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Genome-wide association studies (GWAS) have been helpful in identifying genetic variants predicting cancer risk and providing new insights into cancer biology. Increasing use of genetically informed care, as well as genetically informed prevention and treatment strategies, have also drawn attention to some of the inherent limitations of cancer genetic data. Specifically, genetic endowment is lifelong. However, those recruited into cancer studies tend to be middle-aged or older people, meaning the exposure most likely starts before recruitment, as opposed to exposure and recruitment aligning, as in a trial or a target trial. Studies in survivors can be biased as a result of depletion of the susceptibles, here specifically due to genetic vulnerability and the cancer of interest or a competing risk. In addition, including prevalent cases in a case-control study will make the genetics of survival with cancer look harmful (Neyman bias). Here, we describe ways of designing GWAS to maximize explanatory power and predictive utility, by reducing selection bias due to only recruiting survivors and reducing Neyman bias due to including prevalent cases alongside using other techniques, such as selection diagrams, age-stratification, and Mendelian randomization, to facilitate GWAS interpretability and utility.
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Young breast and bowel cancers (e.g., those diagnosed before age 40 or 50 years) have far greater morbidity and mortality in terms of years of life lost, and are increasing in incidence, but have been less studied. For breast and bowel cancers, the familial relative risks, and therefore the familial variances in age-specific log(incidence), are much greater at younger ages, but little of these familial variances has been explained. Studies of families and twins can address questions not easily answered by studies of unrelated individuals alone. We describe existing and emerging family and twin data that can provide special opportunities for discovery. We present designs and statistical analyses, including novel ideas such as the VALID (Variance in Age-specific Log Incidence Decomposition) model for causes of variation in risk, the DEPTH (DEPendency of association on the number of Top Hits) and other approaches to analyse genome-wide association study data, and the within-pair, ICE FALCON (Inference about Causation from Examining FAmiliaL CONfounding) and ICE CRISTAL (Inference about Causation from Examining Changes in Regression coefficients and Innovative STatistical AnaLysis) approaches to causation and familial confounding. Example applications to breast and colorectal cancer are presented. Motivated by the availability of the resources of the Breast and Colon Cancer Family Registries, we also present some ideas for future studies that could be applied to, and compared with, cancers diagnosed at older ages and address the challenges posed by young breast and bowel cancers.
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Incidence of early-onset (diagnosed before age 50) colorectal cancer (EOCRC) has increased alarmingly since the 1990s in the United States. This study investigated what environmental exposures may have driven this increase. We obtained EOCRC incidence data from the Surveillance, Epidemiology, and End Results Program, and data for 11 exposures, for example, body mass index (BMI), from long-term national surveys. We aggregated these data for 30 to 49-year-olds during 1992 to 2016 by population subgroups defined by calendar period, age, race and sex, and used negative binomial regression models to identify and estimate associations of EOCRC with multiple exposures. Furthermore, we used counterfactual modeling to quantify contributions of identified risk factors to EOCRC incidence. The top models (with lowest Bayesian Information Criteria) consistently identified excess body weight, represented by overweight and obesity (BMI ≥25) or obesity alone (BMI ≥30), as the strongest risk factor. The best-performing model estimated increased EOCRC incidence due to overweight and obesity, with an incidence rate ratio (95% confidence interval) of 1.20 (1.17-1.22) for white men, 1.04 (1.00-1.08) for black men, 1.17 (1.15-1.21) for white women and 1.03 (0.97-1.08) for black women. Increases in overweight and obesity prevalence contributed to an estimated 30% (standard error: 1%) for men and 28% (standard error: 2%) for women of ECORC incidence during 1992 to 2016. These findings suggest excess body weight substantially contributed to and is likely a primary driver of the rising incidence of EOCRC in the United States. Prevention of excess weight gain may help lower colorectal cancer risk early in life.
