The Associations between Intakes of One-Carbon Metabolism-Related Vitamins and Breast Density among Young Women.

BACKGROUND: Folate is the primary methyl donor and B vitamins are cofactors for one-carbon metabolism that maintain DNA integrity and epigenetic signatures implicated in carcinogenesis. Breast tissue is particularly susceptible to stimuli in early life. Only limited data are available on associations of one-carbon metabolism-related vitamin intake during youth and young adulthood with breast density, a strong risk factor for breast cancer. METHODS: Over 18 years in the DISC and DISC06 Follow-up Study, diets of 182 young women were assessed by three 24-hour recalls on five occasions at ages 8 to 18 years and once at 25 to 29 years. Multivariable-adjusted linear mixed-effects regression was used to examine associations of intakes of one-carbon metabolism-related vitamins with MRI-measured percent dense breast volume (%DBV) and absolute dense breast volume (ADBV) at ages 25 to 29 years. RESULTS: Folate intake in youth was inversely associated with %DBV (Ptrend = 0.006) and ADBV (Ptrend = 0.02). These inverse associations were observed with intake during post-, though not premenarche. In contrast, premenarche vitamin B2 intake was positively associated with ADBV (Ptrend < 0.001). Young adult folate and vitamin B6 intakes were inversely associated with %DBV (all Ptrend ≤ 0.04), whereas vitamins B6 and B12 were inversely associated with ADBV (all Ptrend ≤ 0.04). CONCLUSIONS: Among these DISC participants intakes of one-carbon metabolism-related vitamins were associated with breast density. Larger prospective studies among diverse populations are needed to replicate these findings. IMPACT: Our results suggest the importance of one-carbon metabolism-related vitamin intakes early in life with development of breast density and thereby potentially breast cancer risk later in life.

Untargeted serum metabolomic profiles and breast density in young women.

PURPOSE OF THE STUDY: Breast density is an established risk factor for breast cancer. However, little is known about metabolic influences on breast density phenotypes. We conducted untargeted serum metabolomics analyses to identify metabolic signatures associated with breast density phenotypes among young women. METHODS: In a cross-sectional study of 173 young women aged 25-29 who participated in the Dietary Intervention Study in Children 2006 Follow-up Study, 449 metabolites were measured in fasting serum samples using ultra-high-performance liquid chromatography-tandem mass spectrometry. Multivariable-adjusted mixed-effects linear regression identified metabolites associated with magnetic resonance imaging measured breast density phenotypes: percent dense breast volume (%DBV), absolute dense breast volume (ADBV), and absolute non-dense breast volume (ANDBV). Metabolite results were corrected for multiple comparisons using a false discovery rate adjusted p-value (q). RESULTS: The amino acids valine and leucine were significantly inversely associated with %DBV. For each 1 SD increase in valine and leucine, %DBV decreased by 20.9% (q = 0.02) and 18.4% (q = 0.04), respectively. ANDBV was significantly positively associated with 16 lipid and one amino acid metabolites, whereas no metabolites were associated with ADBV. Metabolite set enrichment analysis also revealed associations of distinct metabolic signatures with %DBV, ADBV, and ANDBV; branched chain amino acids had the strongest inverse association with %DBV (p = 0.002); whereas, diacylglycerols and phospholipids were positively associated with ANDBV (p ≤ 0.002), no significant associations were observed for ADBV. CONCLUSION: Our results suggest an inverse association of branched chain amino acids with %DBV. Larger studies in diverse populations are needed.

A comparison of associations of body mass index and dual-energy x-ray absorptiometry measured percentage fat and total fat with global serum metabolites in young women.

