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1.
J Natl Cancer Inst ; 2021 Jan 05.
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 (TME), 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 TME from 1,315 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 three 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 the composition and quality of immune infiltrates differed, regardless of tumor subtypes. Black patients had a stronger CD4+/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 (HR)-positive patients. Among HR-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 indicates an immunobiological basis for their more aggressive disease, and also a rationale for the use of immune checkpoint inhibitors targeting the exhaustion phenotype.

2.
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.

3.
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.

4.
Cancer Epidemiol Biomarkers Prev ; 29(10): 2096-2099, 2020 Oct.
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.

5.
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 , Grupo com Ancestrais do Continente Europeu , 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 Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Taxa de Sobrevida , Saúde da Mulher , Adulto Jovem
6.
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.

7.
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.

8.
Appl Immunohistochem Mol Morphol ; 28(4): 267-273, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31205070

RESUMO

Loss of immunoreactivity in tissue sections has been shown to occur when slide sections are stored at room temperature for prolonged periods of time. We conducted a systematic investigation to determine the extent of staining loss in various storage conditions to determine an optimal storage method. We investigated 6 antibodies that are commonly used for breast cancer subtyping in research studies with immunohistochemistry (ER, PR, HER2, CK5/6, EGFR, and Ki67) in formalin-fixed paraffin-embedded breast tissue microarrays consisting of 148 patients. Tissue microarrays were sectioned at various time points: fresh, 1 week, 1 month, 6 months, and 12 months before staining. Slides sectioned at each time point were stored in 5 storage conditions: desiccator, paraffin dipped, 4°C, -20°C, and -80°C. Immunohistochemistry scores were assessed over time with McNemar Test and Bowker Test of Symmetry. Desiccator storage was the only storage condition that did not show any loss in immunoreactivity for any antibody or time point in our study. Paraffin coated slides were the most difficult storage method operationally and also showed the most loss in immunoreactivity. Storing sections in a desiccator was the most effective method for minimizing immunoreactivity loss. Cold storage at 4°C is an intermediate option that is not as protective as a desiccator, but offers the advantage of being accessible to virtually all research labs.

9.
Cancer Epidemiol Biomarkers Prev ; 29(2): 379-385, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31871111

RESUMO

BACKGROUND: Forkhead box protein A1 (FOXA1) promotes luminal differentiation, and hypermethylation of the gene can be a mechanism of developing estrogen receptor-negative (ER-) breast cancer. We examined FOXA1 in breast tumor and adjacent normal tissue in relation to reproductive factors, particularly higher parity and no breastfeeding, that are associated with ER- tumors. METHODS: We performed IHC for FOXA1 in breast tumors (n = 1,329) and adjacent normal tissues (n = 298) in the Women's Circle of Health Study (949 Blacks and 380 Whites). Protein expression levels were summarized by histology (H) scores. Generalized linear models were used to assess FOXA1 protein expression in relation to reproductive factors by ER status. RESULTS: ER-positive (ER+) versus ER- tumors had higher FOXA1 protein expression (P < 0.001). FOXA1 expression was higher in tumor versus paired adjacent normal tissue in women with ER+ or non-triple-negative cancer (both P < 0.001), but not in those with ER- or triple-negative cancer. Higher number of births (1, 2, and 3+) was associated with lower FOXA1 protein expression in ER+ tumors [differences in H score, or ß = -8.5; 95% confidence interval (CI), -15.1 to -2.0], particularly among parous women who never breastfed (ß = -10.4; 95% CI, -19.7 to -1.0), but not among those who breastfed (ß = -7.5; 95% CI, -16.9 to 1.8). The associations for ER- tumors were similar, although they were not statistically significant. CONCLUSIONS: In this tumor-based study, higher parity was associated with lower FOXA1 expression in ER+ tumors, and breastfeeding may ameliorate the influence. IMPACT: These findings contribute to our understanding of FOXA1 methylation and breast cancer etiology.

10.
Horm Cancer ; 10(4-6): 168-176, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31621000

RESUMO

We previously reported that an accelerated decline in circulating testosterone level is associated with a higher risk of prostate cancer (PCa). This study is to examine whether testosterone change rate is related to serum prostate-specific antigen (PSA) concentration among PCa-free men. Longitudinal data were derived from electronic medical records at a tertiary hospital in the Southeastern USA. PCa-free men with initial-PSA < 4 ng/mL and ≥ 2 testosterone measurements were included (n = 632). Three PSA measures (peak, the most recent, and average PSA) during the study period (from first testosterone measurement to the most recent hospital visit) were examined using multivariable-adjusted geometric means and were compared across quintiles of testosterone change rate (ng/dL/month) and current testosterone level (cross-sectional). Mean (standard deviation, SD) age at baseline was 59.3 (10.5) years; mean study period was 93.0 (55.3) months. After adjusting for covariates including baseline testosterone, the three PSA measures all significantly increased across quintile of testosterone change rate from increase to decline (peak PSA: quint 1 = 1.09, quint 5 = 1.41; the most recent PSA: quint 1 = 0.85, quint 5 = 1.00; average PSA: quint 1 = 0.89, quint 5 = 1.02; all Ptrend < 0.001). But current testosterone level was not associated with PSA levels. Stratified analyses indicated men with higher adiposity (body mass index > 24.1 kg/m2) or lower baseline testosterone (≤ 296 ng/dL) were more sensitive to testosterone change in regard to PSA. Among PCa-free men, accelerated testosterone decline might correlate with higher serum PSA concentration. It will help to elucidate the mechanisms relating aging-accompanying testosterone dynamics to prostate carcinogenesis.