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Neoplasias Colorrectales , Sobrepeso , Masculino , Humanos , Femenino , Estados Unidos/epidemiología , Persona de Mediana Edad , Sobrepeso/epidemiología , Incidencia , Teorema de Bayes , Obesidad/complicaciones , Obesidad/epidemiología , Factores de Riesgo , Aumento de Peso , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/etiologíaRESUMEN
Employment and working conditions are strong social determinants of health, yet many epidemiological studies fail to account for their impact on life expectancy calculations. Integration of working conditions into health estimates requires both valid methodology and data sources. Using the French National Health and Career Path survey and French life tables, we quantified the impact of four major work-related factors (lack of job control, job insecurity, unemployment, and occupational physical activity) in explaining socio-occupational inequalities in life expectancy. Using a formula-based approach, we computed work-related loss in life expectancy by socio-occupational group separately by sex. Based on life expectancy at age 35, we estimated a range from 1.3 to 3.3 years of life lost for men, and from 0.5 to 1.8 years for women are attributed to a combination of these four key factors. Although subject to sources of under- and over-estimation, the differential life expectancy at age 35 between senior executives and manual workers would substantially decrease, had these exposures been set at the theoretical minimum level. This proof-of-concept analysis demonstrates the utility of accounting for occupational factors and the potential to quantify the improvements in life expectancy by modifying working and employment conditions.
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Even though many environmental carcinogens have been identified, studying their effects on specific cancers has been challenging in non-occupational settings where exposures may be chronic but at lower levels. Although exposure measurement methods have improved considerably, along with key opportunities to integrate multi-omic platforms, there remain challenges that need to be considered particularly around the design of studies. Cancer studies typically exclude individuals with prior cancers and start recruitment in midlife. This translates into a failure to capture individuals who may have been most susceptible because of both germline susceptibility and higher early life exposures that lead to premature mortality from cancer and/or other environmentally caused diseases like lung diseases. Using the example of breast cancer, we demonstrate how integration of susceptibility, both for cancer risk and exposure windows, may provide a more complete picture regarding the harm of many different environmental exposures. Choice of study design is critical to examine the effects of environmental exposures, and it will not be enough to just rely on the availability of existing cohorts and samples within these cohorts. In contrast, new, diverse, early onset case-control studies may provide many benefits to understanding the impact of environmental exposures on cancer risk and mortality.
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PURPOSE: Nationally legislated dense breast notification (DBN) informs women of their breast density (BD) and the impact of BD on breast cancer risk and detection, but consequences for screening participation are unclear. We evaluated the association of DBN in New York State (NYS) with subsequent screening mammography in a largely Hispanic/Latina cohort. METHODS: Women aged 40-60 were surveyed in their preferred language (33% English, 67% Spanish) during screening mammography from 2016 to 2018. We used clinical BD classification from mammography records from 2013 (NYS DBN enactment) through enrollment (baseline) to create a 6-category variable capturing prior and new DBN receipt (sent only after clinically dense mammograms). We used this variable to compare the number of subsequent mammograms (0, 1, ≥ 2) from 10 to 30 months after baseline using ordinal logistic regression. RESULTS: In a sample of 728 women (78% foreign-born, 72% Hispanic, 46% high school education or less), first-time screeners and women who received DBN for the first time after prior non-dense mammograms had significantly fewer screening mammograms within 30 months of baseline (Odds Ratios range: 0.33 (95% Confidence Interval (CI) 0.12-0.85) to 0.38 (95% CI 0.17-0.82)) compared to women with prior mammography but no DBN. There were no differences in subsequent mammogram frequency between women with multiple DBN and those who never received DBN. Findings were consistent across age, language, health literacy, and education groups. CONCLUSION: Women receiving their first DBN after previous non-dense mammograms have lower mammography participation within 2.5 years. DBN has limited influence on screening participation of first-time screeners and those with persistent dense mammograms.
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Densidad de la Mama , Neoplasias de la Mama , Detección Precoz del Cáncer , Hispánicos o Latinos , Mamografía , Adulto , Femenino , Humanos , Persona de Mediana Edad , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/etnología , Estudios de Cohortes , Tamizaje Masivo , New York/epidemiologíaRESUMEN
PURPOSE: Liver cancer incidence among American Indians/Alaska Natives has risen over the past 20 years. Peripheral blood DNA methylation may be associated with liver cancer and could be used as a biomarker for cancer risk. We evaluated the association of blood DNA methylation with risk of liver cancer. METHODS: We conducted a prospective cohort study in 2324 American Indians, between age 45 and 75 years, from Arizona, Oklahoma, North Dakota and South Dakota who participated in the Strong Heart Study between 1989 and 1991. Liver cancer deaths (n = 21) were ascertained using death certificates obtained through 2017. The mean follow-up duration (SD) for non-cases was 25.1 (5.6) years and for cases, 11.0 (8.8) years. DNA methylation was assessed from blood samples collected at baseline using MethylationEPIC BeadChip 850 K arrays. We used Cox regression models adjusted for age, sex, center, body mass index, low-density lipoprotein cholesterol, smoking, alcohol consumption, and immune cell proportions to examine the associations. RESULTS: We identified 9 CpG sites associated with liver cancer. cg16057201 annotated to MRFAP1) was hypermethylated among cases vs. non-cases (hazard ratio (HR) for one standard deviation increase in methylation was 1.25 (95% CI 1.14, 1.37). The other eight CpGs were hypomethylated and the corresponding HRs (95% CI) ranged from 0.58 (0.44, 0.75) for cg04967787 (annotated to PPRC1) to 0.77 (0.67, 0.88) for cg08550308. We also assessed 7 differentially methylated CpG sites associated with liver cancer in previous studies. The adjusted HR for cg15079934 (annotated to LPS1) was 1.93 (95% CI 1.10, 3.39). CONCLUSIONS: Blood DNA methylation may be associated with liver cancer mortality and may be altered during the development of liver cancer.