OBJECTIVE: Body mass index (BMI) does not directly measure adiposity, whereas dual-energy x-ray absorptiometry (DXA) provides valid direct estimates of adiposity. Therefore, this study evaluated usefulness of BMI as a measure of adiposity in serum metabolomics studies. METHODS: A cross-sectional analysis was conducted of 202 women aged 25 to 29 years in the Dietary Intervention Study in Children Follow-Up Study. Heights and weights were measured, and body composition was quantified using clinical DXA protocols. Serum metabolomic profiling was performed by liquid chromatography-tandem mass spectrometry. Partial correlations of BMI, percentage fat (%FAT), and total fat (TOTFAT) with log transformed serum metabolites were calculated. RESULTS: There was significant overlap in the 93 metabolites that correlated with BMI, %FAT, and/or TOTFAT; 9 differently correlated with BMI and %FAT, whereas 15 differently correlated with BMI and TOTFAT. Even for these metabolites, absolute differences were modest. Metabolite set enrichment analysis identified diacylglycerol and sphingolipid metabolism as overrepresented among metabolites significantly correlated with all three measures of adiposity. CONCLUSIONS: BMI can be a good proxy for DXA measured %FAT and TOTFAT in descriptive metabolomic studies of healthy, young White women. Larger studies in more diverse populations are needed to endorse more generalized conclusions.

Childhood adiposity, serum metabolites and breast density in young women.

BACKGROUND: Childhood adiposity is inversely associated with young adult percent dense breast volume (%DBV) and absolute dense breast volume (ADBV), which could contribute to its protective effect for breast cancer later in life. The objective of this study was to identify metabolites in childhood serum that may mediate the inverse association between childhood adiposity and young adult breast density. METHODS: Longitudinal data from 182 female participants in the Dietary Intervention Study in Children (DISC) and the DISC 2006 (DISC06) Follow-Up Study were analyzed. Childhood adiposity was assessed by anthropometry at the DISC visit with serum available that occurred closest to menarche and expressed as a body mass index (BMI) z-score. Serum metabolites were measured by untargeted metabolomics using ultra-high-performance liquid chromatography-tandem mass spectrometry. %DBV and ADBV were measured by magnetic resonance imaging at the DISC06 visit when participants were 25-29 years old. Robust mixed effects linear regression was used to identify serum metabolites associated with childhood BMI z-scores and breast density, and the R package mediation was used to quantify mediation. RESULTS: Of the 115 metabolites associated with BMI z-scores (FDR < 0.20), 4 were significantly associated with %DBV and 6 with ADBV before, though not after, adjustment for multiple comparisons. Mediation analysis identified 2 unnamed metabolites, X-16576 and X-24588, as potential mediators of the inverse association between childhood adiposity and dense breast volume. X-16576 mediated 14% (95% confidence interval (CI) = 0.002, 0.46; P = 0.04) of the association of childhood adiposity with %DBV and 11% (95% CI = 0.01, 0.26; P = 0.02) of its association with ADBV. X-24588 also mediated 7% (95% CI = 0.001, 0.18; P = 0.05) of the association of childhood adiposity with ADBV. None of the other metabolites examined contributed to mediation of the childhood adiposity-%DBV association, though there was some support for contributions of lysine, valine and 7-methylguanine to mediation of the inverse association of childhood adiposity with ADBV. CONCLUSIONS: Additional large longitudinal studies are needed to identify metabolites and other biomarkers that mediate the inverse association of childhood adiposity with breast density and possibly breast cancer risk.

Association between Use of Nutrition Labels and Risk of Chronic Kidney Disease: The Korean National Health and Nutrition Examination Survey (KNHANES) 2008-2019.

Nutrition labeling on food packages is increasingly found to promote healthier food choices associated with lower risk of chronic kidney disease (CKD). To examine associations between nutrition labels use and CKD risk, we conducted a nationally representative cross-sectional study of 32,080 adults from the 2008−2019 Korean National Health and Nutrition Examination Survey. Nutrition labels use was collected via self-reported questionnaires. Ascertainment and severity of CKD was determined by estimated glomerular filtration rate or proteinuria. In multivariable-adjusted (MV) logistic regression models, increasing awareness and use of nutrition labels was significantly associated with lower CKD risk (MV-adjusted OR "nutrition labels aware and use" group vs. "nutrition labels unaware" group [95% CIs]: 0.75 [0.59−0.95], Ptrend:0.03). This inverse association varied with CKD's risk of progression, with 21% and 42% reduced risk observed for CKD subtypes with "moderate" and "high" risk of progression, respectively (all Ptrend ≤ 0.04). Furthermore, the nutrition labels use and CKD risk association significantly differed by age, with 35% reduced risk observed in the older group aged 49 years or older, but not in the younger group (Pinteraction < 0.001). Our results suggest increasing perception and use of nutrition labels may contribute to CKD prevention and its early asymptomatic progression, especially in older adults.

