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1.
PLoS Med ; 19(9): e1004101, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36136971

RESUMO

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.


Assuntos
Dor Crônica , Transtornos Relacionados ao Uso de Opioides , Idoso , Analgésicos Opioides/efeitos adversos , Anticonvulsivantes/uso terapêutico , Estudos de Casos e Controles , Dor Crônica/tratamento farmacológico , Dor Crônica/epidemiologia , Feminino , Humanos , Masculino , Medicare , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Prescrições , Estudos Retrospectivos , Estados Unidos/epidemiologia
2.
Front Endocrinol (Lausanne) ; 13: 879164, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35846306

RESUMO

Background: The mechanisms underlying the association of overall and central body fatness with poorer breast cancer outcomes remain unclear; altered gene and/or protein expression of the adipokines and their receptors in breast tumors might play a role. Methods: In a sample of Black and White women with primary invasive breast cancer, we investigated associations of body mass index (BMI), waist circumference, hip circumference, waist-to-hip ratio (WHR), fat mass index (FMI), and percent body fat with protein expression (log-transformed, n = 722) and gene expression (log2-transformed, n = 148) of leptin (LEP), leptin receptor (LEPR), adiponectin (ADIPOQ), and adiponectin receptors 1 and 2 (ADIPOR1, ADIPOR2). Multivariable linear models, adjusting for race, menopausal status, and estrogen receptor status, were used to assess these associations, with Bonferroni correction for multiple comparisons. Results: In multivariable models, we found that increasing BMI (ß = 0.0529, 95% CI: 0.0151, 0.0906) and FMI (ß = 0.0832, 95% CI: 0.0268, 0.1397) were associated with higher LEP gene expression, corresponding to 34.5% and 38.3% increases in LEP gene expression for a standard deviation (SD) increase in BMI and FMI, respectively. Increasing BMI (ß = 0.0028, 95% CI: 0.0011, 0.0045), waist circumference (ß = 0.0013, 95% CI: 0.0005, 0.0022), hip circumference (ß = 0.0015, 95% CI: 0.0007, 0.0024), and FMI (ß = 0.0041, 95% CI: 0.0015, 0.0067) were associated with higher LEPR protein expression. These associations equate to 16.8%, 17.6%, 17.7%, 17.2% increases in LEPR protein expression for a 1-SD increase in BMI, waist circumference, hip circumference, and FMI, respectively. Further, these associations were stronger among White and postmenopausal women and ER+ cases; formal tests of interaction yielded evidence of effect modification by race. No associations of body fatness with LEP protein expression, LEPR gene expression, or protein or gene expression of ADIPOQ, ADIPOR1, and ADIPOR2 were found. Conclusions: These findings support an association of increased body fatness - beyond overall body size measured using BMI - with higher LEP gene expression and higher LEPR protein expression in breast tumor tissues. Clarifying the impact of adiposity-related adipokine and adipokine receptor expression in breast tumors on long-term breast cancer outcomes is a critical next step.


Assuntos
Neoplasias da Mama , Receptores para Leptina , Adipocinas/metabolismo , Adiponectina/metabolismo , Tecido Adiposo/metabolismo , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Estudos Transversais , Feminino , Humanos , Polimorfismo de Nucleotídeo Único , Receptores para Leptina/genética
3.
Discov Oncol ; 13(1): 34, 2022 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-35608730

RESUMO

BACKGROUND: Aberrant activation of the mammalian Target of Rapamycin (mTOR) pathway has been linked to obesity and endocrine therapy resistance, factors that may contribute to Black-White disparities in breast cancer outcomes. We evaluated associations of race and clinicopathological characteristics with mRNA expression of key mTOR pathway genes in breast tumors. METHODS: Surgical tumor tissue blocks were collected from 367 newly diagnosed breast cancer patients (190 Black and 177 White). Gene expression of AKT1, EIF4EBP1, MTOR, RPS6KB2, and TSC1 were quantified by NanoString nCounter. Differential gene expression was assessed using linear regression on log2-transformed values. Gene expression and DNA methylation data from TCGA were used for validation and investigation of race-related differences. RESULTS: Compared to White women, Black women had relative under-expression of AKT1 (log2 fold-change = - 0.31, 95% CI - 0.44, - 0.18) and RPS6KB2 (log2 fold-change = - 0.11, 95% CI - 0.19, - 0.03). Higher vs. lower tumor grade was associated with relative over-expression of EIF4EBP1 and RPS6KB2, but with lower expression of TSC1. Compared to luminal tumors, triple-negative tumors had relative under-expression of TSC1 (log2 fold-change = - 0.42, 95% CI - 0.22, - 0.01). The results were similar in the TCGA breast cancer dataset. Post-hoc analyses identified differential CpG methylation within the AKT1 and RPS6KB2 locus between Black and White women. CONCLUSIONS: Over-expression of RPS6KB2 and EIF4EBP1 and under-expression of TSC1 might be indicators of more aggressive breast cancer phenotypes. Differential expression of AKT1 and RPS6KB2 by race warrants further investigation to elucidate their roles in racial disparities of treatment resistance and outcomes between Black and White women with breast cancer.

