Hypertension and risk of endometrial cancer: a pooled analysis in the Epidemiology of Endometrial Cancer Consortium (E2C2).

BACKGROUND: The incidence rates of endometrial cancer (EC) are increasing, which may partly be explained by the rising prevalence of obesity, an established risk factor for EC. Hypertension, another component of metabolic syndrome, is also increasing in prevalence, and emerging evidence suggests that it may be associated with the development of certain cancers. The role of hypertension independent of other components of metabolic syndrome in the etiology of EC remains unclear. In this study we evaluated hypertension as an independent risk factor for EC and whether this association is modified by other established risk factors. METHODS: We included 15,631 EC cases and 42,239 controls matched on age, race, and study-specific factors from 29 studies in the Epidemiology of Endometrial Cancer Consortium. We used multivariable unconditional logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) to evaluate the association between hypertension and EC and whether this association differed by study design, race/ethnicity, body mass index, diabetes status, smoking status, or reproductive factors. RESULTS: Hypertension was associated with an increased risk of EC (OR=1.14, 95% CI:1.09-1.19). There was significant heterogeneity by study design (Phet<0.01), with a stronger magnitude of association observed among case-control vs. cohort studies. Stronger associations were also noted for pre-/peri-menopausal women and never users of postmenopausal hormone therapy. CONCLUSIONS: Hypertension is associated with EC risk independently from known risk factors. Future research should focus on biologic mechanisms underlying this association. IMPACT: This study provides evidence that hypertension may be an independent risk factor for EC.

Mid-life adherence to the Dietary Approaches to Stop Hypertension (DASH) diet and late-life subjective cognitive complaints in women.

INTRODUCTION: Evidence is limited on the role of mid-life Dietary Approaches to Stop Hypertension (DASH) diet in late-life subjective cognitive complaints (SCCs). METHODS: We included 5116 women (mean age in 1985-1991: 46 years) from the New York University Women's Health Study. SCCs were assessed from 2018 to 2020 (mean age: 79 years) by a 6-item questionnaire. RESULTS: Compared to women in the bottom quartile of the DASH scores, the odds ratio (OR) for having two or more SCCs was 0.83 (95% confidence interval: 0.70-0.99) for women in the top quartile of DASH scores at baseline (P for trend = 0.019). The association was similar with multiple imputation and inverse probability weighting to account for potential selection bias. The inverse association was stronger in women without a history of cancer (P for interaction = 0.003). DISCUSSION: Greater adherence to the DASH diet in mid-life was associated with lower prevalence of late-life SCCs in women.

Association of hormonal and reproductive factors with differentiated thyroid cancer risk in women: a pooled prospective cohort analysis.

BACKGROUND: The incidence of differentiated thyroid cancer (DTC) is higher in women than in men but whether sex steroid hormones contribute to this difference remains unclear. Studies of reproductive and hormonal factors and thyroid cancer risk have provided inconsistent results. METHODS: Original data from 1 252 907 women in 16 cohorts in North America, Europe, Australia and Asia were combined to evaluate associations of DTC risk with reproductive and hormonal factors. Multivariable-adjusted Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% CIs. RESULTS: During follow-up, 2142 women were diagnosed with DTC. Factors associated with higher risk of DTC included younger age at menarche (<10 vs 10-11 years; HR, 1.28; 95% CI, 1.00-1.64), younger (<40; HR, 1.31; 95% CI, 1.05-1.62) and older (≥55; HR, 1.33; 95% CI, 1.05-1.68) ages at menopause (vs 40-44 years), ever use of menopausal hormone therapy (HR, 1.16; 95% CI, 1.02-1.33) and previous hysterectomy (HR, 1.25; 95% CI, 1.13-1.39) or bilateral oophorectomy (HR, 1.14; 95% CI, 1.00-1.29). Factors associated with lower risk included longer-term use (≥5 vs <5 years) of oral contraceptives (HR, 0.86; 95% CI, 0.76-0.96) among those who ever used oral contraception and baseline post-menopausal status (HR, 0.82; 95% CI, 0.70-0.96). No associations were observed for parity, duration of menopausal hormone therapy use or lifetime number of reproductive years or ovulatory cycles. CONCLUSIONS: Our study provides some evidence linking reproductive and hormonal factors with risk of DTC. Results should be interpreted cautiously considering the modest strength of the associations and potential for exposure misclassification and detection bias. Prospective studies of pre-diagnostic circulating sex steroid hormone measurements and DTC risk may provide additional insight.

