Risk versus Benefit of Chemoprevention among Raloxifene and Tamoxifen Users with a Family History of Breast Cancer

Tamoxifen and raloxifene have been approved for the primary prevention of breast cancer in high-risk women, but are associated with an increased risk of serious side effects. Few studies have characterized risk–benefit profiles for chemoprevention among women who initiate tamoxifen or raloxifene outside of a clinical trial setting. Use of raloxifene and tamoxifen for chemoprevention was self-reported in 2014 to 2016 by participants in The Sister Study, a prospective cohort of women with a sister who had been diagnosed with breast cancer. After exclusions, 432 current raloxifene users and 96 current tamoxifen users were matched to 4,307 and 953 nonusers, respectively, on age and year of cohort enrollment. Conditional logistic regression was used to evaluate characteristics associated with chemoprevention use. Risk–benefit profiles were examined using published indices that assess the level of evidence (none, moderate, strong) that the benefits of chemoprevention outweigh the risk of serious side effects. Among current chemoprevention users, 44% of tamoxifen users and 5% of raloxifene users had no evidence of a net benefit. In analyses of factors associated with chemoprevention use, having strong evidence of benefit was a significant predictor of raloxifene use, but not of tamoxifen use. In our sample of women with a first-degree family history of breast cancer, raloxifene was more commonly used for breast cancer prevention than tamoxifen. Most raloxifene users, but <60% of tamoxifen users, were likely to benefit. Use of risk–benefit tables can help women and their healthcare providers make an informed decision about breast cancer chemoprevention

Breast cancer and exposure to tobacco smoke during potential windows of susceptibility

Purpose: An association between smoking and breast cancer is unresolved, although a higher risk from exposure during windows of susceptibility has been proposed. The objective of this prospective study was to evaluate the association between tobacco smoke and breast cancer with a focus on timing of exposure, especially during early life. Methods: Sister study participants (n = 50,884) aged 35–74 were enrolled from 2003 to 2009. Women in the United States and Puerto Rico were eligible if they were breast cancer-free but had a sister with breast cancer. Participants completed questionnaires on smoking and environmental tobacco smoke (ETS) exposure. Cox regression was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) for breast cancer risk. Results: During follow-up (mean = 6.4 years), 1,843 invasive breast cancers were diagnosed. Neither active smoking nor adult ETS was associated with breast cancer risk. However, never smoking women exposed to ETS throughout their childhood had a 17% higher risk of breast cancer (95% CI 1.00–1.36) relative to those with no exposure. In utero ETS exposure was also associated with breast cancer (HR = 1.16, 95% CI 1.01–1.32) and the HR was most elevated for women born in earlier birth cohorts (<1940, HR = 1.44, 95% CI 1.02–2.02; 1940–1949, HR = 1.28, 95% CI 1.01–1.62). Conclusion: In utero ETS and ETS exposure during childhood and adolescence were associated with increased risk of breast cancer and associations varied by birth cohort

Oxidative Stress and Breast Cancer Risk in Premenopausal Women

Detrimental effects of oxidative stress are widely recognized, but induction of apoptosis and senescence may also have benefits for cancer prevention. Recent studies suggest oxidative stress may be associated with lower breast cancer risk before menopause. Methods: We conducted a nested case-control study (N = 457 cases, 910 controls) within the NIEHS Sister Study cohort of 50,884 women. Premenopausal women ages 35-54 were eligible for selection. We matched controls 2:1 to cases on age and enrollment year and were breast cancer-free at the time of the corresponding case's diagnosis. Oxidative stress was measured by urinary F2-isoprostane and metabolite (15-F2t-isoprostane-M) concentrations. Odds ratios (OR) and 95% confidence intervals (CIs) were calculated with multivariable conditional logistic regression. Results: After multivariable adjustment for body mass index (BMI) and other potential confounders, the OR for breast cancer comparing the &gt;90th (≥2.94 ng/mgCr) to &lt;25th percentile (1.01 ng/mgCr) was 1.1 (CI: 0.65, 1.7) for F2-isoprostane and 0.70 (CI: 0.43, 1.1) for the metabolite. Higher metabolite concentrations were associated with lower breast cancer risk among women who were also premenopausal (353 cases, OR: 0.59, CI: 0.34, 1.0) or &lt;46 years (82 cases, OR: 0.15, CI: 0.06, 0.42) at diagnosis. ORs for the metabolite and breast cancer were inverse among women with BMI 18.5-24.9 kg/m2 (OR: 0.47, CI: 0.18, 1.2, 208 cases) and &gt;30 kg/m2 (OR: 0.71, CI: 0.30, 1.7, 107 cases), but not among women with BMI 25-29.9 kg/m2 (OR: 0.98, CI: 0.39, 2.5, 138 cases). Conclusions: Together with other studies, our results support a possible inverse association between oxidative stress and premenopausal breast cancer risk