4.
Artigo em Inglês | MEDLINE | ID: mdl-35457549

RESUMO

BACKGROUND: Triclosan, bisphenol A (BPA), and brominated flame retardants are environmental estrogenic endocrine-disrupting compounds that may influence the prognosis of breast cancer. We examined the urinary concentrations of these compounds and their associations with demographic characteristics and body fatness in a population of women with newly diagnosed breast cancer. METHODS: Overnight urine collection and anthropometric measures were obtained from 302 participants. Triclosan, BPA, tetrabromobisphenol A (TBBPA), and tetrabromobenzoic acid (TBBA) concentrations were determined using ultra-performance liquid chromatography-tandem mass spectrometry. Regression analyses were conducted to examine associations of urinary compound concentration with age, menopause, race, ethnicity, educational level, estrogen receptor status, body size, and body composition. RESULTS: Triclosan, BPA, and TBBA were detected in urine samples from 98.3%, 6.0%, and 0.3% of patients, respectively; TBBPA was undetectable. Among patients with quantifiable values, the geometric mean concentrations were 20.74 µg/L (27.04 µg/g creatinine) for triclosan and 0.82 µg/L (1.08 µg/g creatinine) for BPA. Body mass index ≥ 30 vs. <25 kg/m2 was associated with lower creatinine-corrected urinary concentrations of triclosan (-40.00, 95% confidence interval [CI] = -77.19 to -2.81; p = 0.0351). The observed association was predominantly in postmenopausal women (-66.57; 95% CI: -109.18% to -23.96%). Consistent results were found for associations between triclosan levels and fat mass variables. CONCLUSION: In this study population, women with newly diagnosed breast cancer had triclosan exposure. Assessments of the implications of urinary concentrations of triclosan for women should consider body fatness and menopausal status.


Assuntos
Neoplasias da Mama , Retardadores de Chama , Triclosan , Compostos Benzidrílicos/urina , Neoplasias da Mama/epidemiologia , Creatinina , Demografia , Feminino , Humanos , Masculino , Fenóis , Triclosan/urina
5.
Cancers (Basel) ; 14(7)2022 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-35406618

RESUMO

Obesity measured by anthropometrics is associated with increased risk of triple-negative breast cancer (TNBC). It is unclear to what extent specific adipose tissue components, aside from muscle, are associated with TNBC. This retrospective study included 350 breast cancer patients who received treatment between October 2011 and April 2020 with archived abdominal or pelvic computed tomography (CT) images. We measured the areas of adipose tissue and five-density levels of skeletal muscle on patients' third lumbar vertebra (L3) image. Logistic regression was performed to examine the associations of specific adiposity and skeletal muscles components and a four-category body composition phenotype with the TNBC subtype. Results showed that higher vs. lower areas (3rd vs. 1st tertiles) of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were associated with increased odds of TNBC vs. non-TNBC after adjusting for age, race, stage, tumor grade, tumor size, and skeletal muscle areas (adjusted odds ratio [AOR], 11.25 [95% CI = 3.46-36.52]) and (AOR, 10.34 [95% CI = 2.90-36.90]) respectively. Higher areas of low density muscle was also associated with increased odds of TNBC (AOR, 3.15 [95% CI = 1.05-10.98]). Compared to normal body composition (low adipose tissue/high muscle), high adiposity/high muscle was associated with higher odds of TNBC (AOR, 5.54 [95% CI = 2.12-14.7]). These associations were mainly in premenopausal women and among patients with the CT performed after breast cancer surgery. Specific adipose tissue and low-density muscle can be associated with the TNBC subtype in breast cancer patients. The direction of association warrants confirmation by prospective studies.