International Pooled Analysis of Leisure-Time Physical Activity and Premenopausal Breast Cancer in Women From 19 Cohorts.

PURPOSE: There is strong evidence that leisure-time physical activity is protective against postmenopausal breast cancer risk but the association with premenopausal breast cancer is less clear. The purpose of this study was to examine the association of physical activity with the risk of developing premenopausal breast cancer. METHODS: We pooled individual-level data on self-reported leisure-time physical activity across 19 cohort studies comprising 547,601 premenopausal women, with 10,231 incident cases of breast cancer. Multivariable Cox regression was used to estimate hazard ratios (HRs) and 95% CIs for associations of leisure-time physical activity with breast cancer incidence. HRs for high versus low levels of activity were based on a comparison of risk at the 90th versus 10th percentiles of activity. We assessed the linearity of the relationship and examined subtype-specific associations and effect modification across strata of breast cancer risk factors, including adiposity. RESULTS: Over a median 11.5 years of follow-up (IQR, 8.0-16.1 years), high versus low levels of leisure-time physical activity were associated with a 6% (HR, 0.94 [95% CI, 0.89 to 0.99]) and a 10% (HR, 0.90 [95% CI, 0.85 to 0.95]) reduction in breast cancer risk, before and after adjustment for BMI, respectively. Tests of nonlinearity suggested an approximately linear relationship (Pnonlinearity = .94). The inverse association was particularly strong for human epidermal growth factor receptor 2-enriched breast cancer (HR, 0.57 [95% CI, 0.39 to 0.84]; Phet = .07). Associations did not vary significantly across strata of breast cancer risk factors, including subgroups of adiposity. CONCLUSION: This large, pooled analysis of cohort studies adds to evidence that engagement in higher levels of leisure-time physical activity may lead to reduced premenopausal breast cancer risk.

Long-Term Exposure to Walkable Residential Neighborhoods and Risk of Obesity-Related Cancer in the New York University Women's Health Study (NYUWHS).

BACKGROUND: Living in neighborhoods with higher levels of walkability has been associated with a reduced risk of obesity and higher levels of physical activity. Obesity has been linked to increased risk of 13 cancers in women. However, long-term prospective studies of neighborhood walkability and risk for obesity-related cancer are scarce. OBJECTIVES: We evaluated the association between long-term average neighborhood walkability and obesity-related cancer risk in women. METHODS: The New York University Women's Health Study (NYUWHS) is a prospective cohort with 14,274 women recruited between 1985 and 1991 in New York City and followed over nearly three decades. We geocoded residential addresses for each participant throughout follow-up and calculated an average annual measure of neighborhood walkability across years of follow-up using data on population density and accessibility to destinations associated with geocoded residential addresses. We used ICD-9 codes to characterize first primary obesity-related cancers and employed Cox proportional hazards models to assess the association between average neighborhood walkability and risk of overall and site-specific obesity-related cancers. RESULTS: Residing in neighborhoods with a higher walkability level was associated with a reduced risk of overall and site-specific obesity-related cancers. The hazards ratios associated with a 1-standard deviation increase in average annual neighborhood walkability were 0.88 (95% CI: 0.85, 0.93) for overall obesity-related cancer, 0.89 (95% CI: 0.84, 0.95) for postmenopausal breast cancer, 0.82 (95% CI: 0.68, 0.99) for ovarian cancer, 0.87 (95% CI: 0.76, 0.99) for endometrial cancer, and 0.68 (95% CI: 0.49, 0.94) for multiple myeloma, adjusting for potential confounders at both the individual and neighborhood level. The association between neighborhood walkability and risk of overall obesity-related cancer was stronger among women living in neighborhoods with higher levels of poverty compared with women living in areas with lower poverty levels (pInteraction=0.006). DISCUSSION: Our study highlights a potential protective role of neighborhood walkability in preventing obesity-related cancers in women. https://doi.org/10.1289/EHP11538.

