Jessica M. Faupel-Badger

Lack of association between serum levels of 25-hydroxyvitamin D and the subsequent risk of prostate cancer in Finnish men.

Ecologic studies support an inverse association between sunlight exposure and incidence of prostate cancer ([1][1]-[3][2]). Because sun exposure is the major source of human vitamin D production, several authors have hypothesized that the link between reduced prostate cancer incidence and increased

Comparison of Liquid Chromatography-Tandem Mass Spectrometry, RIA, and ELISA Methods for Measurement of Urinary Estrogens

Absolute and relative concentrations of estrogens and estrogen metabolites are important for clinical decisions as well as for epidemiologic, experimental, and clinical research on hormonal carcinogenesis. RIA and ELISA are routinely used for measuring estrogen metabolites in blood and urine due to efficiency and low cost. Here, we compare absolute and ranked concentrations of estrone, estradiol, and estriol measured by indirect RIA and of 2-hydroxyestrone and 16α-hydroxyestrone measured by ELISA to the concentrations obtained using a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, which measures 15 estrogen metabolites concurrently. We used overnight urine samples collected from control women (362 premenopausal and 168 postmenopausal) participating in a population-based case-control study of breast cancer among Asian American women ages 20 to 55 years. When comparing RIA or ELISA levels to LC-MS/MS, absolute concentrations for the five estrogen metabolites ranged from 1.6 to 2.9 and 1.4 to 11.8 times higher in premenopausal and postmenopausal women, respectively (all P < 0.0001). However, LC-MS/MS measurements were highly correlated [Spearman r (rs) = 0.8-0.9] with RIA and ELISA measurements in premenopausal women and moderately correlated (rs = 0.4-0.8) in postmenopausal women. Measurements of the 2-hydroxyestrone:16α-hydroxyestrone ratio, a putative biomarker of breast cancer risk, were moderately correlated in premenopausal women (rs = 0.6-0.7) but only weakly correlated in postmenopausal women (rs = 0.2). LC-MS/MS had higher intraclass correlation coefficients (≥99.6%) and lower coefficients of variation (≤9.4%) than ELISA (≥97.2% and ≤14.2%) and RIA (≥95.2% and ≤17.8%). Comparison with the LC-MS/MS method suggests that the widely used RIA and ELISA estrogen metabolite measures may be problematic, especially at low estrogen metabolite levels characteristic of postmenopausal women. Cancer Epidemiol Biomarkers Prev; 19(1); 292–300

Plasma Volume Expansion in Pregnancy: Implications for Biomarkers in Population Studies

There is a growing body of literature focused on endogenous hormone exposures during pregnancy and subsequent cancer risk for both mother and offspring. Examples of these studies include those focused on the biological mechanism for the association of preeclampsia with reduced risk of breast cancer for mother and female offspring or studies that have examined hormone concentrations during pregnancy between different ethnic groups who vary in their rates of breast cancer incidence. Although these studies seem relatively straightforward in conception and analysis, measurement of the concentration of hormones and other biomarkers in pregnant subjects is influenced by plasma volume expansion (PVE). During pregnancy, the maternal plasma volume expands 45% on average to provide for the greater circulatory needs of the maternal organs. Consequently, serum protein and hormone concentrations are greatly altered when comparing the pregnant with nonpregnant state. Assessing PVE also is complicated by the vast individual variation in PVE, ranging from minimal to a 2-fold increase. We propose that PVE needs to be evaluated when comparing biomarker concentrations during pregnancy in two populations that may differ with respect to PVE. Small body size is associated with lower PVE compared with higher body size. Therefore, we hypothesize that variation in PVE will influence the interpretation of differences in biomarker concentrations across population groups with respect to the etiologic significance of the biomarker to the disease under study (e.g., breast cancer). It is possible that some observations may be due only to differences in dilution between the two groups. We present PVE as a topic for consideration in population-based studies, examples of the types of studies where PVE may be relevant, and our own analysis of one such study in the text below. (Cancer Epidemiol Biomarkers Prev 2007;16(9):1720–3)

Postpartum remodeling, lactation, and breast cancer risk: summary of a National Cancer Institute-sponsored workshop.