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Indígenas Norteamericanos , Neoplasias Hepáticas , Humanos , Persona de Mediana Edad , Anciano , Indio Americano o Nativo de Alaska , Metilación de ADN , Estudios Prospectivos , Indígenas Norteamericanos/genética , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/genéticaRESUMEN
INTRODUCTION: Height, body mass index (BMI), and weight gain are associated with breast cancer risk in the general population. It is unclear whether these associations also exist for carriers of pathogenic variants in the BRCA1 or BRCA2 genes. PATIENTS AND METHODS: An international pooled cohort of 8091 BRCA1/2 variant carriers was used for retrospective and prospective analyses separately for premenopausal and postmenopausal women. Cox regression was used to estimate breast cancer risk associations with height, BMI, and weight change. RESULTS: In the retrospective analysis, taller height was associated with risk of premenopausal breast cancer for BRCA2 variant carriers (HR 1.20 per 10 cm increase, 95% CI 1.04-1.38). Higher young-adult BMI was associated with lower premenopausal breast cancer risk for both BRCA1 (HR 0.75 per 5 kg/m2, 95% CI 0.66-0.84) and BRCA2 (HR 0.76, 95% CI 0.65-0.89) variant carriers in the retrospective analysis, with consistent, though not statistically significant, findings from the prospective analysis. In the prospective analysis, higher BMI and adult weight gain were associated with higher postmenopausal breast cancer risk for BRCA1 carriers (HR 1.20 per 5 kg/m2, 95% CI 1.02-1.42; and HR 1.10 per 5 kg weight gain, 95% CI 1.01-1.19, respectively). CONCLUSION: Anthropometric measures are associated with breast cancer risk for BRCA1 and BRCA2 variant carriers, with relative risk estimates that are generally consistent with those for women from the general population.
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Neoplasias de la Mama , Genes BRCA2 , Adulto , Femenino , Humanos , Índice de Masa Corporal , Proteína BRCA1/genética , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Proteína BRCA2/genética , Riesgo , Estudios Retrospectivos , Aumento de Peso/genética , Heterocigoto , Predisposición Genética a la EnfermedadRESUMEN
PURPOSE: Deep learning techniques, including convolutional neural networks (CNN), have the potential to improve breast cancer risk prediction compared to traditional risk models. We assessed whether combining a CNN-based mammographic evaluation with clinical factors in the Breast Cancer Surveillance Consortium (BCSC) model improved risk prediction. METHODS: We conducted a retrospective cohort study among 23,467 women, age 35-74, undergoing screening mammography (2014-2018). We extracted electronic health record (EHR) data on risk factors. We identified 121 women who subsequently developed invasive breast cancer at least 1 year after the baseline mammogram. Mammograms were analyzed with a pixel-wise mammographic evaluation using CNN architecture. We used logistic regression models with breast cancer incidence as the outcome and predictors including clinical factors only (BCSC model) or combined with CNN risk score (hybrid model). We compared model prediction performance via area under the receiver operating characteristics curves (AUCs). RESULTS: Mean age was 55.9 years (SD, 9.5) with 9.3% non-Hispanic Black and 36% Hispanic. Our hybrid model did not significantly improve risk prediction compared to the BCSC model (AUC of 0.654 vs 0.624, respectively, p = 0.063). In subgroup analyses, the hybrid model outperformed the BCSC model among non-Hispanic Blacks (AUC 0.845 vs. 0.589; p = 0.026) and Hispanics (AUC 0.650 vs 0.595; p = 0.049). CONCLUSION: We aimed to develop an efficient breast cancer risk assessment method using CNN risk score and clinical factors from the EHR. With future validation in a larger cohort, our CNN model combined with clinical factors may help predict breast cancer risk in a cohort of racially/ethnically diverse women undergoing screening.