Neighborhood walkability and sex steroid hormone levels in women.

BACKGROUND: Neighborhood walkability (NW) has been linked to increased physical activity, which in turn is associated with lower concentrations of sex hormones and higher concentration of SHBG in women. However, no study has directly examined the association of NW with female sex hormone levels. OBJECTIVE: We conducted a cross-sectional study to evaluate the association between NW and circulating levels of sex hormones and SHBG in pre- and post-menopausal women. METHODS: We included 797 premenopausal and 618 postmenopausal women from the New York University Women's Health Study (NYUWHS) who were healthy controls in previous nested case-control studies in which sex hormones (androstenedione, testosterone, DHEAS, estradiol and estrone) and SHBG had been measured in serum at enrollment. Baseline residential addresses were geo-coded and the Built Environment and Health Neighborhood Walkability Index (BEH-NWI) was calculated. Generalized Estimating Equations were used to assess the association between BEH-NWI and sex hormone and SHBG concentrations adjusting for individual- and neighborhood-level factors. RESULTS: In premenopausal women, a one standard deviation (SD) increment in BEH-NWI was associated with a 3.5% (95% CI 0.9%-6.1%) lower DHEAS concentration. In postmenopausal women, a one SD increment in BEH-NWI was related to an 8.5% (95% CI 5.4%-11.5%) lower level of DHEAS, a 3.7% (95% CI 0.5%-6.8%) lower level of testosterone, a 1.8% (95% CI 0.5%-3.0%) lower level of estrone, and a 4.2% (95% CI 2.7%-5.7%) higher level of SHBG. However, the associations with respect to DHEAS and estrone became apparent only after adjusting for neighborhood-level variables. Sensitivity analyses using fixed effects meta-analysis and inverse probability weighting accounting for potential selection bias yielded similar results. CONCLUSION: Our findings suggest that NW is associated with lower concentrations of androgens and estrone, and increased SHBG, in postmenopausal women, and lower levels of DHEAS in premenopausal women.

Gut Microbiota and Subjective Memory Complaints in Older Women.

BACKGROUND: Epidemiological studies that investigate alterations in gut microbial composition associated with cognitive dysfunction are limited. OBJECTIVE: To examine the association between the gut microbiota and subjective memory complaints (SMCs), a self-reported, validated indicator of cognitive dysfunction. METHODS: In this cross-sectional study of 95 older women selected from the New York University Women's Health Study (NYUWHS), we characterized the gut microbial composition using 16S rRNA gene sequencing. We estimated odds ratio (OR) from beta regression which approximates the ratio of mean relative abundances of individual bacterial taxon from phylum to genus levels by binary (2+ versus < 2) and continuous SMCs. RESULTS: Women reporting 2 or more SMCs had higher relative abundances of genus Holdemania and family Desulfovibrionaceae compared with those reporting one or no complaint. Compared with women with < 2 SMCs, the relative abundances of Holdemania and family Desulfovibrionaceae were 2.09 times (OR: 2.09, 95% confidence interval [CI]: 1.38-3.17) and 2.10 times (OR: 2.10, 95% CI: 1.43-3.09) higher in women with 2+ SMCs, respectively (false discovery rate (FDR)-adjusted p = 0.038 and 0.010, respectively). A dose-response association was observed for genus Sutterella and family Desulfovibrionaceae. Every one-unit increase in SMCs was associated with 25% and 27% higher relative abundances of Sutterella (OR: 1.25; 95% CI: 1.11-1.40) and Desulfovibrionaceae (OR: 1.27; 95% CI: 1.13-1.42), respectively (FDR-adjusted p = 0.018 and 0.006, respectively). CONCLUSION: Our findings support an association between alterations in the gut bacterial composition and cognitive dysfunction.