Life-years lost due to cancer among solid organ transplant recipients in the United States, 1987 to 2014.

BACKGROUND: Solid organ transplant recipients have an elevated risk of cancer. Quantifying the life-years lost (LYL) due to cancer provides a complementary view of the burden of cancer distinct from other metrics and may identify subgroups of transplant recipients who are most affected. METHODS: Linked transplant and cancer registry data were used to identify incident cancers and deaths among solid organ transplant recipients in the United States (1987-2014). Data on LYL due to cancer within 10 years posttransplant were derived using mean survival estimates from Cox models. RESULTS: Among 221,962 transplant recipients, 13,074 (5.9%) developed cancer within 10 years of transplantation. During this period, the mean LYL due to cancer were 0.16 years per transplant recipient and 2.7 years per cancer case. Cancer was responsible for a loss of 1.9% of the total life-years expected in the absence of cancer in this population. Lung recipients had the highest proportion of total LYL due to cancer (0.45%) followed by heart recipients (0.29%). LYL due to cancer increased with age, from 0.5% among those aged birth to 34 years at transplant to 3.2% among those aged 50 years and older. Among recipients overall, lung cancer was the largest contributor, accounting for 24% of all LYL due to cancer, and non-Hodgkin lymphoma had the next highest contribution (15%). CONCLUSIONS: Transplant recipients have a shortened lifespan after developing cancer. Lung cancer and non-Hodgkin lymphoma contribute strongly to LYL due to cancer within the first 10 years after transplant, highlighting opportunities to reduce cancer mortality through prevention and screening.

Breast Cancer Risk Factors and Circulating Anti-Müllerian Hormone Concentration in Healthy Premenopausal Women.

CONTEXT: We previously reported that anti-Müllerian hormone (AMH), a marker of ovarian reserve, is positively associated with breast cancer risk, consistent with other studies. OBJECTIVE: This study assessed whether risk factors for breast cancer are correlates of AMH concentration. METHODS: This cross-sectional study included 3831 healthy premenopausal women (aged 21-57, 87% aged 35-49) from 10 cohort studies among the general population. RESULTS: Adjusting for age and cohort, AMH positively associated with age at menarche (P < 0.0001) and parity (P = 0.0008) and inversely associated with hysterectomy/partial oophorectomy (P = 0.0008). Compared with women of normal weight, AMH was lower (relative geometric mean difference 27%, P < 0.0001) among women who were obese. Current oral contraceptive (OC) use and current/former smoking were associated with lower AMH concentration than never use (40% and 12% lower, respectively, P < 0.0001). We observed higher AMH concentrations among women who had had a benign breast biopsy (15% higher, P = 0.03), a surrogate for benign breast disease, an association that has not been reported. In analyses stratified by age (<40 vs ≥40), associations of AMH with body mass index and OCs were similar in younger and older women, while associations with the other factors (menarche, parity, hysterectomy/partial oophorectomy, smoking, and benign breast biopsy) were limited to women ≥40 (P-interaction < 0.05). CONCLUSION: This is the largest study of AMH and breast cancer risk factors among women from the general population (not presenting with infertility), and it suggests that most associations are limited to women over 40, who are approaching menopause and whose AMH concentration is declining.

Alcohol consumption and serum metabolite concentrations in young women.