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Neoplasias de la Mama , Femenino , Humanos , Persona de Mediana Edad , Adulto , Anciano , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/epidemiología , Mamografía/métodos , Estudios Retrospectivos , Detección Precoz del Cáncer , Redes Neurales de la ComputaciónRESUMEN
Peripheral blood mononuclear cells (PBMCs) are a useful model for biochemical assays, particularly for etiological studies. We describe here a method for measuring DNA repair capacity (DRC) in archival cryogenically preserved PBMCs. To model DRC, we measured γ-H2AX repair kinetics in thawed PBMCs after irradiation with 3 Gy gamma rays. Time-dependent fluorescently labeled γ-H2AX levels were measured at five time points from 1 to 20 h, yielding an estimate of global DRC repair kinetics as well as a measure of unrepaired double strand breaks at 20 h. While γ-H2AX levels are traditionally measured by either microscopy or flow-cytometry, we developed a protocol for imaging flow cytometry (IFC) that combines the detailed information of microscopy with the statistical power of flow methods. The visual imaging component of the IFC allows for monitoring aspects such as cellular health and apoptosis as well as fluorescence localization of the γ-H2AX signal, which ensures the power and significance of this technique. Application of a machine-learning based image classification improved flow cytometry fluorescent measurements by identifying apoptotic cells unable to undergo DNA repair. We present here DRC repair parameters from 18 frozen archival PBMCs and 28 fresh blood samples collected from a demographically diverse cohort of women measured in a high-throughput IFC format. This thaw method and assay can be used alone or in conjunction with other assays to measure etiological phenotypes in cryogenic biobanks of PBMCs.
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Histonas , Leucocitos Mononucleares , Femenino , Animales , Leucocitos Mononucleares/metabolismo , Histonas/genética , Histonas/metabolismo , Roturas del ADN de Doble Cadena , Reparación del ADN , CriopreservaciónRESUMEN
Environmental exposure to polycyclic aromatic hydrocarbons (PAH) has been shown to be associated with chronic disease outcomes through multiple mechanisms including altered regulation of the transcription factor peroxisome proliferator-activated receptor gamma (Ppar) γ. Because PAH exposure and Pparγ each have been associated with mammary cancer, we asked whether PAH would induce altered regulation of Pparγ in mammary tissue, and whether this association may underlie the association between PAH and mammary cancer. Pregnant mice were exposed to aerosolized PAH at proportions that mimic equivalent human exposures in New York City air. We hypothesized that prenatal PAH exposure would alter Pparγ DNA methylation and gene expression and induce the epithelial to mesenchymal transition (EMT) in mammary tissue of offspring (F1) and grandoffspring (F2) mice. We also hypothesized that altered regulation of Pparγ in mammary tissue would associate with biomarkers of EMT, and examined associations with whole body weight. We found that prenatal PAH exposure lowered Pparγ mammary tissue methylation among grandoffspring mice at postnatal day (PND) 28. However, PAH exposure did not associate with altered Pparγ gene expression or consistently with biomarkers of EMT. Finally, lower Pparγ methylation, but not gene expression, was associated with higher body weight among offspring and grandoffspring mice at PND28 and PND60. Findings suggest additional evidence of multi-generational adverse epigenetic effects of prenatal PAH exposure among grandoffspring mice.
