Cher M. Dallal

Purpose Randomized clinical trials support reductions in contralateral breast cancer (CBC) risk with use of adjuvant endocrine therapy, however, real-world treatment effects, particularly for subgroups of breast cancer survivors, remain inconclusive. To address this, population-based observational studies of adjuvant endocrine therapy and CBC were synthesized and meta-analyzed. Methods PubMed and Embase databases were systematically searched for observational studies of endocrine therapy use and CBC risk. Random effects meta-analyses estimated summary relative risks (RRs) and 95% confidence intervals (CIs) for associations between endocrine therapy (ever use of tamoxifen and/or aromatase inhibitors (AIs)) and CBC risk. Heterogeneity across studies was assessed using the I² test. Subgroup analyses were conducted by study design, menopausal status, and CBC estrogen receptor (ER)-status. Results Seventeen eligible observational studies (n = 287,576 breast cancer survivors) published between 1995 and 2019 were included. Endocrine therapy use was associated with reduced CBC risk (RR:0.62, 95% CI:0.53, 0.73, I² = 84.8%, p < 0.0001). No heterogeneity was observed by study design (p_het = 0.9). Similar reductions were observed in analyses restricted to tamoxifen use. As only two studies assessed AI use, estimates could not be meta-analyzed. In subgroup analyses, there were no differences in CBC risk reduction by menopausal status (p_het = 0.22). Endocrine therapy reduced risk of ER-positive (RR:0.55, 95% CI:0.43, 0.70) but not ER-negative CBC (RR:1.26, 95% CI:0.95, 1.66) (p_het < 0.001). Conclusion This meta-analysis of observational studies supports a reduction in CBC risk with endocrine therapy among breast cancer survivors, in concert with evidence synthesized from randomized clinical trials, and highlights differences in endocrine therapy effectiveness by ER-status of CBC.

Phthalates, plasticizers ubiquitous in household and personal care products, have been associated with metabolic disturbances. Despite the noted racial differences in phthalate exposure and the prevalence of metabolic syndrome (MetS), it remains unclear whether associations between phthalate metabolites and MetS vary by race and sex. A cross-sectional analysis was conducted among 10,017 adults from the National Health and Nutritional Examination Survey (2005–2014). Prevalence odds ratios (POR) and 95% confidence intervals (CIs) were estimated for the association between 11 urinary phthalate metabolites and MetS using weighted sex and race stratified multivariable logistic regression. Higher MCOP levels were significantly associated with increased odds of MetS among women but not men, and only remained significant among White women (POR _{Q4 vs. Q1} = 1.68, 95% CI: 1.24, 2.29; p-trend = 0.001). Similarly, the inverse association observed with MEHP among women, persisted among White women only (POR _{Q4 vs. Q1} = 0.53, 95% CI: 0.35, 0.80; p-trend = 0.003). However, ΣDEHP metabolites were associated with increased odds of MetS only among men, and this finding was limited to White men (POR _{Q4 vs. Q1} = 1.54, 95% CI: 1.01, 2.35; p-trend = 0.06). Among Black men, an inverse association was observed with higher MEP levels (POR _{Q4 vs. Q1} = 0.43, 95% CI: 0.24, 0.77; p-trend = 0.01). The findings suggest differential associations between phthalate metabolites and MetS by sex and race/ethnicity.

Background Few studies have investigated the consequences of caregiving on the objectively measured physiological health outcomes in China. This study used population-based longitudinal data to examine the association between parental caregiving and blood pressure among Chinese women. Method This is a retrospective analysis of 2586 women using five waves of data from the Ever-Married Women Survey component of the China Health and Nutrition Survey (2000, 2004, 2006, 2009, and 2011). We applied growth curve models to examine trajectories of systolic blood pressure (SBP) and diastolic blood pressure (DBP) associated with parental caregiving among women in China. Results In multivariable analyses of blood pressure trajectories adjusting for potential confounders, parental caregivers had higher systolic (β-coefficient (β) = 1.16; p ≤ 0.01) and diastolic blood pressure (β = 0.75; p ≤ 0.01) compared with non-caregivers across multiple waves. Caregivers and non-caregivers had similar levels of systolic blood pressure at baseline, but caregivers exhibited relatively higher growth rate over time. Diastolic blood pressure was much higher among caregivers at the baseline measure, and across time relative to non-caregivers. Moreover, low-intensity but not high-intensity caregivers showed higher growth rate compared with non-caregivers for both SBP and DBP. Discussion Our results demonstrate the negative cardiovascular consequences of parental caregiving among Chinese women. Findings from the study can be used to develop future stress management interventions to decrease hypertension risk within women who provide care to their parents.