6.
J Cancer Surviv ; 2022 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-35089522

RESUMO

PURPOSE: This report describes a cancer survivor cohort from a community engagement program and compares characteristics and willingness to participate in health research between the cancer survivors and non-cancer community members. METHODS: Among 11,857 members enrolled in HealthStreet at the University of Florida (10/2011-03/2020), 991 cancer survivors were identified and 1:1 matched to control members without cancer on sex, age, and zip code. Demographics, body weight, height, social determinants of health, history of cancer, and willingness to participate in research were recorded by Community Health Workers as a part of the baseline Health Needs Assessment. RESULTS: Among the cancer survivors, 71.6% were female and 19.2% lived in rural areas with a mean age of 56.7 years in females and 60.8 years in males. At baseline, 44.7% received a cancer diagnosis within 5 years, while 15.8%, more than 20 years. Cancer survivors (vs. matched non-cancer controls) were less likely to be Black (31.1% vs. 63.6%) but more likely to be divorced, separated, or widowed (49.5% vs. 41.2%), be normal/underweight (34.0% vs. 25.6%) and have health insurance (80.0% vs. 68.6%; all p < 0.05). Cancer survivors versus matched controls reported higher rates of ever being in a health research study (32.4% vs. 24.9%) and interest in participating in studies ranging from minimal risk to greater-than-minimal risk. CONCLUSIONS: Cancer survivors from this community engagement program agnostic to cancer types and treatment are diverse in geography, race, and social determinants of health and can be a valuable resource for observational, interventional, and biospecimen research in cancer survivorship.

7.
J Clin Densitom ; 25(2): 189-197, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34404568

RESUMO

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.


Assuntos
Gordura Intra-Abdominal , Pós-Menopausa , Absorciometria de Fóton/métodos , Tecido Adiposo , Idoso , Feminino , Humanos , Gordura Intra-Abdominal/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Gordura Subcutânea
8.
J Nutr ; 152(4): 1099-1106, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-34967850

RESUMO

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.


Assuntos
Metilenotetra-Hidrofolato Redutase (NADPH2) , Pós-Menopausa , Idoso , Biomarcadores , Carbono/metabolismo , Feminino , Ácido Fólico , Genótipo , Antígenos de Histocompatibilidade , Histona-Lisina N-Metiltransferase/genética , Homocisteína , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Pessoa de Meia-Idade , Pós-Menopausa/genética , Saúde da Mulher
9.
Nutr Diabetes ; 11(1): 29, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34531372

RESUMO

BACKGROUND/OBJECTIVES: There is evidence of black-white differences in vitamin D status and cardiometabolic health. This study aimed to further evaluate the joint associations of 25-hydroxyvitamin D [25(OH)D] and parathyroid hormone (PTH) with risks of diabetes and related cardiometabolic comorbidities among white and black women. SUBJECTS/METHODS: We cross-sectionally and prospectively analyzed data from 1850 black and 3000 white postmenopausal women without cardiovascular disease or dialysis at baseline from the Women's Health Initiative-Observational Study. Weighted Cox proportional hazards analyses and weighted logistic regression models were used to examine the joint associations of 25(OH)D and PTH with incident diabetes and prevalence of other diabetes-related cardiometabolic comorbidities (including CKD, hypertension, or obesity). RESULTS: We identified 3322 cases of obesity (n = 1629), hypertension (n = 2759), or CKD (n = 318) at baseline and 453 incident cases of diabetes during 11 years of follow-up. Cross-sectionally, lower 25(OH)D and higher PTH were independently associated with higher prevalence of hypertension [odds ratio (OR) = 0.79; 95% confidence interval (CI): 0.72-0.87 and OR = 1.55; 95% CI: 1.39-1.73] among white women only. When stratified by diabetes status, compared to women with 25(OH)D ≥50 nmol/L and PTH ≤6.89 pmol/L (65 pg/mL), women who did not have diabetes with vitamin D deficiency (<50 nmol/L) and PTH excess (>6.89 pmol/L) had higher prevalence of CKD, hypertension, or obesity (OR = 4.23; 95% CI: 2.90-6.18) than women who had diabetes (OR = 1.89; 95% CI: 0.96-3.71). Prospectively, lower 25(OH)D was associated with lower diabetes incidence [hazard ratio (HR) = 0.73; 95% CI: 0.62-0.86] in white women. Jointly, compared to the group with 25(OH)D ≥50 nmol/L and PTH ≤6.89 pmol/L, white women with 25(OH)D deficiency (<50 nmol/L) had elevated risk for diabetes, regardless of PTH levels. CONCLUSIONS: Low 25(OH)D and high PTH were jointly associated with increased risk of diabetes among white women only. Their joint associations with high prevalence of CKD, hypertension, and obesity were more pronounced among women without diabetes.