Neighborhood Walkability and Mortality in a Prospective Cohort of Women.

BACKGROUND: There is a paucity of prospective cohort studies evaluating neighborhood walkability in relation to the risk of death. METHODS: We geocoded baseline residential addresses of 13,832 women in the New York University Women's Health Study (NYUWHS) and estimated the Built Environment and Health Neighborhood Walkability Index (BEH-NWI) for each participant circa 1990. The participants were recruited from 1985 to 1991 in New York City and followed for an average of 27 years. We conducted survival analyses using Cox proportional hazards models to assess the association between neighborhood walkability and risk of death from any cause, obesity-related diseases, cardiometabolic diseases, and obesity-related cancers. RESULTS: Residing in a neighborhood with a higher neighborhood walkability score was associated with a lower mortality rate. Comparing women in the top versus the lowest walkability tertile, the hazards ratios (and 95% CIs) were 0.96 (0.93, 0.99) for all-cause, 0.91 (0.86, 0.97) for obesity-related disease, and 0.72 (0.62, 0.85) for obesity-related cancer mortality, respectively, adjusting for potential confounders at both the individual and neighborhood level. We found no association between neighborhood walkability and risk of death from cardiometabolic diseases. Results were similar in analyses censoring participants who moved during follow-up, using multiple imputation for missing covariates, and using propensity scores matching women with high and low neighborhood walkability on potential confounders. Exploratory analyses indicate that outdoor walking and average BMI mediated the association between neighborhood walkability and mortality. CONCLUSION: Our findings are consistent with a protective role of neighborhood walkability in obesity-related mortality in women, particularly obesity-related cancer mortality.

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.

Circulating unmetabolized folic acid and 5-methyltetrahydrofolate and risk of breast cancer: a nested case-control study.

BACKGROUND/OBJECTIVES: Folates found in natural foods are thought to protect against cancer. However, folic acid (FA), a synthetic form of folate used in supplements and fortified foods, may increase breast cancer risk if present in unmetabolized form (UMFA) in the circulation. This study examined the associations of serum UMFA and 5-methyltetrahydrofolate (5-mTHF), the predominant form of circulating folate, with breast cancer risk. SUBJECTS/METHODS: We conducted a nested case-control study in a prospective cohort. In total, 553 cases of invasive breast cancer, diagnosed before mandatory FA fortification of grain in the US in 1998, were individually-matched to 1059 controls. Serum UMFA and 5-mTHF were measured using liquid chromatography-tandem mass spectrometry in stored serum samples, and 5-mTHF was corrected for storage degradation. RESULTS: Serum UMFA was not associated with breast cancer risk: the percentage of women with detectable levels of UMFA was similar in cases and controls (18% and 20%, respectively; p = 0.46). Two tag-SNPs in the promoter region of the FA-metabolizing gene were also not associated with risk. There was a marginally significant inverse association of 5-mTHFcorrected with breast cancer risk (odds ratio for the highest vs. lowest quintile = 0.69, 95% CI = 0.49 to 0.97; ptrend = 0.08). CONCLUSIONS: Circulating UMFA was not associated with breast cancer risk. These results apply to countries without mandatory FA food fortification. Studies are needed in countries with mandatory fortification, where levels of UMFA are much higher than in our study.

Reproductive and Hormonal Factors and Risk of Ovarian Cancer by Tumor Dominance: Results from the Ovarian Cancer Cohort Consortium (OC3).