PURPOSE: Alcohol consumption is an established breast cancer risk factor, though further research is needed to advance our understanding of the mechanism underlying the association. We used global metabolomics profiling to identify serum metabolites and metabolic pathways that could potentially mediate the alcohol-breast cancer association. METHODS: A cross-sectional analysis of reported alcohol consumption and serum metabolite concentrations was conducted among 211 healthy women 25-29 years old who participated in the Dietary Intervention Study in Children 2006 Follow-Up Study (DISC06). Alcohol-metabolite associations were evaluated using multivariable linear mixed-effects regression. RESULTS: Alcohol was significantly (FDR p < 0.05) associated with several serum metabolites after adjustment for diet composition and other potential confounders. The amino acid sarcosine, the omega-3 fatty acid eicosapentaenoate, and the steroid 4-androsten-3beta,17beta-diol monosulfate were positively associated with alcohol intake, while the gamma-tocopherol metabolite gamma-carboxyethyl hydroxychroman (CEHC) was inversely associated. Positive associations of alcohol with 2-methylcitrate and 4-androsten-3beta,17beta-diol disulfate were borderline significant (FDR p < 0.10). Metabolite set enrichment analysis identified steroids and the glycine pathway as having more members associated with alcohol consumption than expected by chance. CONCLUSIONS: Most of the metabolites associated with alcohol in the current analysis participate in pathways hypothesized to mediate the alcohol-breast cancer association including hormonal, one-carbon metabolism, and oxidative stress pathways, but they could also affect risk via alternative pathways. Independent replication of alcohol-metabolite associations and prospective evaluation of confirmed associations with breast cancer risk are needed.

Pubertal timing and breast density in young women: a prospective cohort study.

BACKGROUND: Earlier age at onset of pubertal events and longer intervals between them (tempo) have been associated with increased breast cancer risk. It is unknown whether the timing and tempo of puberty are associated with adult breast density, which could mediate the increased risk. METHODS: From 1988 to 1997, girls participating in the Dietary Intervention Study in Children (DISC) were clinically assessed annually between ages 8 and 17 years for Tanner stages of breast development (thelarche) and pubic hair (pubarche), and onset of menses (menarche) was self-reported. In 2006-2008, 182 participants then aged 25-29 years had their percent dense breast volume (%DBV) measured by magnetic resonance imaging. Multivariable, linear mixed-effects regression models adjusted for reproductive factors, demographics, and body size were used to evaluate associations of age and tempo of puberty events with %DBV. RESULTS: The mean (standard deviation) and range of %DBV were 27.6 (20.5) and 0.2-86.1. Age at thelarche was negatively associated with %DBV (p trend = 0.04), while pubertal tempo between thelarche and menarche was positively associated with %DBV (p trend = 0.007). %DBV was 40% higher in women whose thelarche-to-menarche tempo was 2.9 years or longer (geometric mean (95%CI) = 21.8% (18.2-26.2%)) compared to women whose thelarche-to-menarche tempo was less than 1.6 years (geometric mean (95%CI) = 15.6% (13.9-17.5%)). CONCLUSIONS: Our results suggest that a slower pubertal tempo, i.e., greater number of months between thelarche and menarche, is associated with higher percent breast density in young women. Future research should examine whether breast density mediates the association between slower tempo and increased breast cancer risk.

Cancer-attributable mortality among solid organ transplant recipients in the United States: 1987 through 2014.

BACKGROUND: Solid organ transplant recipients have an elevated risk of cancer. Quantifying deaths attributable to cancer can inform priorities to reduce cancer burden. METHODS: Linked transplantation and cancer registry data were used to identify incident cancers and deaths among solid organ transplant recipients in the United States (1987-2014). Population-attributable fractions (PAFs) of deaths due to cancer and corresponding cancer-attributable mortality rates were estimated using Cox models. RESULTS: Among 221,962 solid organ transplant recipients, 15,012 developed cancer. Approximately 13% of deaths (PAF, 13.2%) were attributable to cancer, corresponding to a cancer-attributable mortality rate of 516 per 100,000 person-years. Lung cancer was the largest contributor to mortality (PAF, 3.1%), followed by non-Hodgkin lymphoma (NHL; PAF, 1.9%), colorectal cancer (PAF, 0.7%), and kidney cancer (PAF, 0.5%). Cancer-attributable mortality rates increased with age at transplantation, reaching 1229 per 100,000 person-years among recipients aged ≥65 years. NHL was the largest contributor among children (PAF, 4.1%) and lung cancer was the largest contributor among recipients aged ≥50 years (PAFs, 3.7%-4.3%). Heart recipients had the highest PAF (16.4%), but lung recipients had the highest cancer-attributable mortality rate (1241 per 100,000 person-years). Overall, mortality attributable to cancer increased steadily with longer time since transplantation, reaching 15.7% of deaths (810 per 100,000 person-years) at ≥10 years after transplantation. Comparison of cancer-attributable mortality rates with specified causes of death indicated that some deaths recorded as other causes might instead be caused by cancer or its treatment. CONCLUSIONS: Cancer is a substantial cause of mortality among solid organ transplant recipients, with major contributions reported from lung cancer and NHL. Cancer-attributable mortality increases with age and time since transplantation, and therefore cancer deaths will become an increasing burden as recipients live longer.