Assuntos
Afro-Americanos/estatística & dados numéricos , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus/epidemiologia , Hormônio Paratireóideo/sangue , Vitamina D/análogos & derivados , /estatística & dados numéricos , Idoso , Comorbidade , Estudos Transversais , Feminino , Humanos , Hipertensão/epidemiologia , Pessoa de Meia-Idade , Obesidade/epidemiologia , Pós-Menopausa , Prevalência , Estudos Prospectivos , Insuficiência Renal Crônica/epidemiologia , Fatores de Risco , Estados Unidos/epidemiologia , Vitamina D/sangue , Deficiência de Vitamina D/epidemiologia
10.
J Nutr ; 151(12): 3725-3737, 2021 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-34494098

RESUMO

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.


Assuntos
Neoplasias da Mama , Vitamina A , Afro-Americanos , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etiologia , Estudos de Casos e Controles , Feminino , Humanos , Modelos Logísticos , Receptores de Estrogênio , Fatores de Risco
11.
Breast Cancer Res ; 23(1): 86, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34407845

RESUMO

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.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Mutação em Linhagem Germinativa , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Prognóstico , Análise de Sobrevida
12.
Breast Cancer Res ; 23(1): 77, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34330319

RESUMO

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.


Assuntos
Afro-Americanos/estatística & dados numéricos , Neoplasias da Mama/metabolismo , Obesidade/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Adiposidade/etnologia , Adulto , Índice de Massa Corporal , Tamanho Corporal/etnologia , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etnologia , Estudos de Casos e Controles , Feminino , Humanos , Pessoa de Meia-Idade , New Jersey/epidemiologia , Cidade de Nova Iorque/epidemiologia , Obesidade/epidemiologia , Obesidade/etnologia , Razão de Chances , Fosforilação
13.
Breast Cancer Res Treat ; 188(1): 283-293, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33677722

RESUMO

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.


Assuntos
Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Feminino , Disparidades nos Níveis de Saúde , Humanos , Incidência , Análise de Mediação , Pós-Menopausa
14.
J Natl Cancer Inst ; 113(8): 1036-1043, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-33395700

RESUMO

BACKGROUND: Blacks tend to have a stronger inflammatory immune response than Whites. We hypothesized that racial differences in host immunity also manifest in the tumor microenvironment, constituting part of a distinct aggressive tumor biology underlying higher mortality in Black women. METHODS: Pathological and gene expression profiling approaches were used for characterizing infiltrating immune cells in breast tumor microenvironment from 1315 patients from the Women's Circle of Health Study. Racial differences in tumor immune phenotypes were compared, with results validated in a publicly accessible dataset. Prognostic associations of immune phenotypes were assessed in 3 independent cohorts. RESULTS: We found marked and consistent differences in tumor immune responses between Black and White patients. Not only did tumors from Blacks display a stronger overall immune presence but also the composition and quality of immune infiltrates differed, regardless of tumor subtypes. Black patients had a stronger CD4+ and B-cell response, and further, a more exhausted CD8+ T-cell profile. A signature indicating a higher ratio of exhausted CD8+ T cells to total CD8+ T cells (ExCD8-r) was consistently associated with poorer survival, particularly among hormone receptor-positive patients. Among hormone receptor-negative patients, combinations of the absolute fraction of CD8+ T cells and ExCD8-r signature identified the CD8lowExCD8-rhigh subgroup, the most prevalent among Blacks, with the worst survival. CONCLUSIONS: Our findings of a distinct exhausted CD8+ T-cell signature in Black breast cancer patients indicate an immunobiological basis for their more aggressive disease and a rationale for the use of immune checkpoint inhibitors targeting the exhaustion phenotype.