R and 15 urinary estrogens and estrogen metabolites (EM) among postmenopausal controls from a population-based breast cancer case-control study conducted in Poland (2000–2003). Methods Postmenopausal women (N = 542) were ages 40 to 72 yr and not currently using hormone therapy. Accelerometers, worn for 7 d, were used to derive measures of average activity (counts per day) and sedentary behavior (<100 counts per minute per day). Estrogen metabolites were measured in 12-h urine samples using liquid chromatography-tandem mass spectrometry. Estrogen metabolites were analyzed individually, in metabolic pathways (C-2, -4, or -16), and as ratios relative to parent estrogens. Geometric means of estrogen metabolites by tertiles of accelerometer-measures, adjusted for age and body mass, were computed using linear models. Results High activity was associated with lower levels of estrone and estradiol (P trend = 0.01), whereas increased sedentary time was positively associated with these parent estrogens (P trend = 0.04). Inverse associations were observed between high activity and 2-methoxyestradiol, 4-methoxyestradiol, 17-epiestriol, and 16-epiestriol (P trend = 0.03). Sedentary time was positively associated with methylated catechols in the 2- and 4-hydroxylation pathways (P trend ≤ 0.04). Women in the highest tertile of activity had increased hydroxylation at the C-2, -4, and -16 sites relative to parent estrogens (P trend ≤ 0.02), whereas increased sedentary time was associated with a lower 16-pathway/parent estrogen ratio (P trend = 0.01). Conclusions Higher activity was associated with lower urinary estrogens, possibly through increased estrogen hydroxylation and subsequent metabolism, whereas sedentary behavior may reduce metabolism....

Estrogen metabolites may have different genotoxic and mitogenic properties yet their relationship with endometrial and ovarian cancer risk remains unclear. Within the Breast and Bone Follow-up to the Fracture Intervention Trial (B∼FIT, n = 15,595), we conducted a case-cohort study to evaluate 15 pre-diagnostic serum estrogens and estrogen metabolites with risk of incident endometrial and ovarian cancer among postmenopausal women not on hormone therapy. Participants included 66 endometrial and 67 ovarian cancer cases diagnosed during follow-up (∼10 years) and subcohorts of 346 and 416 women, respectively, after relevant exclusions. Serum concentrations were measured by liquid chromatography-tandem mass spectrometry. Hazard ratios (HRs) and 95 % confidence intervals (CIs) were estimated using Cox proportional hazard regression. Exposures were categorized in tertiles (T) and analyzed individually, as metabolic pathways (C-2, -4, or -16) and as ratios to parent estrogens (estradiol, estrone). Estradiol was significantly associated with increased endometrial cancer risk (BMI-adjusted HR_T3vsT1 = 4.09, 95 % CI 1.70, 9.85; p trend = 0.003). 2-Hydroxyestrone and 16α-hydroxyestrone were not associated with endometrial risk after estradiol adjustment (2-OHE₁:HR_T3vsT1 = 1.97, 95 % CI 0.78, 4.94; 16-OHE₁:HR_T3vsT1 = 1.50, 95 % CI 0.65, 3.46; p trend = 0.16 and 0.36, respectively). Ratios of 2- and 4-pathway catechol-to-methylated estrogens remained positively associated with endometrial cancer after BMI or estradiol adjustment (2-pathway catechols-to-methylated: HR_T3vsT1 = 4.02, 95 % CI 1.60, 10.1; 4-pathway catechols-to-methylated: HR_T3vsT1 = 4.59, 95 % CI 1.64, 12.9; p trend = 0.002 for both). Estrogens and estrogen metabolites were not associated with ovarian cancer risk; however, larger studies are needed to better evaluate these relationships. Estrogen metabolism may be important in endometrial carcinogenesis, particularly with less extensive methylation of 2- or 4-pathway catechols associated with elevated endometrial cancer risk.

Although elevated circulating estrogens are associated with increased postmenopausal breast cancer risk, less is known regarding the role of estrogen metabolism in breast carcinogenesis. We conducted a case–cohort study within the Breast and Bone Follow-up to the Fracture Intervention Trial to assess serum estrogens and estrogen metabolites (EMs) in 407 incident breast cancer cases diagnosed during follow-up and a subcohort of 496 women. In 1992–93, women completed a baseline questionnaire and provided blood samples. Hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted for geography and trial participation status, were estimated using Cox proportional hazard regression. Serum concentrations of EMs were measured by liquid chromatography–tandem mass spectrometry. EMs (quintiles, Q) were analyzed individually, as metabolic pathways (C-2, -4 or -16) and as ratios. Elevated circulating estradiol was associated with increased breast cancer risk (HR _Q5vsQ1 = 1.86; 95% CI: 1.19–2.90; P trend = 0.04). An elevated ratio of the 2-hydroxylation pathway (HR _Q5vsQ1 = 0.69; 95% CI: 0.46–1.05; P trend = 0.01) and 4-hydroxylation pathway (HR _Q5vsQ1 = 0.61; 95% CI: 0.40–0.93; P trend = 0.004) to parent estrogens (estradiol and estrone) was inversely associated with risk. A higher ratio of the 2/16-hydroxylation pathways was associated with reduced risk (HR _Q5vsQ1 = 0.60; 95% CI: 0.40–0.90; P trend = 0.002). Increased 2- or 4-hydroxylation of parent estrogens may lower risk of postmenopausal breast cancer. Analyses of metabolic pathways may help elucidate the role of estrogen metabolism in breast carcinogenesis.