHW women, 5,10-methylenetetrahydrofolate reductase (MTHFR) rs1801133 (677C→T) variant T was associated with lower plasma folate (-13.0%; 95% CI: -17.3%, -8.6%) and higher plasma homocysteine (3.5%; 95% CI: 1.7%, 5.3%) concentrations. Other associations for nonsynonymous SNVs included DNMT3A rs11695471 (T→A) with plasma PLP; EHMT2 rs535586 (G→A), TCN2 rs1131603 (L349S A→G), and TCN2 rs35838082 (R188W G→A) with plasma vitamin B-12; CBS rs2851391 (G→A) with plasma homocysteine; and MTHFD1 rs2236224 (G→A) and rs2236225 (R653Q G→A) with plasma cysteine. The influence of FA fortification on the associations was limited. Highest compared with lowest quartiles of aggregated genetic risk scores from SNVs in MTHFR and MTRR were associated with 14.8% to 18.9% lower RBC folate concentrations. Gene-biomarker associations were similar in women of other races/ethnicities. CONCLUSIONS: Our findings on genetic variants associated with several one-carbon metabolism biomarkers may help elucidate mechanisms of maintaining B vitamin status in postmenopausal women.

MRI Based Validation of Abdominal Adipose Tissue Measurements From DXA in Postmenopausal Women.

INTRODUCTION: Visceral adipose tissue (VAT) is a hypothesized driver of chronic disease. Dual-energy X-ray absorptiometry (DXA) potentially offers a lower cost and more available alternative compared to gold-standard magnetic resonance imaging (MRI) for quantification of abdominal fat sub-compartments, VAT and subcutaneous adipose tissue (SAT). We sought to validate VAT and SAT area (cm2) from historical DXA scans against MRI. METHODOLOGY: Participants (n = 69) from the Women's Health Initiative (WHI) completed a 3 T MRI scan and a whole body DXA scan (Hologic QDR2000 or QDR4500; 2004-2005). A subset of 43 participants were scanned on both DXA devices. DXA-derived VAT and SAT at the 4th lumbar vertebrae (5 cm wide) were analyzed using APEX software (v4.0, Hologic, Inc., Marlborough, MA). MRI VAT and SAT areas for the corresponding DXA region of interest were quantified using sliceOmatic software (v5.0, Tomovision, Magog, Canada). Pearson correlations between MRI and DXA-derived VAT and SAT were computed, and a Bland-Altman analysis was performed. RESULTS: Participants were primarily non-Hispanic white (86%) with a mean age of 70.51 ± 5.79 years and a mean BMI of 27.33 ± 5.40 kg/m2. Correlations between MRI and DXA measured VAT and SAT were 0.90 and 0.92, respectively (p ≤ 0.001). Bland-Altman plots showed that DXA-VAT slightly overestimated VAT on the QDR4500 (-3.31 cm2); this bias was greater in the smaller subset measured on the older DXA model (QDR2000; -30.71 cm2). The overestimation of DXA-SAT was large (-85.16 to -118.66 cm2), but differences were relatively uniform for the QDR4500. CONCLUSIONS: New software applied to historic Hologic DXA scans provide estimates of VAT and SAT that are well-correlated with criterion MRI among postmenopausal women.

Body fatness and breast cancer risk in relation to phosphorylated mTOR expression in a sample of predominately Black women.