Assuntos
Neoplasias da Mama , Microambiente Tumoral , Neoplasias da Mama/metabolismo , Linfócitos T CD8-Positivos , Feminino , Humanos , Linfócitos do Interstício Tumoral , Prognóstico
15.
Breast Cancer (Auckl) ; 14: 1178223420972369, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33281450

RESUMO

PURPOSE: We examined the association of adipose tissue distribution with type 2 diabetes (T2D) in breast cancer patients. METHODS: Participants (N = 238) diagnosed with breast cancer at 20-75 years old who received breast cancer treatment at a major hospital from January 1, 2012, to December 31, 2017, with at least one completed and identifiable abdominal or pelvic computed tomography (CT) scan and data regarding race and ethnicity were included. Thirty-two breast cancer patients were identified as T2D patients after their breast cancer diagnoses. The adipose tissue distribution (visceral fat area [VFA], subcutaneous fat area [SFA], and the ratio of VFA to SFA [VFA/SFA]) was quantified on CT images of the third lumbar vertebra. T2D status was retrieved from patients' electronic medical records. The association of adipose tissue distribution with T2D in women with breast cancer was examined using multivariable logistic regression. RESULTS: Participants with T2D had significantly smaller SFA compared to those without T2D (odds ratio [OR] = 0.88, 95% confidence interval [95% CI] = 0.81-0.96, per 10 cm2 SFA). A positive association of VFA/SFA ratio with T2D was observed (OR = 19.57, 95% CI = 3.26-117.42, per unit VFA/SFA), although the estimate was imprecise. CONCLUSIONS: The amount of subcutaneous adipose tissue was inversely associated with T2D, and the ratio of the amount of visceral adipose tissue to the amount of subcutaneous adipose tissue was positively associated with T2D in breast cancer patients.

16.
NPJ Breast Cancer ; 6: 45, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33024820

RESUMO

Energy imbalance has an important role in breast cancer prognosis. Hyperactive mechanistic Target of Rapamycin (mTOR) pathway is associated with breast tumor growth, but the extent to which body fatness is associated with mTOR pathway activities in breast cancer is unclear. We performed immunostaining for mTOR, phosphorylated (p)-mTOR, p-AKT, and p-p70S6K in tumor tissue from 590 women (464 African Americans/Blacks and 126 Whites) with newly diagnosed invasive breast cancer in the Women's Circle of Health Study. Anthropometric measures were taken by study staff, and body composition was measured by bioelectrical impedance analysis. Linear regressions were used to estimate percent differences in protein expression between categories of body mass index (BMI), waist circumference, waist/hip ratio, fat mass, fat mass index, and percent body fat. We observed that BMI ≥ 35.0 vs. <25 kg/m2 was associated with 108.3% (95% CI = 16.9%-270.9%) and 101.8% (95% CI = 17.0%-248.8%) higher expression in p-mTOR and normalized p-mTOR, i.e., p-mTOR/mTOR, respectively. Quartiles 4 vs. 1 of waist/hip ratio was associated with 41.8% (95% CI = 5.81%-89.9%) higher mTOR expression. Similar associations were observed for the body fat measurements, particularly in patients with estrogen receptor-negative (ER-) tumors, but not in those with ER+ tumors, although the differences in associations were not significant. This tumor-based study found positive associations between body fatness and mTOR pathway activation, evident by a p-mTOR expression, in breast cancer. Our findings suggest that mTOR inhibition can be a treatment strategy to prevent the recurrence of these tumors in obese individuals.