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Neoplasias de la Mama , Hidrocarburos Policíclicos Aromáticos , Animales , Femenino , Humanos , Ratones , Embarazo , Biomarcadores , Peso Corporal , Neoplasias de la Mama/inducido químicamente , Transición Epitelial-Mesenquimal , Hidrocarburos Policíclicos Aromáticos/metabolismo , Hidrocarburos Policíclicos Aromáticos/toxicidad , PPAR gamma/genética , PPAR gamma/metabolismoRESUMEN
PURPOSE: In the United States, Hispanic-Latino children reach puberty earlier on average than non-Hispanic white children. Yet among U.S. Hispanic/Latino children, pubertal timing comparisons between immigrant generations have not been made, hence we examined whether pubertal timing differs by immigrant generational status, independent of BMI and acculturation measures. METHODS: Cross-sectional data on 724 boys and 735 girls, aged 10-15 years, from the Hispanic Community Children's Health Study/Study of Latino (SOL) Youth, were used to predict the median ages of thelarche, pubarche, and menarche in girls, and pubarche and voice change in boys, using Weibull survival models, while adjusting for SOL center, BMI, and acculturation. RESULTS: In girls, the first generation began thelarche earlier than second and third generations (median age [years] [95% confidence interval]: 7.4 [6.1, 8.8] vs. 8.5 [7.3, 9.7] and 9.1 [7.6, 10.7], respectively), but began menarche later (12.9 [12.0,137] vs. 11.8 [11.0, 12.5] and 11.6 [10.6, 12.6], respectively). Pubertal timing and tempo for boys did not differ by generational status. CONCLUSIONS: First-generation U.S. Hispanic/Latino girls had the earliest thelarche, latest menarche and longest pubertal tempo, compared to second and third generations. Factors beyond BMI and acculturation may account for the differences in pubertal timing by generational status of U.S. Hispanic/Latino girls.
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Emigrantes e Inmigrantes , Pubertad , Masculino , Niño , Femenino , Adolescente , Humanos , Estados Unidos , Estudios Transversales , Menarquia , Hispánicos o LatinosRESUMEN
BACKGROUND: Dense breast notification (DBN) legislation aims to increase a woman's awareness of her personal breast density and the implications of having dense breasts for breast cancer detection and risk. This information may adversely affect women's breast cancer worry, perceptions of risk, and uncertainty about screening, which may persist over time or vary by sociodemographic factors. We examined short- and long-term psychological responses to DBN and awareness of breast density (BD). METHODS: In a predominantly Hispanic New York City screening cohort (63% Spanish-speaking), ages 40-60 years, we assessed breast cancer worry, perceived breast cancer risk, and uncertainties about breast cancer risk and screening choices, in short (1-3 months)- and long-term (9-18 months) surveys following the enrollment screening mammogram (between 2016 and 2018). We compared psychological responses by women's dense breast status (as a proxy for DBN receipt) and BD awareness and examined multiplicative interaction by education, health literacy, nativity, and preferred interview language. RESULTS: In multivariable models using short-term surveys, BD awareness was associated with increased perceived risk (odds ratio (OR) 2.27, 95% confidence interval (CI) 0.99, 5.20 for high, OR 2.19, 95% CI 1.34, 3.58 for moderate, vs. low risk) in the overall sample, and with increased uncertainty about risk (OR 1.97 per 1-unit increase, 95% CI 1.15, 3.39) and uncertainty about screening choices (OR 1.73 per 1-unit increase, 95% CI 1.01, 2.9) in Spanish-speaking women. DBN was associated with decreased perceived risk among women with at least some college education (OR 0.32, 95% CI 0.11, 0.89, for high, OR 0.50, 95% CI 0.29, 0.89, for moderate vs. low risk), while those with a high school education or less experienced an increase (OR 3.01, 95% CI 1.05, 8.67 high vs. low risk). There were no associations observed between DBN or BD awareness and short-term breast cancer worry, nor with any psychological outcomes at long-term surveys. CONCLUSIONS: Associations of BD awareness and notification with breast cancer-related psychological outcomes were limited to short-term increases in perceived breast cancer risk dependent on educational attainment, and increases in uncertainty around breast cancer risk and screening choices among Spanish-speaking women.