BACKGROUND: The mechanistic target of rapamycin (mTOR) pathway promoted by positive energy imbalance and insulin-like growth factors can be a mechanism by which obesity influences breast cancer risk. We evaluated the associations of body fatness with the risk of breast cancer varied with phosphorylated (p)-mTOR protein expression, an indication of the pathway activation. METHODS: Women with newly diagnosed breast cancer (n = 715; 574 [80%] Black and 141 [20%] White) and non-cancer controls (n = 1983; 1280 [64%] Black and 713 [36%] White) were selected from the Women's Circle of Health Study. Surgical tumor samples among the cases were immunostained for p-mTOR (Ser2448) and classified as p-mTOR-overexpressed, if the expression level ≥ 75th percentile, or p-mTOR-negative/low otherwise. Anthropometrics were measured by trained staff, and body composition was determined by bioelectrical impedance analysis. Odds ratios (ORs) of p-mTOR-overexpressed tumors and p-mTOR-negative/low tumors compared to controls were estimated using polytomous logistic regression. The differences in the associations by the p-mTOR expression status were assessed by tests for heterogeneity. RESULTS: Cases with p-mTOR-overexpressed tumors, but not cases with p-mTOR-negative/low tumors, compared to controls were more likely to have higher body mass index (BMI), percent body fat, and fat mass index (P-heterogeneity < 0.05), although the OR estimates were not significant. For the measurement of central adiposity, cases with p-mTOR overexpressed tumors had a higher odds of being at the Q3 (OR = 2.52, 95% CI = 1.46 to 4.34) and Q4 (OR = 1.99, 95% CI = 1.12 to 3.50) of waist circumference (WC) compared to controls. Similarly, cases with p-mTOR overexpressed tumors had a higher odds of being at the Q3 (OR = 1.82, 95% CI = 1.11 to 2.98) and Q4 (OR = 1.81, 95% CI = 1.11 to 2.98) of WHR compared to controls. These associations of WC and waist-to-hip ratio (WHR) did not differ by tumor p-mTOR status (P-heterogeneity = 0.27 and 0.48, respectively). CONCLUSIONS: Our findings suggest that in this population composed of predominately Black women, body fatness is associated with breast cancer differently for p-mTOR overexpression and p-mTOR negative/low expression. Whether mTOR plays a role in the obesity and breast cancer association warrants confirmation by prospective studies.

Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment.

BACKGROUND: Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. METHODS: We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP < 0.15). RESULTS: Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy. CONCLUSIONS: We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited.

Mediation analysis of racial disparities in triple-negative breast cancer incidence among postmenopausal women.

BACKGROUND: Triple-negative breast cancer (TNBC) is disproportionately higher in Black women relative to White women. The objective of this study was to examine to what extent the association between race/ethnicity and risk of TNBC is mediated by potentially modifiable factors. METHODS: A total of 128,623 Black and White women aged 50-79 years from the Women's Health Initiative were followed for a mean of 15.8 years. 643 incident TNBC cases (92 Black women and 551 White women) were confirmed by medical record review. Mediation analyses were conducted using an approach under a counterfactual framework. RESULTS: Black women had approximately twofold higher risk of TNBC compared with white women (HR = 1.93, 95% CI 1.52-2.45). We observed that 48% of the racial disparity was mediated by metabolic dysfunction defined by having 3 or more cardiometabolic risk factors including elevated waist circumference, having history of diabetes, high cholesterol and hypertension. The racial disparity was not significantly mediated by other factors studied, including socioeconomic, lifestyle or reproductive factors. CONCLUSION: Our study observed that approximately half of the racial disparity between postmenopausal Black and White women in TNBC incidence was driven by metabolic dysfunction.

Dietary Vitamin A and Breast Cancer Risk in Black Women: The African American Breast Cancer Epidemiology and Risk (AMBER) Consortium.

BACKGROUND: Studies in women of European descent showed an inverse association of dietary vitamin A (retinol and carotenoids) intake with breast cancer risks, mainly in premenopausal women. OBJECTIVES: We examined whether higher compared with lower levels of dietary vitamin A are associated with reduced breast cancer risks among Black women by estrogen receptor (ER) and menopausal statuses. METHODS: In this pooled analysis, data were from 3564 breast cancer cases and 11,843 controls (mean ages = 56.4 and 56.3 years, respectively) in the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium. Dietary intake was assessed by FFQs. Multivariable logistic regressions were performed to estimate ORs and 95% CIs for study-specific quintiles of total vitamin A equivalents and individual carotenoids, and a pooled OR was estimated by a random-effect model. RESULTS: We observed an inverse association of total vitamin A equivalents with ER-positive breast cancer (quintiles 5 compared with 1: pooled OR: 0.82; 95% CI: 0.67-1.00; P-trend = 0.045). The association was seen among premenopausal women (pooled OR: 0.60; 95% CI: 0.43-0.83; P-trend = 0.004), but not among postmenopausal women (pooled OR: 0.99; 95% CI: 0.77-1.28; P-trend = 0.78). Additionally, there were inverse associations of dietary ß-carotene (quintiles 5 compared with 1: pooled OR: 0.70; 95% CI: 0.51-0.95; P-trend = 0.08) and lutein (pooled OR: 0.63; 95% CI: 0.45-0.87; P-trend = 0.020) with ER-positive breast cancer among premenopausal women. There was no evidence for an association of total vitamin A equivalents or individual carotenoids with ER-negative breast cancer, regardless of menopausal status. CONCLUSIONS: Our findings on dietary vitamin A and breast cancer risks in Black women are consistent with observations in women of European descent and advance the literature showing an inverse association for ER-positive disease.