17.
Cancer Epidemiol Biomarkers Prev ; 29(10): 2096-2099, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32699078

RESUMO

BACKGROUND: It is biologically plausible that genotoxic estrogens, namely estrogen DNA adducts (EDA), have a role in breast cancer development. Support comes from three prior studies that reported elevated concentrations of EDA relative to estrogen metabolites and conjugates (EDA:EMC) in women with breast cancer relative to control women. METHODS: In postmenopausal women in the Women's Health Initiative (WHI), EDA:EMC in 191 controls was compared with findings in 194 prediagnosis urine samples from breast cancer cases. EDA:EMC determinations were by mass spectrometry as previously described, and logistic regression was employed to estimate ORs. RESULTS: EDA:EMC did not differ in breast cancer cases compared with controls overall [0.93 (95% confidence interval, 0.71-1.23)], with a mean (SD) of 2.3 (0.8) and 2.4 (1.1) in cases and controls, respectively. Similarly, the ratio did not differ when examined by estrogen receptor or recency of biospecimen collection prior to breast cancer. CONCLUSIONS: Despite the demonstrated genotoxic properties of certain catechol estrogens resulting in EDAs, this analysis did not provide evidence for an increased breast cancer risk in relation to an elevated EDA:EMC. IMPACT: This analysis, conducted prospectively within postmenopausal women in the WHI study, suggests that a strong association between EDA:EMC and breast cancer could be ruled out, as this study was powered to detect an OR of 2.2 or greater.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Adutos de DNA/genética , Estrogênios/metabolismo , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Fatores de Risco
18.
Cancer ; 126(16): 3638-3647, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32530506

RESUMO

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.


Assuntos
Neoplasias da Mama/genética , Mama/diagnóstico por imagem , Resistência à Insulina/genética , Saúde da Mulher , Idoso , Glicemia , Índice de Massa Corporal , Mama/patologia , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/mortalidade , Gerenciamento de Dados , Jejum , Feminino , Humanos , Mamografia , Pessoa de Meia-Idade , Pós-Menopausa/genética , Modelos de Riscos Proporcionais , Fatores de Risco
19.
Breast Cancer Res ; 22(1): 62, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32517730

RESUMO

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.


Assuntos
Afro-Americanos , Neoplasias da Mama/etnologia , Neoplasias da Mama/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos do Interstício Tumoral/imunologia , Adulto , Idoso , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linfócitos T CD8-Positivos/patologia , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Linfócitos do Interstício Tumoral/patologia , Pessoa de Meia-Idade , Prognóstico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Taxa de Sobrevida , Saúde da Mulher , Adulto Jovem
20.
Cancer Epidemiol Biomarkers Prev ; 29(3): 591-598, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31915146

RESUMO

BACKGROUND: Obesity-related cancers disproportionately affect the Black community. We assessed the relationship between diet quality, physical activity, and their combined effect on obesity-related cancer risk and mortality in Black women enrolled in the Women's Health Initiative (WHI). METHODS: Data from postmenopausal (50-79 years of age) Black women enrolled in WHI clinical trials or observational studies were analyzed. Exposure variables included baseline physical activity [metabolic equivalent of tasks (MET)-hours/week of moderate-to-vigorous physical activity (MVPA)] and diet quality [Healthy Eating Index (HEI)-2015]. Outcomes included adjudicated obesity-related cancer incidence and mortality. Cox proportional hazard models were used to evaluate the association between MVPA and HEI-2015 and obesity-related cancer risk and mortality. RESULTS: The analytical sample included 9,886 Black women, with a baseline mean body mass index (BMI) of 31.1 kg/m2 (SD = 6.8); mean HEI-2015 score of 63.2 (SD = 11.0, possible range 0 to 100); and mean MVPA of 5.0 (SD = 9.4) MET-hours/week. Over an average of 13 years of follow-up, 950 (9.6%) obesity-related cancer cases were observed, with 313 (32.9%) resulting in death. Physical activity [HR, 1.05; 95% confidence interval (CI), 0.86-1.30], diet quality (HR, 0.99; 95% CI, 0.92-1.08), and their combination (HR, 1.05; 95% CI, 0.85-1.29) were not associated with risk for any or site-specific obesity-related cancers. Similarly, these health behaviors had no association with mortality. CONCLUSIONS: Diet quality, physical activity and their combined effect, as measured, were not associated with obesity-related cancer risk and mortality in Black women enrolled in WHI. IMPACT: Other social, behavioral, and biological factors may contribute to racial disparities observed in obesity-related cancer rates.


Assuntos
Exercício Físico , Comportamento Alimentar , Estilo de Vida , Neoplasias/epidemiologia , Obesidade/epidemiologia , Afro-Americanos/estatística & dados numéricos , Idoso , Índice de Massa Corporal , Feminino , Seguimentos , Disparidades nos Níveis de Saúde , Humanos , Incidência , Pessoa de Meia-Idade , Mortalidade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Medição de Risco/métodos , Fatores de Risco , Estados Unidos/epidemiologia
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