BACKGROUND: Laterality of epithelial ovarian tumors may reflect the underlying carcinogenic pathways and origins of tumor cells. METHODS: We pooled data from 9 prospective studies participating in the Ovarian Cancer Cohort Consortium. Information on measures of tumor size or tumor dominance was extracted from surgical pathology reports or obtained through cancer registries. We defined dominant tumors as those restricted to one ovary or where the dimension of one ovary was at least twice as large as the other, and nondominant tumors as those with similar dimensions across the two ovaries or peritoneal tumors. Competing risks Cox models were used to examine whether associations with reproductive and hormonal risk factors differed by ovarian tumor dominance. RESULTS: Of 1,058 ovarian cancer cases with tumor dominance information, 401 were left-dominant, 363 were right-dominant, and 294 were nondominant. Parity was more strongly inversely associated with risk of dominant than nondominant ovarian cancer (P heterogeneity = 0.004). Ever use of oral contraceptives (OC) was associated with lower risk of dominant tumors, but was not associated with nondominant tumors (P heterogeneity = 0.01). Higher body mass index was associated with higher risk of left-dominant tumors, but not significantly associated with risk of right-dominant or nondominant tumors (P heterogeneity = 0.08). CONCLUSIONS: These data suggest that reproductive and hormonal risk factors appear to have a stronger impact on dominant tumors, which may have an ovarian or endometriosis origin. IMPACT: Examining the associations of ovarian cancer risk factors by tumor dominance may help elucidate the mechanisms through which these factors influence ovarian cancer risk.

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.

Ovarian cancer risk factors by tumor aggressiveness: An analysis from the Ovarian Cancer Cohort Consortium.

Ovarian cancer risk factors differ by histotype; however, within subtype, there is substantial variability in outcomes. We hypothesized that risk factor profiles may influence tumor aggressiveness, defined by time between diagnosis and death, independent of histology. Among 1.3 million women from 21 prospective cohorts, 4,584 invasive epithelial ovarian cancers were identified and classified as highly aggressive (death in <1 year, n = 864), very aggressive (death in 1 to < 3 years, n = 1,390), moderately aggressive (death in 3 to < 5 years, n = 639), and less aggressive (lived 5+ years, n = 1,691). Using competing risks Cox proportional hazards regression, we assessed heterogeneity of associations by tumor aggressiveness for all cases and among serous and endometrioid/clear cell tumors. Associations between parity (phet = 0.01), family history of ovarian cancer (phet = 0.02), body mass index (BMI; phet ≤ 0.04) and smoking (phet < 0.01) and ovarian cancer risk differed by aggressiveness. A first/single pregnancy, relative to nulliparity, was inversely associated with highly aggressive disease (HR: 0.72; 95% CI [0.58-0.88]), no association was observed for subsequent pregnancies (per pregnancy, 0.97 [0.92-1.02]). In contrast, first and subsequent pregnancies were similarly associated with less aggressive disease (0.87 for both). Family history of ovarian cancer was only associated with risk of less aggressive disease (1.94 [1.47-2.55]). High BMI (≥35 vs. 20 to < 25 kg/m2 , 1.93 [1.46-2.56] and current smoking (vs. never, 1.30 [1.07-1.57]) were associated with increased risk of highly aggressive disease. Results were similar within histotypes. Ovarian cancer risk factors may be directly associated with subtypes defined by tumor aggressiveness, rather than through differential effects on histology. Studies to assess biological pathways are warranted.

Circulating Vitamin D and Colorectal Cancer Risk: An International Pooling Project of 17 Cohorts.