Breast cancer risk prediction in women aged 35-50 years: impact of including sex hormone concentrations in the Gail model.

BACKGROUND: Models that accurately predict risk of breast cancer are needed to help younger women make decisions about when to begin screening. Premenopausal concentrations of circulating anti-Müllerian hormone (AMH), a biomarker of ovarian reserve, and testosterone have been positively associated with breast cancer risk in prospective studies. We assessed whether adding AMH and/or testosterone to the Gail model improves its prediction performance for women aged 35-50. METHODS: In a nested case-control study including ten prospective cohorts (1762 invasive cases/1890 matched controls) with pre-diagnostic serum/plasma samples, we estimated relative risks (RR) for the biomarkers and Gail risk factors using conditional logistic regression and random-effects meta-analysis. Absolute risk models were developed using these RR estimates, attributable risk fractions calculated using the distributions of the risk factors in the cases from the consortium, and population-based incidence and mortality rates. The area under the receiver operating characteristic curve (AUC) was used to compare the discriminatory accuracy of the models with and without biomarkers. RESULTS: The AUC for invasive breast cancer including only the Gail risk factor variables was 55.3 (95% CI 53.4, 57.1). The AUC increased moderately with the addition of AMH (AUC 57.6, 95% CI 55.7, 59.5), testosterone (AUC 56.2, 95% CI 54.4, 58.1), or both (AUC 58.1, 95% CI 56.2, 59.9). The largest AUC improvement (4.0) was among women without a family history of breast cancer. CONCLUSIONS: AMH and testosterone moderately increase the discriminatory accuracy of the Gail model among women aged 35-50. We observed the largest AUC increase for women without a family history of breast cancer, the group that would benefit most from improved risk prediction because early screening is already recommended for women with a family history.

Intake of dietary carbohydrates in early adulthood and adolescence and breast density among young women.

PURPOSE: Carbohydrate intake increases postprandial insulin secretion and may affect breast density, a strong risk factor for breast cancer, early in life. We examined associations of adolescent and early adulthood intakes of total carbohydrates, glycemic index/load, fiber, and simple sugars with breast density among 182 young women. METHODS: Diet was assessed using three 24-h recalls at each of five Dietary Intervention Study in Children (DISC) clinic visits when participants were age 10-19 years and at the DISC06 Follow-Up Study clinic visit when participants were age 25-29 years. Associations between energy-adjusted carbohydrates and MRI-measured percent dense breast volume (%DBV) and absolute dense breast volume (ADBV) at 25-29 years were quantified using multivariable-adjusted mixed-effects linear models. RESULTS: Adolescent sucrose intakes and premenarcheal total carbohydrates intakes were modestly associated with higher %DBV (mean %DBVQ1 vs Q4, 16.6 vs 23.5% for sucrose; and 17.2 vs 22.3% for premenarcheal total carbohydrates, all Ptrend ≤ 0.02), but not with ADBV. However, adolescent intakes of fiber and fructose were not associated with %DBV and ADBV. Early adulthood intakes of total carbohydrates, glycemic index/load, fiber, and simple sugars were not associated with %DBV and ADBV. CONCLUSIONS: Insulinemic carbohydrate diet during puberty may be associated with adulthood breast density, but our findings need replication in larger studies. Clinical Trials Registration ClinicalTrials.gov Identifier, NCT00458588 April 9, 2007; NCT00000459 October 27, 1999.

Circulating anti-Müllerian hormone and breast cancer risk: A study in ten prospective cohorts.