Assuntos
Envelhecimento/sangue , Antígeno Prostático Específico/sangue , Testosterona/sangue , Idoso , Estudos Transversais , Registros Eletrônicos de Saúde , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Centros de Atenção Terciária
11.
Br J Cancer ; 120(6): 647-657, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30787463

RESUMO

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.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Teorema de Bayes , Neoplasias da Mama/metabolismo , Cromossomos Humanos Par 7 , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Prognóstico , Modelos de Riscos Proporcionais , Receptores Estrogênicos/genética , Receptores Estrogênicos/metabolismo
12.
J Natl Cancer Inst ; 111(10): 1059-1067, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30629220

RESUMO

BACKGROUND: Growing laboratory and animal model evidence supports the potentially carcinogenic effects of some phthalates, chemicals used as plasticizers in a wide variety of consumer products, including cosmetics, medications, and vinyl flooring. However, prospective data on whether phthalates are associated with human breast cancer risk are lacking. METHODS: We conducted a nested case-control study within the Women's Health Initiative (WHI) prospective cohort (n = 419 invasive case subjects and 838 control subjects). Control subjects were matched 2:1 to case subjects on age, enrollment date, follow-up time, and WHI study group. We quantified 13 phthalate metabolites and creatinine in two or three urine samples per participant over one to three years. Multivariable conditional logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for breast cancer risk associated with each phthalate biomarker up to 19 years of follow-up. RESULTS: Overall, we did not observe statistically significant positive associations between phthalate biomarkers and breast cancer risk in multivariable analyses (eg, 4th vs 1st quartile of diethylhexyl phthalate, OR = 1.03, 95% CI = 0.91 to 1.17). Results were generally similar in analyses restricted to disease subtypes, to nonusers of postmenopausal hormone therapy, stratified by body mass index, or to case subjects diagnosed within three, five, or ten years. CONCLUSIONS: In the first prospective analysis of phthalates and postmenopausal breast cancer, phthalate biomarker concentrations did not result in an increased risk of developing invasive breast cancer.


Assuntos
Biomarcadores , Neoplasias da Mama/etiologia , Neoplasias da Mama/urina , Suscetibilidade a Doenças , Ácidos Ftálicos/urina , Idoso , Biomarcadores Tumorais , Neoplasias da Mama/metabolismo , Estudos de Casos e Controles , Creatinina/urina , Feminino , Humanos , Pessoa de Meia-Idade , Razão de Chances , Medição de Risco , Fatores de Risco
13.
Nat Genet ; 50(7): 968-978, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29915430

RESUMO

The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10-6, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.


Assuntos
Neoplasias da Mama/genética , Estudos de Casos e Controles , Feminino , Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Humanos , Polimorfismo de Nucleotídeo Único , Risco , Transcriptoma
14.
Epidemiology ; 29(5): 604-613, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29864084

RESUMO

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.


Assuntos
Viés , Índice de Massa Corporal , Obesidade/diagnóstico , Pós-Menopausa , Tecido Adiposo/patologia , Idoso , Estatura , Peso Corporal , Feminino , Humanos , Pessoa de Meia-Idade , Obesidade/mortalidade , Probabilidade
16.
Breast Cancer Res ; 20(1): 12, 2018 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-29409530

RESUMO

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.


Assuntos
Neoplasias da Mama/genética , Receptor ErbB-2/genética , Receptores Estrogênicos/genética , Receptores de Progesterona/genética , Adulto , Afro-Americanos/genética , Idoso , Biomarcadores Tumorais/genética , Neoplasias da Mama/classificação , Neoplasias da Mama/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica/métodos , Antígeno Ki-67/genética , Pessoa de Meia-Idade , Gradação de Tumores
17.
Cancer Epidemiol Biomarkers Prev ; 27(3): 321-330, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29339359