Racial differences in CD8+ T cell infiltration in breast tumors from Black and White women.

BACKGROUND: African American/Black women with breast cancer have poorer survival than White women, and this disparity persists even after adjusting for non-biological factors. Differences in tumor immune biology have been reported between Black and White women, and the tumor immune milieu could potentially drive racial differences in breast cancer etiology and outcome. METHODS: We examined the association of CD8+ cytotoxic T cells with clinical-pathological variables in the Women's Circle of Health Study (WCHS) population of predominantly Black breast cancer patients. We evaluated 688 invasive breast tumor samples (550 Black, 138 White) using immunohistochemical staining of tissue microarray slides. CD8+ T cells were scored for each patient tumor sample with digital image analysis. RESULTS: Black women had a significantly higher percentage of high-grade, estrogen receptor (ER)-negative, and triple-negative tumors than White women and significantly higher CD8+ T cell density (median 87.6/mm2 vs. 53.1/mm2; p < 0.001). Within the overall population and in the population of Black women only, CD8+ T cell density was significantly higher in younger patients and patients with high-grade and ER/PR-negative tumors. No significant associations were observed between CD8+ T cell density and overall survival or breast cancer-specific survival in the overall population, or when Black patients were analyzed as a separate group. However, when stratified by subtype, Black women with triple-negative breast cancer and high CD8+ T cell density showed a trend towards better overall survival in comparison with patients with low CD8+ T cell density (HR = 0.51; 95% CI 0.25-1.04). CONCLUSIONS: Our data raise the possibility that distinct mechanisms of immune cell action may occur in different racial groups.

Insulin resistance and breast cancer incidence and mortality in postmenopausal women in the Women's Health Initiative.

BACKGROUND: Insulin resistance is associated with higher all-cause and cancer-specific mortality in postmenopausal women. However, to the authors' knowledge, information regarding insulin resistance and breast cancer mortality risk is limited. Therefore, the authors examined associations between insulin resistance and breast cancer incidence and mortality in a subsample of Women's Health Initiative participants. METHODS: A total of 22,837 postmenopausal women with fasting baseline glucose and insulin levels were followed for incident breast cancer and breast cancer mortality. Breast cancers were verified by medical record review and serial National Death Index linkage-enhanced mortality findings. Insulin resistance was estimated using the homeostatic model assessment of insulin resistance (HOMA-IR). Multivariable Cox proportional hazards models were used to compute hazard ratios (HRs) with 95% confidence intervals (95% CIs) for quartile comparisons. Outcomes included breast cancer incidence, deaths from breast cancer, and deaths after breast cancer (breast cancer followed by death from any cause). RESULTS: During a median of 19.8 years of follow-up of 1328 breast cancer cases, there were 512 deaths reported, 151 of which were from breast cancer. Breast cancer incidence was higher in women in the highest HOMA-IR quartile (HR, 1.34; 95% CI, 1.12-1.61 [P for trend = .003]). Although HOMA-IR was not found to be associated with risk of death from breast cancer (HR, 1.04; 95% CI, 0.60-1.79), women in the highest versus those in the lowest HOMA-IR quartile were at a higher risk of death after breast cancer (HR, 1.78; 95% CI, 1.32-2.39 [P for trend <.001]). CONCLUSIONS: Higher levels of insulin resistance in postmenopausal women are associated with higher breast cancer incidence and higher all-cause mortality after breast cancer.

Genome-wide association study of germline variants and breast cancer-specific mortality.

BACKGROUND: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. METHODS: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). RESULTS: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10-8. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10-7, hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10-7, HR = 1.27, 95% CI = 1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. CONCLUSIONS: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.

Frequency of breast cancer subtypes among African American women in the AMBER consortium.