A strong positive association has been observed between circulating anti-Müllerian hormone (AMH), a biomarker of ovarian reserve, and breast cancer risk in three prospective studies. Confirming this association is important because of the paucity of biomarkers of breast cancer risk in premenopausal women. We conducted a consortium study including ten prospective cohorts that had collected blood from premenopausal women. A nested case-control design was implemented within each cohort. A total of 2,835 invasive (80%) and in situ (20%) breast cancer cases were individually matched to controls (n = 3,122) on age at blood donation. AMH was measured using a high sensitivity enzyme-linked immunoabsorbent assay. Conditional logistic regression was applied to the aggregated dataset. There was a statistically significant trend of increasing breast cancer risk with increasing AMH concentration (ptrend across quartiles <0.0001) after adjusting for breast cancer risk factors. The odds ratio (OR) for breast cancer in the top vs. bottom quartile of AMH was 1.60 (95% CI = 1.31-1.94). Though the test for interaction was not statistically significant (pinteraction = 0.15), the trend was statistically significant only for tumors positive for both estrogen receptor (ER) and progesterone receptor (PR): ER+/PR+: ORQ4-Q1 = 1.96, 95% CI = 1.46-2.64, ptrend <0.0001; ER+/PR-: ORQ4-Q1 = 0.82, 95% CI = 0.40-1.68, ptrend = 0.51; ER-/PR+: ORQ4-Q1 = 3.23, 95% CI = 0.48-21.9, ptrend = 0.26; ER-/PR-: ORQ4-Q1 = 1.15, 95% CI = 0.63-2.09, ptrend = 0.60. The association was observed for both pre- (ORQ4-Q1 = 1.35, 95% CI = 1.05-1.73) and post-menopausal (ORQ4-Q1 = 1.61, 95% CI = 1.03-2.53) breast cancer (pinteraction = 0.34). In this large consortium study, we confirmed that AMH is associated with breast cancer risk, with a 60% increase in risk for women in the top vs. bottom quartile of AMH.

Anti-Müllerian hormone and risk of ovarian cancer in nine cohorts.

Animal and experimental data suggest that anti-Müllerian hormone (AMH) serves as a marker of ovarian reserve and inhibits the growth of ovarian tumors. However, few epidemiologic studies have examined the association between AMH and ovarian cancer risk. We conducted a nested case-control study of 302 ovarian cancer cases and 336 matched controls from nine cohorts. Prediagnostic blood samples of premenopausal women were assayed for AMH using a picoAMH enzyme-linked immunosorbent assay. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariable-adjusted conditional logistic regression. AMH concentration was not associated with overall ovarian cancer risk. The multivariable-adjusted OR (95% CI), comparing the highest to the lowest quartile of AMH, was 0.99 (0.59-1.67) (Ptrend : 0.91). The association did not differ by age at blood draw or oral contraceptive use (all Pheterogeneity : ≥0.26). There also was no evidence for heterogeneity of risk for tumors defined by histologic developmental pathway, stage, and grade, and by age at diagnosis and time between blood draw and diagnosis (all Pheterogeneity : ≥0.39). In conclusion, this analysis of mostly late premenopausal women from nine cohorts does not support the hypothesized inverse association between prediagnostic circulating levels of AMH and risk of ovarian cancer.

Anti-Mullerian hormone and endometrial cancer: a multi-cohort study.

BACKGROUND: The Mullerian ducts are the embryological precursors of the female reproductive tract, including the uterus; anti-Mullerian hormone (AMH) has a key role in the regulation of foetal sexual differentiation. Anti-Mullerian hormone inhibits endometrial tumour growth in experimental models by stimulating apoptosis and cell cycle arrest. To date, there are no prospective epidemiologic data on circulating AMH and endometrial cancer risk. METHODS: We investigated this association among women premenopausal at blood collection in a multicohort study including participants from eight studies located in the United States, Europe, and China. We identified 329 endometrial cancer cases and 339 matched controls. Anti-Mullerian hormone concentrations in blood were quantified using an enzyme-linked immunosorbent assay. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) across tertiles and for a doubling of AMH concentrations (ORlog2). Subgroup analyses were performed by ages at blood donation and diagnosis, oral contraceptive use, and tumour characteristics. RESULTS: Anti-Mullerian hormone was not associated with the risk of endometrial cancer overall (ORlog2: 1.07 (0.99-1.17)), or with any of the examined subgroups. CONCLUSIONS: Although experimental models implicate AMH in endometrial cancer growth inhibition, our findings do not support a role for circulating AMH in the aetiology of endometrial cancer.