Adult physical activity and breast cancer risk in women with a family history of breast cancer

Background: Recreational physical activity has been consistently associated with reduced breast cancer risk. Less is known about how family history of breast cancer affects the association and whether it varies by menopausal status. Methods: The Sister Study is a cohort of 50,884 women who had a sister with breast cancer but no prior breast cancer themselves at enrollment. Women reported all recreational sport/exercise activities they participated in over the past 12 months. Hours/week and MET-hours/week of physical activity were considered in association with breast cancer risk. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated with Cox regression. Extent of family history, examined as a modifier, was characterized by a Bayesian score incorporating characteristics of the family structure. Results: During follow-up (average 8.4 years), 3,023 cases were diagnosed. Higher hours/week (HR ≥7vs&lt;1 = 0.77; 95% CI, 0.66–0.90) and MET-hours/week (HR quartile4vs1 = 0.75; 95% CI, 0.67–0.85) of physical activity were associated with reduced postmenopausal breast cancer risk. Hours/week and MET-hours/week were associated with suggestively increased premenopausal breast cancer risk (MET-hours/week HR quartile4vs1 = 1.25; 95% CI, 0.98–1.60). Associations did not vary with extent of family history. However, the increased risk in premenopausal women may be limited to those with stronger family history. Conclusions: In women with a family history of breast cancer, physical activity was associated with reduced postmenopausal, but not premenopausal, breast cancer risk and was not modified by extent of family history. Impact: This was the first study to examine the association between physical activity and breast cancer risk in a large population with a family history of breast cancer

Changes in cardiovascular disease risk and risk factors among women with and without breast cancer

Background: Cardiovascular disease (CVD) risk is an important health concern among survivors of breast cancer. However, few studies to date have examined whether trajectories of CVD risk and major risk factors are worse among women with a breast cancer diagnosis compared with those without. Methods: Changes in weight, body mass index, waist circumference, systolic blood pressure, and 10-year CVD risk were compared between women with (813 women) and without (1049 women) an incident breast cancer diagnosis while they were enrolled in the National Institute of Environmental Health Sciences Sister Study cohort. Blood pressure and adiposity measures were collected by trained examiners at an enrollment visit (≥1 year before breast cancer diagnosis) and a second home visit 4 to 11 years later (≥1 year after breast cancer diagnosis). The non–laboratory-based Framingham risk score, a measure of 10-year general CVD risk, was calculated at both the enrollment and second visits. All analyses were stratified by menopausal status at the time of enrollment. Results: Women who were premenopausal at the time of enrollment experienced moderate increases in weight, waist circumference, systolic blood pressure, and CVD risk over the study period. Those who were postmenopausal at the time of enrollment demonstrated little change in weight, but were found to have increases in waist circumference, systolic blood pressure, and CVD risk. In both groups, changes over time did not differ significantly according to breast cancer status. Neither chemotherapy nor endocrine therapy were found to be associated with greater increases in CVD risk or risk factors. Conclusions: In the current study cohort, changes over time in CVD risk, adiposity measures, and blood pressure were similar between women who developed an incident breast cancer and those who did not

Cardiovascular disease risk factors and oxidative stress among premenopausal women

Oxidative stress is one hypothesized mechanism linking anthropometric, behavioral, and medical risk factors with cardiovascular disease (CVD). We evaluated cross-sectional associations between CVD risk factors and biomarkers of oxidative stress, and investigated these biomarkers as predictors of incident diabetes and hypertension among premenopausal women. F 2 -isoprostane (F 2 -IsoP) and metabolite (15-F 2t -IsoP-M), reliable biomarkers of oxidative stress, were measured in urine samples collected at enrollment from 897 premenopausal women (ages 35–54) enrolled in the Sister Study cohort without a CVD history. Blood pressure, waist circumference, and body mass index (BMI) were measured at enrollment by trained study personnel. Diabetes and cigarette smoking were self-reported via enrollment questionnaires. Over a maximum follow-up of 11.5 years, participants self-reported incident diabetes and hypertension diagnoses on mailed questionnaires. In cross-sectional analyses, both F 2 -IsoP and 15-F 2t -IsoP-M were positively associated with BMI, waist circumference, diastolic blood pressure, and current smoking. F 2 -IsoP was elevated among those with diabetes, and 15-F 2t -IsoP-M increased with higher systolic blood pressure. Prospective analyses suggested an increased hypertension risk among those with elevated 15-F 2t -IsoP-M (highest vs. lowest quartile: hazard ratio=2.34; 95% CI: 1.20–4.56). Our results suggest that urinary F 2 -IsoP and 15-F 2t -IsoP-M are positively associated with adiposity measures, blood pressure, and cigarette smoking. Further investigation is warranted to evaluate 15-F 2t -IsoP-M as a predictor of hypertension