BACKGROUND: Breast cancer subtype can be classified using standard clinical markers (estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2)), supplemented with additional markers. However, automated biomarker scoring and classification schemes have not been standardized. The aim of this study was to optimize tumor classification using automated methods in order to describe subtype frequency in the African American Breast Cancer Epidemiology and Risk (AMBER) consortium. METHODS: Using immunohistochemistry (IHC), we quantified the expression of ER, PR, HER2, the proliferation marker Ki67, and two basal-like biomarkers, epidermal growth factor receptor (EGFR) and cytokeratin (CK)5/6, in 1381 invasive breast tumors from African American women. RNA-based (prediction analysis of microarray 50 (PAM50)) subtype, available for 574 (42%) cases, was used to optimize classification. Subtype frequency was calculated, and associations between subtype and tumor characteristics were estimated using logistic regression. RESULTS: Relative to ER, PR and HER2 from medical records, central IHC staining and the addition of Ki67 or combined tumor grade improved accuracy for classifying PAM50-based luminal subtypes. Few triple negative cases (< 2%) lacked EGFR and CK5/6 expression, thereby providing little improvement in accuracy for identifying basal-like tumors. Relative to luminal A subtype, all other subtypes had higher combined grade and were larger, and ER-/HER2+ tumors were more often lymph node positive and late stage tumors. The frequency of basal-like tumors was 31%, exceeded only slightly by luminal A tumors (37%). CONCLUSIONS: Our findings indicate that automated IHC-based classification produces tumor subtype frequencies approximating those from PAM50-based classification and highlight high frequency of basal-like and low frequency of luminal A breast cancer in a large study of African American women.

Stratified Probabilistic Bias Analysis for Body Mass Index-related Exposure Misclassification in Postmenopausal Women.

BACKGROUND: There is widespread concern about the use of body mass index (BMI) to define obesity status in postmenopausal women because it may not accurately represent an individual's true obesity status. The objective of the present study is to examine and adjust for exposure misclassification bias from using an indirect measure of obesity (BMI) compared with a direct measure of obesity (percent body fat). METHODS: We used data from postmenopausal non-Hispanic black and non-Hispanic white women in the Women's Health Initiative (n=126,459). Within the Women's Health Initiative, a sample of 11,018 women were invited to participate in a sub-study involving dual-energy x-ray absorptiometry scans. We examined indices of validity comparing BMI-defined obesity (≥30 kg/m), with obesity defined by percent body fat. We then used probabilistic bias analysis models stratified by age and race to explore the effect of exposure misclassification on the obesity-mortality relationship. RESULTS: Validation analyses highlight that using a BMI cutpoint of 30 kg/m to define obesity in postmenopausal women is associated with poor validity. There were notable differences in sensitivity by age and race. Results from the stratified bias analysis demonstrated that failing to adjust for exposure misclassification bias results in attenuated estimates of the obesity-mortality relationship. For example, in non-Hispanic white women 50-59 years of age, the conventional risk difference was 0.017 (95% confidence interval = 0.01, 0.023) and the bias-adjusted risk difference was 0.035 (95% simulation interval = 0.028, 0.043). CONCLUSIONS: These results demonstrate the importance of using quantitative bias analysis techniques to account for nondifferential exposure misclassification of BMI-defined obesity. See video abstract at, http://links.lww.com/EDE/B385.

Trends in Dietary Vitamin A Intake Among US Adults by Race and Ethnicity, 2003-2018.

This study uses data from the 2003-2004 to 2017-2018 National Health and Nutrition Examination Surveys (NHANES) to assess whether a difference exists in dietary vitamin A intake as a marker of consumption of vitamin A­rich foods among Black, Hispanic, and White adults in the US.

Methodological considerations for disentangling a risk factor's influence on disease incidence versus postdiagnosis survival: The example of obesity and breast and colorectal cancer mortality in the Women's Health Initiative.