Demographic, lifestyle, and other factors in relation to antimüllerian hormone levels in mostly late premenopausal women.

OBJECTIVE: To identify reproductive, lifestyle, hormonal, and other correlates of circulating antimüllerian hormone (AMH) concentrations in mostly late premenopausal women. DESIGN: Cross-sectional study. SETTING: Not applicable. PATIENT(S): A total of 671 premenopausal women not known to have cancer. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Concentrations of AMH were measured in a single laboratory using the picoAMH ELISA. Multivariable-adjusted median (and interquartile range) AMH concentrations were calculated using quantile regression for several potential correlates. RESULT(S): Older women had significantly lower AMH concentrations (≥40 [n = 444] vs. <35 years [n = 64], multivariable-adjusted median 0.73 ng/mL vs. 2.52 ng/mL). Concentrations of AMH were also significantly lower among women with earlier age at menarche (<12 [n = 96] vs. ≥14 years [n = 200]: 0.90 ng/mL vs. 1.12 ng/mL) and among current users of oral contraceptives (n = 27) compared with never or former users (n = 468) (0.36 ng/mL vs. 1.15 ng/mL). Race, body mass index, education, height, smoking status, parity, and menstrual cycle phase were not significantly associated with AMH concentrations. There were no significant associations between AMH concentrations and androgen or sex hormone-binding globulin concentrations or with factors related to blood collection (e.g., sample type, time, season, and year of blood collection). CONCLUSION(S): Among premenopausal women, lower AMH concentrations are associated with older age, a younger age at menarche, and currently using oral contraceptives, suggesting these factors are related to a lower number or decreased secretory activity of ovarian follicles.

Association of Estrogen Metabolism with Breast Cancer Risk in Different Cohorts of Postmenopausal Women.

Endogenous estradiol and estrone are linked causally to increased risks of breast cancer. In this study, we evaluated multiple competing hypotheses for how metabolism of these parent estrogens may influence risk. Prediagnostic concentrations of estradiol, estrone, and 13 metabolites were measured in 1,298 postmenopausal cases of breast cancer and 1,524 matched controls in four separate patient cohorts. The median time between sample collection and diagnosis was 4.4 to 12.7 years across the cohorts. Estrogen analytes were measured in serum or urine by liquid chromatography-tandem mass spectrometry. Total estrogen levels (summing all 15 estrogens/estrogen metabolites) were associated strongly and positively with breast cancer risk. Normalizing total estrogen levels, we also found that a relative increase in levels of 2-hydroxylation pathway metabolites, or in the ratio of 2-hydroxylation:16-hydroxylation pathway metabolites, were associated inversely with breast cancer risk. These associations varied by total estrogen levels, with the largest risk reductions occurring in women in the highest tertile. With appropriate validation, these findings suggest opportunities for breast cancer prevention by modifying individual estrogen metabolism profiles through either lifestyle alterations or chemopreventive strategies. Cancer Res; 77(4); 918-25. ©2017 AACR.

Dietary Fat Intake During Adolescence and Breast Density Among Young Women.

BACKGROUND: Lack of association between fat intake and breast cancer risk in cohort studies might be attributed to the disregard of temporal effects during adolescence when breasts develop and are particularly sensitive to stimuli. We prospectively examined associations between adolescent fat intakes and breast density. METHOD: Among 177 women who participated in the Dietary Intervention Study in Children, dietary intakes at ages 10-18 years were assessed on five occasions by 24-hour recalls and averaged. We calculated geometric mean and 95% confidence intervals for MRI-measured breast density at ages 25-29 years across quartiles of fat intake using linear mixed-effect regression. RESULTS: Comparing women in the extreme quartiles of adolescent fat intakes, percent dense breast volume (%DBV) was positively associated with saturated fat (mean = 16.4% vs. 21.5%; Ptrend < 0.001). Conversely, %DBV was inversely associated with monounsaturated fat (25.0% vs. 15.8%; Ptrend < 0.001) and the ratio of polyunsaturated fat to saturated fat (P/S ratio; 19.1% vs. 14.3%; Ptrend < 0.001). When examining intake by pubertal stages, %DBV was inversely associated with intake of polyunsaturated fat (20.8% vs. 16.4%; Ptrend = 0.04), long-chain omega-3 fat (17.8% vs. 15.8%; Ptrend < 0.001), and P/S ratio (22.5% vs. 16.1%; Ptrend < 0.001) before menarche, but not after. These associations observed with %DBV were consistently observed with absolute dense breast volume but not with absolute nondense breast volume. CONCLUSIONS: In our study, adolescent intakes of higher saturated fat and lower mono- and polyunsaturated fat are associated with higher breast density measured approximately 15 years later. IMPACT: The fat subtype composition in adolescent diet may be important in early breast cancer prevention. Cancer Epidemiol Biomarkers Prev; 25(6); 918-26. ©2016 AACR.