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Neoplasias de la Mama , Humanos , Femenino , Adulto , Persona de Mediana Edad , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/epidemiología , Densidad de la Mama , Mamografía , Incertidumbre , Detección Precoz del Cáncer , Tamizaje MasivoRESUMEN
BACKGROUND: Polycyclic aromatic hydrocarbons (PAH), which are found in air pollution, have carcinogenic and endocrine disrupting properties that might increase breast cancer risk. PAH exposure might be particularly detrimental during pregnancy, as this is a time when the breast tissue of both the mother and daughter is undergoing structural and functional changes. In this study, we tested the hypothesis that ambient PAH exposure during pregnancy is associated with breast tissue composition, measured one to two decades later, in adolescent daughters and their mothers. METHODS: We conducted a prospective analysis using data from a New York City cohort of non-Hispanic Black and Hispanic mother-daughter dyads (recruited 1998-2006). During the third trimester of pregnancy, women wore backpacks containing a continuously operating air sampling pump for two consecutive days that measured ambient exposure to eight carcinogenic higher molecular weight nonvolatile PAH compounds (Σ8 PAH) and pyrene. When daughters (n = 186) and mothers (n = 175) reached ages 11-20 and 29-55 years, respectively, optical spectroscopy (OS) was used to evaluate measures of breast tissue composition (BTC) that positively (water content, collagen content, optical index) and negatively (lipid content) correlate with mammographic breast density, a recognized risk factor for breast cancer. Multivariable linear regression was used to evaluate associations between ambient PAH exposure and BTC, overall and by exposure to household tobacco smoke during pregnancy (yes/no). Models were adjusted for race/ethnicity, age, and percent body fat at OS. RESULTS: No overall associations were found between ambient PAH exposure (Σ8 PAH or pyrene) and BTC, but statistically significant additive interactions between Σ8 PAH and household tobacco smoke exposure were identified for water content and optical index in both daughters and mothers (interaction p values < 0.05). Σ8 PAH exposure was associated with higher water content (ßdaughters = 0.42, 95% CI = 0.15-0.68; ßmothers = 0.32, 95% CI = 0.05-0.61) and higher optical index (ßdaughters = 0.38, 95% CI = 0.12-0.64; ßmothers = 0.38, 95% CI = 0.12-0.65) in those exposed to household tobacco smoke during pregnancy; no associations were found in non-smoking households (interaction p values < 0.05). CONCLUSIONS: Exposure to ambient Σ8 PAH and tobacco smoke during pregnancy might interact synergistically to impact BTC in mothers and daughters. If replicated in other cohorts, these findings might have important implications for breast cancer risk across generations.
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Neoplasias de la Mama , Hidrocarburos Policíclicos Aromáticos , Contaminación por Humo de Tabaco , Adolescente , Densidad de la Mama , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/etiología , Estudios de Cohortes , Femenino , Humanos , Madres , Núcleo Familiar , Hidrocarburos Policíclicos Aromáticos/efectos adversos , Embarazo , Estudios Prospectivos , Pirenos/análisis , Contaminación por Humo de Tabaco/análisis , Agua/análisisRESUMEN
PURPOSE: The American Cancer Society (ACS) published an updated Guideline for Cancer Prevention (ACS Guideline) in 2020. Research suggests that adherence to the 2012 ACS Guideline might lower breast cancer risk, but there is limited evidence that this applies to women at increased familial and genetic risk of breast cancer. METHODS: Using the Breast Cancer Family Registry (BCFR), a cohort enriched for increased familial and genetic risk of breast cancer, we examined adherence to three 2020 ACS Guideline recommendations (weight management (body mass index), physical activity, and alcohol consumption) with breast cancer risk in 9615 women. We used Cox proportional hazard regression modeling to calculate hazard ratios (HRs) and 95% confidence intervals (CI) overall and stratified by BRCA1 and BRCA2 pathogenic variant status, family history of breast cancer, menopausal status, and estrogen receptor-positive (ER +) breast cancer. RESULTS: We observed 618 incident invasive or in situ breast cancers over a median 12.9 years. Compared with being adherent to none (n = 55 cancers), being adherent to any ACS recommendation (n = 563 cancers) was associated with a 27% lower breast cancer risk (HR = 0.73, 95% CI: 0.55-0.97). This was evident for women with a first-degree family history of breast cancer (HR = 0.68, 95% CI: 0.50-0.93), women without BRCA1 or BRCA2 pathogenic variants (HR = 0.71, 95% CI: 0.53-0.95), postmenopausal women (HR = 0.63, 95% CI: 0.44-0.89), and for risk of ER+ breast cancer (HR = 0.63, 95% CI: 0.40-0.98). DISCUSSION: Adherence to the 2020 ACS Guideline recommendations for BMI, physical activity, and alcohol consumption could reduce breast cancer risk for postmenopausal women and women at increased familial risk.