Often, studies modeling an exposure's influence on time to disease-specific death from study enrollment are incorrectly interpreted as if based on time to death from disease diagnosis. We studied 151,996 postmenopausal women without breast or colorectal cancer in the Women's Health Initiative with weight and height measured at enrollment (1993-1998). Using Cox regression models, we contrast hazard ratios (HR) from two time-scales and corresponding study subpopulations: time to cancer death after enrollment among all women and time to cancer death after diagnosis among only cancer survivors. Median follow-up from enrollment to diagnosis/censoring was 13 years for both breast (7,633 cases) and colorectal cancer (2,290 cases). Median follow-up from diagnosis to death/censoring was 7 years for breast and 5 years for colorectal cancer. In analyses of time from enrollment to death, body mass index (BMI) ≥ 35 kg/m2 versus 18.5-<25 kg/m2 was associated with higher rates of cancer mortality: HR = 1.99; 95% CI: 1.54, 2.56 for breast cancer (p trend <0.001) and HR = 1.40; 95% CI: 1.04, 1.88 for colorectal cancer (p trend = 0.05). However, in analyses of time from diagnosis to cancer death, trends indicated no significant association (for BMI ≥ 35 kg/m2 , HR = 1.25; 95% CI: 0.94, 1.67 for breast [p trend = 0.33] and HR = 1.18; 95% CI: 0.84, 1.86 for colorectal cancer [p trend = 0.39]). We conclude that a risk factor that increases disease incidence will increase disease-specific mortality. Yet, its influence on postdiagnosis survival can vary, and requires consideration of additional design and analysis issues such as selection bias. Quantitative tools allow joint modeling to compare an exposure's influence on time from enrollment to disease incidence and time from diagnosis to death.

Benign breast disease and risk of thyroid cancer.

BACKGROUND: It has been suggested that breast and thyroid diseases may be linked. The aim of this study was to investigate the association between benign breast disease and subsequent risk of thyroid cancer. METHODS: Postmenopausal women (n = 133,875) aged 50-79 years were followed up for a mean of 14 years. Benign breast disease was defined by history of biopsy. Incident thyroid cancer cases were confirmed by medical record review. Multivariable Cox proportional hazard modeling was used to estimate hazard ratios. RESULTS: There were 370 incident thyroid cancer cases during the follow-up period. Compared to women without BBD, women with BBD had a significant increased risk of thyroid cancer after adjusting for potential confounders (HR 1.38 95% CI 1.10-1.73), especially for women with more than two biopsies (HR 1.59 95% CI 1.10-2.26). There were no significant differences in thyroid tumor size, stage or histologic types between women with and without BBD. CONCLUSION: Our large prospective study observed that postmenopausal women with BBD had an increased risk for thyroid cancer compared with women without BBD. A more detailed investigation of thyroid cancer risk according to different subtypes of benign breast disease is needed to better understand the association observed between thyroid and benign breast diseases.

Serum 25-hydroxyvitamin D concentrations and lung cancer risk in never-smoking postmenopausal women.

PURPOSE: Vitamin D has been implicated in lowering lung cancer risk, but serological data on the association among never-smoking women are limited. We report results examining the association of serum 25-hydroxyvitamin D [25(OH)D] concentrations with lung cancer risk among female never smokers. We also examined whether the association was modified by vitamin D supplementation and serum vitamin A concentrations. METHODS: In the Women's Health Initiative, including the calcium/vitamin D (CaD) Trial, we selected 298 incident cases [191 non-small cell lung cancer (NSCLC) including 170 adenocarcinoma] and 298 matched controls of never smokers. Baseline serum 25(OH)D was assayed by a chemiluminescent method. Logistic regression was used to estimate odds ratios (ORs) for quartiles and predefined clinical cutoffs of serum 25(OH)D concentrations. RESULTS: Comparing quartiles 4 versus 1 of serum 25(OH)D concentrations, ORs were 1.06 [95% confidence interval (CI) 0.61-1.84] for all lung cancer, 0.94 (95% CI 0.52-1.69) for NSCLC, and 0.91 (95% CI 0.49-1.68) for adenocarcinoma. Comparing serum 25(OH)D ≥ 75 (high) versus <30 nmol/L (deficient), ORs were 0.76 (95% CI 0.31-1.84) for all lung cancer, 0.71 (95% CI 0.27-1.86) for NSCLC, and 0.81 (95% CI 0.31-2.14) for adenocarcinoma. There is suggestive evidence that CaD supplementation (1 g calcium + 400 IU D3/day) and a high level of circulating vitamin A may modify the associations of 25(OH)D with lung cancer overall and subtypes (p interaction <0.10). CONCLUSIONS: In this group of never-smoking postmenopausal women, the results did not support the hypothesis of an association between serum 25(OH)D and lung cancer risk.