Dietary factors and serum antimüllerian hormone concentrations in late premenopausal women

Objective: To study the associations between dietary factors and circulating antimüllerian hormone (AMH) concentrations among late premenopausal women. Design: AMH concentrations were measured in serum samples collected at enrollment from 296 women (aged 35−45 years) in the Sister Study cohort. Usual dietary intakes in the past 12 months were assessed using a validated food frequency questionnaire. Dietary exposures of interest included macronutrients, dietary fat subtypes, fiber, and glycemic index. Multivariable linear regression was used to evaluate associations between dietary variables and serum AMH concentrations. We also used nutrient density models to examine isocaloric replacement of macronutrients. Setting: Not applicable. Patients: Women aged 35−45 years. Interventions: Not applicable. Main outcome measures: Serum AMH concentrations in nanograms per milliliter (ng/mL). Results: AMH concentrations were positively associated with percentage of energy from carbohydrates (β per 5% calories = 0.141 [95% CI 0.023, 0.259]; P trend =.019), and inversely associated with percentage of energy from fat (β per 5% calories = −0.152 [95% CI −0.299, −0.004]; P trend =.044). In analyses of dietary fat subtypes, AMH decreased with increasing monounsaturated fatty acids (P trend =.082) and polyunsaturated fatty acids (P trend =.043), particularly ω-6 fatty acids (P trend =.044), whereas no strong trend was observed for saturated fatty acids. Protein and alcohol intake were not strongly associated with AMH. Conclusions: Our cross-sectional analyses in a sample of late premenopausal women suggest that dietary fat intake may be inversely associated with circulating AMH concentrations. Further research in prospective studies is warranted to evaluate dietary factors as potential modifiers of ovarian reserve

Tea consumption and breast cancer risk in a cohort of women with family history of breast cancer

Laboratory studies have observed chemopreventive effects of black and green tea on breast cancer development, but few epidemiologic studies have identified such effects. We investigated the association between tea consumption and breast cancer risk using data from 45,744 U.S. and Puerto Rican women participating in the Sister Study. Frequency and serving size of black and green tea consumption were measured at cohort enrollment. Breast cancer diagnoses were reported during follow-up and confirmed by medical record review. Multivariable Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI). We further investigated potential variation according to estrogen receptor (ER) status, menopausal status and body mass index (BMI). Overall, 81.6 and 56.0% of women drank black or green tea, respectively. A total of 2,809 breast cancer cases were identified in the cohort. The multivariable model suggested an inverse association between black (≥5 vs. 0 cups/week: HR = 0.88, 95% CI 0.78, 1.00, p-trend = 0.08) and green tea (≥5 vs. 0 cups/week: HR = 0.82, 95% CI 0.70, 0.95, p-trend < 0.01) consumption and breast cancer risk. We did not observe differences by ER characteristics, menopausal status or BMI. In conclusion, our study suggests drinking at least five cups of green or black tea per week may be associated with decreased breast cancer risk

Measurement of mitochondrial DNA copy number in dried blood spots: A pilot study

Background: We evaluated the feasibility of mitochondrial DNA (mtDNA) copy number measurement in dried blood spots (DBS), its comparability with measurement in whole blood samples, and stability of mtDNA copy number from DBS over time. Methods: Women in this pilot study were participants in the Sister Study, a large prospective cohort. Sister Study participants provided a whole blood sample and DBS at enrollment. A second DBS sample was collected 5–10 years later from a subcohort of women with and without an incident breast cancer diagnosis between collections. Among 54 women (27 with breast cancer, 27 without) we measured mtDNA copy number from whole blood at enrollment and from DBS at both time points. Results: The average age at enrollment was 58.7 years (range:50–69). Values of mtDNA copy number measured in whole blood samples and DBS from enrollment were moderately correlated (Spearman R = 0.45; p = 0.005). Stability of mtDNA copy number in DBS from the two time points was moderate overall (ICC = 0.50) and similar between women with (ICC = 0.50) and without (ICC = 0.51) a breast cancer diagnosis between the two collections. Conclusions: Our results suggest that measurement of mtDNA copy number in DBS is feasible and may be a valid alternative to measurement in whole blood samples