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Neoplasias de la Mama , Consumo de Bebidas Alcohólicas/efectos adversos , Consumo de Bebidas Alcohólicas/epidemiología , American Cancer Society , Neoplasias de la Mama/etiología , Neoplasias de la Mama/genética , Ejercicio Físico , Femenino , Humanos , Sistema de Registros , Factores de Riesgo , Estados Unidos/epidemiologíaRESUMEN
PURPOSE: The nonsteroidal anti-inflammatory drug aspirin is an agent of interest for breast cancer prevention. However, it is unclear if aspirin affects mammographic breast density (MBD), a marker of elevated breast cancer risk, particularly in the context of concurrent use of medications indicated for common cardiometabolic conditions, which may also be associated with MBD. METHODS: We used data from the New York Mammographic Density Study for 770 women age 40-60 years old with no history of breast cancer. We evaluated the association between current regular aspirin use and MBD, using linear regression for continuous measures of absolute and percent dense areas and absolute non-dense area, adjusted for body mass index (BMI), sociodemographic and reproductive factors, and use of statins and metformin. We assessed effect modification by BMI and reproductive factors. RESULTS: After adjustment for co-medication, current regular aspirin use was only positively associated with non-dense area (ß = 18.1, 95% CI: 6.7, 29.5). Effect modification by BMI and parity showed current aspirin use to only be associated with larger non-dense area among women with a BMI ≥ 30 (ß = 28.2, 95% CI: 10.8, 45.7), and with lower percent density among parous women (ß = -3.3, 95% CI: -6.4, -0.3). CONCLUSIONS: Independent of co-medication use, current regular aspirin users had greater non-dense area with stronger estimates for women with higher BMI. We found limited support for an association between current aspirin use and mammographically dense breast tissue among parous women.
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Neoplasias de la Mama , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Metformina , Adulto , Aspirina/farmacología , Densidad de la Mama , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/epidemiología , Estudios Transversales , Femenino , Humanos , Mamografía , Persona de Mediana Edad , Embarazo , Factores de RiesgoRESUMEN
PURPOSE: Germline genetic testing for BRCA1 and BRCA2 variants has been a part of clinical practice for >2 decades. However, no studies have compared the cancer risks associated with missense pathogenic variants (PVs) with those associated with protein truncating (PTC) variants. METHODS: We collected 582 informative pedigrees segregating 1 of 28 missense PVs in BRCA1 and 153 pedigrees segregating 1 of 12 missense PVs in BRCA2. We analyzed 324 pedigrees with PTC variants in BRCA1 and 214 pedigrees with PTC variants in BRCA2. Cancer risks were estimated using modified segregation analysis. RESULTS: Estimated breast cancer risks were markedly lower for women aged >50 years carrying BRCA1 missense PVs than for the women carrying BRCA1 PTC variants (hazard ratio [HR] = 3.9 [2.4-6.2] for PVs vs 12.8 [5.7-28.7] for PTC variants; P = .01), particularly for missense PVs in the BRCA1 C-terminal domain (HR = 2.8 [1.4-5.6]; P = .005). In case of BRCA2, for women aged >50 years, the HR was 3.9 (2.0-7.2) for those heterozygous for missense PVs compared with 7.0 (3.3-14.7) for those harboring PTC variants. BRCA1 p.[Cys64Arg] and BRCA2 p.[Trp2626Cys] were associated with particularly low risks of breast cancer compared with other PVs. CONCLUSION: These results have important implications for the counseling of at-risk women who harbor missense PVs in the BRCA1/2 genes.
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Neoplasias de la Mama , Neoplasias Ováricas , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Femenino , Genes BRCA1 , Genes BRCA2 , Predisposición Genética a la Enfermedad , Pruebas Genéticas/métodos , Mutación de Línea Germinal/genética , Humanos , Persona de Mediana Edad , Neoplasias Ováricas/genéticaRESUMEN
OBJECTIVE: To evaluate the risks, benefits, and utility of testing for adult-onset hereditary breast and ovarian cancer (HBOC) in adolescents and young adults. STUDY DESIGN: We evaluated interest in genetic testing of adolescents for adult-onset HBOC genes through semistructured interviews with mothers and adolescents who had previously participated in breast cancer research or had pursued (mothers) clinical testing for HBOC. RESULTS: The majority of mothers (73%) and daughters (75%) were interested in the daughter having genetic testing and were motivated by the future medical utility and current social utility of relieving anxiety and allowing them to prepare. Mothers and daughters both reported that approximately 3 years in the future was the best time to test the daughter regardless of the current age of the daughter. Overall, both mothers and daughters expressed the importance of the involvement of the mother to provide educational and emotional support but ultimately it was the daughter's decision to test. Balancing the independence and maturity of the daughter while reinforcing communication and support within the dyad was a prominent theme throughout the interviews. CONCLUSIONS: There is interest among some high-risk adolescents and young adults to engage in genetic counseling and undergo testing. Providing pretest and posttest genetic counseling, assessing preferences for parent involvement, and offering psychosocial support may be important if genetic testing for HBOC is offered to adolescents and young adults before age 25 years.