RESUMO

Background: Constitutional immunity shaped by exposure to endemic infectious diseases and parasitic worms in Sub-Saharan Africa may play a role in the etiology of breast cancer among African American (AA) women.Methods: A total of 149,514 gene variants in 433 genes across 45 immune pathways were analyzed in the AMBER consortium among 3,663 breast cancer cases and 4,687 controls. Gene-based pathway analyses were conducted using the adaptive rank truncated product statistic for overall breast cancer risk, and risk by estrogen receptor (ER) status. Unconditional logistic regression analysis was used to estimate ORs and 95% confidence intervals (CIs) for single variants.Results: The top pathways were Interleukin binding (P = 0.01), Biocarta TNFR2 (P = 0.005), and positive regulation of cytokine production (P = 0.024) for overall, ER+, and ER- cancers, respectively. The most significant gene was IL2RB (P = 0.001) for overall cancer, with rs228952 being the top variant identified (OR = 0.85; 95% CI, 0.79-0.92). Only BCL3 contained a significant variant for ER+ breast cancer. Variants in IL2RB, TLR6, IL8, PRKDC, and MAP3K1 were associated with ER- disease. The only genes showing heterogeneity between ER- and ER+ cancers were TRAF1, MAP3K1, and MAPK3 (P ≤ 0.02). We also noted genes associated with autoimmune and atopic disorders.Conclusions: Findings from this study suggest that genetic variants in immune pathways are relevant to breast cancer susceptibility among AA women, both for ER+ and ER- breast cancers.Impact: Results from this study extend our understanding of how inherited genetic variation in immune pathways is relevant to breast cancer susceptibility. Cancer Epidemiol Biomarkers Prev; 27(3); 321-30. ©2018 AACR.


Assuntos
Afro-Americanos/genética , Doenças Autoimunes/epidemiologia , Neoplasias da Mama/epidemiologia , Predisposição Genética para Doença , Mapas de Interação de Proteínas/genética , Adulto , Idoso , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Proteína Quinase Ativada por DNA/genética , Proteína Quinase Ativada por DNA/imunologia , Proteína Quinase Ativada por DNA/metabolismo , Feminino , Humanos , Subunidade beta de Receptor de Interleucina-2/genética , Subunidade beta de Receptor de Interleucina-2/imunologia , Subunidade beta de Receptor de Interleucina-2/metabolismo , Interleucina-8/genética , Interleucina-8/imunologia , Interleucina-8/metabolismo , MAP Quinase Quinase Quinase 1/genética , MAP Quinase Quinase Quinase 1/imunologia , MAP Quinase Quinase Quinase 1/metabolismo , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Proteínas Nucleares/imunologia , Proteínas Nucleares/metabolismo , Polimorfismo de Nucleotídeo Único , Mapas de Interação de Proteínas/imunologia , Receptores Estrogênicos/metabolismo , Fatores de Risco , Receptor 6 Toll-Like/genética , Receptor 6 Toll-Like/imunologia , Receptor 6 Toll-Like/metabolismo
18.
J Natl Cancer Inst ; 110(7): 734-742, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29346580

RESUMO

Background: To what extent steroid hormones contribute to lung cancer in male and female never smokers and smokers is unclear. We examined expression of hormone receptors in lung tumors by sex and smoking. Methods: Patients with primary non-small cell lung cancer were recruited into an Intergroup study in the United States and Canada, led by SWOG (S0424). Tumors from 813 cases (450 women and 363 men) were assayed using immunohistochemistry for estrogen receptor (ER)-α, ER-ß, progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Linear regression was used to examine differences in expression by sex and smoking status. Cox proportional hazard models were used to estimate survival associated with the receptors. All statistical tests were two-sided. Results: In ever smokers, postmenopause and oral contraceptive use were associated with lower nuclear ER-ß (P = .02) and total (nuclear + cytoplasmic) PR expression (P = .02), respectively. Women had lower cytoplasmic ER-α (regression coefficient [ß], or differences in H-scores = -15.8, P = .003) and nuclear ER-ß (ß = -12.8, P = .04) expression than men, adjusting for age, race, and smoking. Ever smokers had both higher cytoplasmic ER-α (ß = 45.0, P < .001) and ER-ß (ß = 25.9, P < .001) but lower total PR (ß = -42.1, P < .001) than never smokers. Higher cytoplasmic ER-α and ER-ß were associated with worse survival (hazard ratio = 1.73, 95% confidence interval [CI] = 1.15 to 2.58, and HR = 1.59, 95% CI = 1.08 to 2.33, respectively; quartiles 4 vs 1). Conclusions: Lower expression of nuclear ER-ß in women supports the estrogen hypothesis in lung cancer etiology. Increasing cytoplasmic ER-α and ER-ß and decreasing PR protein expression may be mechanisms whereby smoking disrupts hormone pathways.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/metabolismo , Receptores de Esteroides/metabolismo , Fumar/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Canadá/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Estados Unidos/epidemiologia
19.
Cancer Causes Control ; 28(10): 1053-1063, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28900765

RESUMO

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.


Assuntos
Adenocarcinoma/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Neoplasias Pulmonares/epidemiologia , Pós-Menopausa/sangue , Vitamina D/análogos & derivados , Adenocarcinoma/sangue , Idoso , Carcinoma Pulmonar de Células não Pequenas/sangue , Estudos de Casos e Controles , Feminino , Humanos , Modelos Logísticos , Neoplasias Pulmonares/sangue , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco , Vitamina D/sangue
20.
Int J Cancer ; 141(11): 2281-2290, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-28833074

RESUMO

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.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias Colorretais/epidemiologia , Métodos Epidemiológicos , Obesidade/complicações , Idoso , Neoplasias da Mama/etiologia , Neoplasias Colorretais/etiologia , Feminino , Humanos , Incidência , Pessoa de Meia-Idade , Modelos Estatísticos , Modelos de Riscos Proporcionais , Fatores de Risco
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