BACKGROUND: Experimental and epidemiological studies suggest a protective role for vitamin D in colorectal carcinogenesis, but evidence is inconclusive. Circulating 25-hydroxyvitamin D (25(OH)D) concentrations that minimize risk are unknown. Current Institute of Medicine (IOM) vitamin D guidance is based solely on bone health. METHODS: We pooled participant-level data from 17 cohorts, comprising 5706 colorectal cancer case participants and 7107 control participants with a wide range of circulating 25(OH)D concentrations. For 30.1% of participants, 25(OH)D was newly measured. Previously measured 25(OH)D was calibrated to the same assay to permit estimating risk by absolute concentrations. Study-specific relative risks (RRs) for prediagnostic season-standardized 25(OH)D concentrations were calculated using conditional logistic regression and pooled using random effects models. RESULTS: Compared with the lower range of sufficiency for bone health (50-<62.5 nmol/L), deficient 25(OH)D (<30 nmol/L) was associated with 31% higher colorectal cancer risk (RR = 1.31, 95% confidence interval [CI] = 1.05 to 1.62); 25(OH)D above sufficiency (75-<87.5 and 87.5-<100 nmol/L) was associated with 19% (RR = 0.81, 95% CI = 0.67 to 0.99) and 27% (RR = 0.73, 95% CI = 0.59 to 0.91) lower risk, respectively. At 25(OH)D of 100 nmol/L or greater, risk did not continue to decline and was not statistically significantly reduced (RR = 0.91, 95% CI = 0.67 to 1.24, 3.5% of control participants). Associations were minimally affected when adjusting for body mass index, physical activity, or other risk factors. For each 25 nmol/L increment in circulating 25(OH)D, colorectal cancer risk was 19% lower in women (RR = 0.81, 95% CI = 0.75 to 0.87) and 7% lower in men (RR = 0.93, 95% CI = 0.86 to 1.00) (two-sided Pheterogeneity by sex = .008). Associations were inverse in all subgroups, including colorectal subsite, geographic region, and season of blood collection. CONCLUSIONS: Higher circulating 25(OH)D was related to a statistically significant, substantially lower colorectal cancer risk in women and non-statistically significant lower risk in men. Optimal 25(OH)D concentrations for colorectal cancer risk reduction, 75-100 nmol/L, appear higher than current IOM recommendations.

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.

Ovarian Cancer Risk Factors by Histologic Subtype: An Analysis From the Ovarian Cancer Cohort Consortium.

PURPOSE: An understanding of the etiologic heterogeneity of ovarian cancer is important for improving prevention, early detection, and therapeutic approaches. We evaluated 14 hormonal, reproductive, and lifestyle factors by histologic subtype in the Ovarian Cancer Cohort Consortium (OC3). PATIENTS AND METHODS: Among 1.3 million women from 21 studies, 5,584 invasive epithelial ovarian cancers were identified (3,378 serous, 606 endometrioid, 331 mucinous, 269 clear cell, 1,000 other). By using competing-risks Cox proportional hazards regression stratified by study and birth year and adjusted for age, parity, and oral contraceptive use, we assessed associations for all invasive cancers by histology. Heterogeneity was evaluated by likelihood ratio test. RESULTS: Most risk factors exhibited significant heterogeneity by histology. Higher parity was most strongly associated with endometrioid (relative risk [RR] per birth, 0.78; 95% CI, 0.74 to 0.83) and clear cell (RR, 0.68; 95% CI, 0.61 to 0.76) carcinomas (P value for heterogeneity [P-het] < .001). Similarly, age at menopause, endometriosis, and tubal ligation were only associated with endometrioid and clear cell tumors (P-het ≤ .01). Family history of breast cancer (P-het = .008) had modest heterogeneity. Smoking was associated with an increased risk of mucinous (RR per 20 pack-years, 1.26; 95% CI, 1.08 to 1.46) but a decreased risk of clear cell (RR, 0.72; 95% CI, 0.55 to 0.94) tumors (P-het = .004). Unsupervised clustering by risk factors separated endometrioid, clear cell, and low-grade serous carcinomas from high-grade serous and mucinous carcinomas. CONCLUSION: The heterogeneous associations of risk factors with ovarian cancer subtypes emphasize the importance of conducting etiologic studies by ovarian cancer subtypes. Most established risk factors were more strongly associated with nonserous carcinomas, which demonstrate challenges for risk prediction of serous cancers, the most fatal subtype.

Premenopausal Circulating Androgens and Risk of Endometrial Cancer: results of a Prospective Study.