Asunto(s)
Neoplasias de la Mama , Madres , Adulto Joven , Femenino , Adolescente , Humanos , Adulto , Asesoramiento Genético , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Neoplasias de la Mama/psicología , Núcleo Familiar , Pruebas GenéticasRESUMEN
BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are endocrine-disrupting chemicals. Few studies have evaluated the association between pubertal development in girls and PAH exposures quantified by urinary biomarkers. METHODS: We examined associations of urinary PAH metabolites with pubertal development in 358 girls 6-16 years of age from the San Francisco Bay Area enrolled in a prospective cohort from 2011 to 2013 and followed until 2020. Using baseline data, we assessed associations of urinary PAH metabolites with pubertal development stage. In prospective analyses limited to girls who at baseline had not yet started breast (N = 176) or pubic hair (N = 179) development or menstruation (N = 267), we used multivariable Cox proportional hazards regression to assess associations of urinary PAH metabolites with the onset of breast and pubic hair development, menstruation, and pubertal tempo (interval between the onset of breast development and menstruation). RESULTS: We detected PAH metabolites in >98% of girls. In cross-sectional analyses using baseline data, PAH metabolites were not associated with the pubertal development stage. In prospective analyses, higher concentrations (≥ median) of some PAH metabolites were associated with two-fold higher odds of earlier breast development (2-hydroxy naphthalene, 1-hydroxy phenanthrene, summed hydroxy phenanthrenes) or pubic hair development (1-hydroxy naphthalene) among girls overweight at baseline (body mass index-for-age percentile ≥85) compared with nonoverweight girls with lower metabolites concentrations. PAH metabolites were not associated with age at menarche or pubertal tempo. CONCLUSIONS: PAH exposures were widespread in our sample. Our results support the hypothesis that, in overweight girls, PAHs impact the timing of pubertal development, an important risk factor for breast cancer.
Asunto(s)
Fenantrenos , Hidrocarburos Policíclicos Aromáticos , Biomarcadores/orina , Estudios Transversales , Femenino , Humanos , Naftalenos , Sobrepeso , Hidrocarburos Policíclicos Aromáticos/orina , Estudios Prospectivos , Pubertad , San Francisco/epidemiologíaRESUMEN
BACKGROUND: Polycyclic aromatic hydrocarbon (PAH) exposures from tobacco smoke, automobile exhaust, grilled or smoked meat and other sources are widespread and are a public health concern, as many are classified as probable carcinogens and suspected endocrine-disrupting chemicals. PAH exposures can be quantified using urinary biomarkers. METHODS: Seven urinary metabolites of naphthalene, fluorene, phenanthrene, and pyrene were measured in two samples collected from girls aged 6-16 years from the San Francisco Bay Area. We used Spearman correlation coefficients (SCC) to assess correlations among metabolite concentrations (corrected for specific gravity) separately in first (n = 359) and last (N = 349) samples, and to assess consistency of measurements in samples collected up to 72 months apart. Using multivariable linear regression, we assessed variation in mean metabolites across categories of participant characteristics and potential outdoor, indoor, and dietary sources of PAH exposures. RESULTS: The detection rate of PAH metabolites was high (4 metabolites in ≥98% of first samples; 5 metabolites in ≥95% of last samples). Correlations were moderate to strong between fluorene, phenanthrene and pyrene metabolites (SCC 0.43-0.82), but weaker between naphthalene and the other metabolites (SCC 0.18-0.36). SCC between metabolites in first and last samples ranged from 0.15 to 0.49. When classifying metabolite concentrations into tertiles based on single samples (first or last samples) vs. the average of the two samples, agreement was moderate to substantial (weighted kappa statistics 0.52-0.65). For specific metabolites, concentrations varied by age, race/ethnicity, and body mass index percentile, as well as by outdoor sources (season of sample collection, street traffic), indoor sources (heating with gas, cigarette smoke), and dietary sources (frequent use of grill, consumption of smoked meat or fish) of PAH exposures. CONCLUSIONS: Urinary PAH exposure was widespread in girls aged 6-16 years and associated with several sources of exposure. Tertile classification of a single urine sample provides reliable PAH exposure ranking.