Early Life Body Fatness, Serum Anti-Müllerian Hormone, and Breast Density in Young Adult Women.

BACKGROUND: Emerging evidence suggests positive associations between serum anti-Müllerian hormone (AMH), a marker of ovarian function, and breast cancer risk. Body size at young ages may influence AMH levels, but few studies have examined this. Also, no studies have examined the relation of AMH levels with breast density, a strong predictor of breast cancer risk. METHODS: We examined associations of early life body fatness, AMH concentrations, and breast density among 172 women in the Dietary Intervention Study in Children (DISC). Height and weight were measured at baseline (ages 8-10) and throughout adolescence. Serum AMH concentrations and breast density were assessed at ages 25-29 at the DISC 2006 Follow-up visit. We used linear mixed effects models to quantify associations of AMH (dependent variable) with quartiles of age-specific youth body mass index (BMI) Z-scores (independent variable). We assessed cross-sectional associations of breast density (dependent variable) with AMH concentration (independent variable). RESULTS: Neither early life BMI nor current adult BMI was associated with AMH concentrations. There were no associations between AMH and percent or absolute dense breast volume. In contrast, women with higher AMH concentrations had significantly lower absolute nondense breast volume (Ptrend < 0.01). CONCLUSIONS: We found no evidence that current or early life BMI influences AMH concentrations in later life. Women with higher concentrations of AMH had similar percent and absolute dense breast volume, but lower nondense volume. IMPACT: These results suggest that AMH may be associated with lower absolute nondense breast volume; however, future prospective studies are needed to establish temporality. Cancer Epidemiol Biomarkers Prev; 25(7); 1151-7. ©2016 AACR.

Genetic variants in hypothalamic-pituitary-adrenal axis genes and breast cancer risk in Caucasians and African Americans.

Elevated circulating levels of the adrenal androgen dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) are associated with increased breast cancer risk in prospective studies. Genetic variants in hypothalamic-pituitary-adrenal (HPA) axis genes may contribute to these circulating hormone levels, and consequently to breast cancer risk. No previous studies have examined the effects of genetic variants in HPA axis genes on breast cancer risk. We evaluated the associations of 49 single nucleotide polymorphisms (SNPs) in five HPA axis genes (NR3C1, NR3C2, CRH, CRHR1, and CRHBP) with the risk of breast cancer in the Women's Insights and Shared Experiences (WISE) Study of Caucasians (346 cases and 442 controls), as well as African Americans (149 cases and 246 controls). Of the 49 SNPs evaluated, one showed a nominal significant association (P for trend < 0.05) with breast cancer risk among Caucasians, and another two among African Americans. The age-adjusted additive odds ratio (OR) (95% confidence interval (95% CI)) of the SNP rs11747190[A] in the CRHBP gene for the risk of breast cancer among Caucasian women was 1.45 (1.09-1.94). The age-adjusted additive ORs (95% CIs) of two SNPs (CRHBP rs1700688[T] and CRHR1 rs17689471[C]) for the risk of breast cancer among African American women were 1.84 (1.13-2.98) and 2.48 (1.20-5.13), respectively. However, these SNPs did not show significant associations after correction for multiple testing. Our findings do not provide strong supportive evidence for the contribution of genetic variants in these HPA axis genes to the risk of developing breast cancer in either Caucasians or African Americans.