Endometrial cancer risk is increased by estrogens unopposed by progesterone. In premenopausal women, androgen excess is often associated with progesterone insufficiency, suggesting that premenopausal androgen concentrations may be associated with risk. In a case-control study nested within three cohorts, we assessed the relationship between premenopausal androgens and risk of endometrial cancer (161 cases and 303 controls matched on age and date of blood donation). Testosterone, DHEAS, androstenedione, and SHBG were measured in serum or plasma. Free testosterone was calculated from testosterone and SHBG. We observed trends of increasing risk across tertiles of testosterone (ORT3-T1 = 1.59, 95 % CI = 0.96, 2.64, p = 0.08) and free testosterone (ORT3-T1 = 1.76, 95 % CI = 1.01, 3.07, p = 0.047), which were not statistically significant after adjustment for body mass index (BMI). There was no association for DHEAS, androstenedione, or SHBG. There were significant interactions by age at diagnosis (<55 years, n = 51 cases; ≥55 years, n = 110 cases). Among women who were ≥55 years of age (predominantly postmenopausal) at diagnosis, the BMI-adjusted OR was 2.08 (95 % CI = 1.25, 3.44, p = 0.005) for a doubling in testosterone and 1.55 (95 % CI = 1.04, 2.31, p = 0.049) for a doubling in free testosterone. There was no association among women aged <55 years at diagnosis, consistent with the only other prospective study to date. If pre- and post-menopausal concentrations of androgens are correlated, our observation of an association of premenopausal androgens with risk among women aged ≥55 years at diagnosis could be due to the effect on the endometrium of postmenopausal androgen-derived estrogens in the absence of progesterone, which is no longer secreted.

Genetic Polymorphisms in Vitamin D Metabolism and Signaling Genes and Risk of Breast Cancer: A Nested Case-Control Study.

Genetic polymorphisms in vitamin D metabolism and signaling genes have been inconsistently associated with risk of breast cancer, though few studies have examined SNPs in vitamin D-related genes other than the vitamin D receptor (VDR) gene and particularly have not examined the association with the retinoid X receptor alpha (RXRA) gene which may be a key vitamin D pathway gene. We conducted a nested case-control study of 734 cases and 1435 individually matched controls from a population-based prospective cohort study, the Northern Sweden Mammary Screening Cohort. Tag and functional SNPs were genotyped for the VDR, cytochrome p450 24A1 (CYP24A1), and RXRA genes. We also genotyped specific SNPs in four other genes related to vitamin D metabolism and signaling (GC/VDBP, CYP2R1, DHCR7, and CYP27B1). SNPs in the CYP2R1, DHCR7, and VDBP gene regions that were associated with circulating 25(OH)D concentration in GWAS were also associated with plasma 25(OH)D in our study (p-trend <0.005). After taking into account the false discovery rate, these SNPs were not significantly associated with breast cancer risk, nor were any of the other SNPs or haplotypes in VDR, RXRA, and CYP24A1. We observed no statistically significant associations between polymorphisms or haplotypes in key vitamin D-related genes and risk of breast cancer. These results, combined with the observation in this cohort and most other prospective studies of no association of circulating 25(OH)D with breast cancer risk, do not support an association between vitamin D and breast cancer risk.

Genotyping of Single Nucleotide Polymorphisms in DNA Isolated from Serum Using Sequenom MassARRAY Technology.

BACKGROUND: Large epidemiologic studies have the potential to make valuable contributions to the assessment of gene-environment interactions because they prospectively collected detailed exposure data. Some of these studies, however, have only serum or plasma samples as a low quantity source of DNA. METHODS: We examined whether DNA isolated from serum can be used to reliably and accurately genotype single nucleotide polymorphisms (SNPs) using Sequenom multiplex SNP genotyping technology. We genotyped 81 SNPs using samples from 158 participants in the NYU Women's Health Study. Each participant had DNA from serum and at least one paired DNA sample isolated from a high quality source of DNA, i.e. clots and/or cell precipitates, for comparison. RESULTS: We observed that 60 of the 81 SNPs (74%) had high call frequencies (≥95%) using DNA from serum, only slightly lower than the 85% of SNPs with high call frequencies in DNA from clots or cell precipitates. Of the 57 SNPs with high call frequencies for serum, clot, and cell precipitate DNA, 54 (95%) had highly concordant (>98%) genotype calls across all three sample types. High purity was not a critical factor to successful genotyping. CONCLUSIONS: Our results suggest that this multiplex SNP genotyping method can be used reliably on DNA from serum in large-scale epidemiologic studies.