The pregnancy-lactation cycle (PLC) is a period in which the breast is transformed from a less-developed, nonfunctional organ into a mature, milk-producing gland that has evolved to meet the nutritional, developmental, and immune protection needs of the newborn. Cessation of lactation initiates a process whereby the breast reverts to a resting state until the next pregnancy. Changes during this period permanently alter the morphology and molecular characteristics of the breast (molecular histology) and produce important, yet poorly understood, effects on breast cancer risk. To provide a state-of-the-science summary of this topic, the National Cancer Institute invited a multidisciplinary group of experts to participate in a workshop in Rockville, Maryland, on March 2, 2012. Topics discussed included: 1) the epidemiology of the PLC in relation to breast cancer risk, 2) breast milk as a biospecimen for molecular epidemiological and translational research, and 3) use of animal models to gain mechanistic insights into the effects of the PLC on breast carcinogenesis. This report summarizes conclusions of the workshop, proposes avenues for future research on the PLC and its relationship with breast cancer risk, and identifies opportunities to translate this knowledge to improve breast cancer outcomes.

A new approach to measuring estrogen exposure and metabolism in epidemiologic studies.

Endogenous estrogen plays an integral role in the etiology of breast and endometrial cancer, and conceivably ovarian cancer. However, the underlying mechanisms and the importance of patterns of estrogen metabolism and specific estrogen metabolites have not been adequately explored. Long-standing hypotheses, derived from laboratory experiments, have not been tested in epidemiologic research because of the lack of robust, rapid, accurate measurement techniques appropriate for large-scale studies. We have developed a stable isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS(2)) method that can measure concurrently all 15 estrogens and estrogen metabolites (EM) in urine and serum with high sensitivity (level of detection=2.5-3.0fmol EM/mL serum), specificity, accuracy, and precision [laboratory coefficients of variation (CVs) < or =5% for nearly all EM]. The assay requires only extraction, a single chemical derivatization, and less than 0.5mL of serum or urine. By incorporating enzymatic hydrolysis, the assay measures total (glucuronidated+sulfated+unconjugated) EM. If the hydrolysis step is omitted, the assay measures unconjugated EM. Interindividual differences in urinary EM concentrations (pg/mL creatinine), which reflect total EM production, were consistently large, with a range of 10-100-fold for nearly all EM in premenopausal and postmenopausal women and men. Correlational analyses indicated that urinary estrone and estradiol, the most commonly measured EM, do not accurately represent levels of total urinary EM or of the other EM. In serum, all 15 EM were detected as conjugates, but only 5 were detected in unconjugated form. When we compared our assay methods with indirect radioimmunoassays for estrone, estradiol, and estriol and enzyme-linked immunosorbent assays for 2-hydroxyestrone and 16alpha-hydroxyestrone, ranking of individuals agreed well for premenopausal women [Spearman r (r(s))=0.8-0.9], but only moderately for postmenopausal women (r(s)=0.4-0.8). Our absolute readings were consistently lower, especially at the low concentrations characteristic of postmenopausal women, possibly because of improved specificity. We are currently applying our EM measurement techniques in several epidemiologic studies of premenopausal and postmenopausal breast cancer.

Anthropometric Correlates of Insulin-Like Growth Factor 1 (IGF-1) and IGF Binding Protein-3 (IGFBP-3) Levels by Race/Ethnicity and Gender

PURPOSE Insulin-like growth factor 1 (IGF-1) levels are positively related to some cancers and negatively related to cardiovascular disease. These conditions are also related to insulin resistance and high body weight, leading to the hypothesis that IGF-1 levels may, in part, mediate the association of high body weight with these health outcomes. Using the National Health and Nutrition Examination Survey (NHANES) III population, we examined the associations between IGF-1, IGF binding protein-3 (IGFBP-3), and the IGF-1/IGFBP-3 molar ratio with anthropometric measures in a large, U.S. population-based study where these associations could also be stratified by race/ethnicity and gender. METHODS The study population consisted of 3,168 women and 2,635 men (44% non-Hispanic white, 28.2% non-Hispanic black, and 27.7% Mexican-American). Anthropometric measures were obtained by trained personnel in the NHANES mobile examination centers. IGF-1 and IGFBP-3 were measured using immunoassays by staff at Diagnostic System Laboratories (DSL) Inc. (Webster, TX). Associations of IGF-1, IGFBP-3, and IGF-1/IGFBP-3 molar ratio with anthropometric variables across race/ethnicity and gender were evaluated by using linear regression modeling. RESULTS Body mass index (BMI) was inversely associated with IGF-1 levels across all of the race/ethnicity and gender subgroups. In contrast, BMI, waist to hip ratio (WHR), and waist circumference were positively associated with IGFBP-3 levels only in non-Hispanic black men and non-Hispanic white women. The IGF-1/IGFBP-3 molar ratio was inversely associated with all anthropometric measures, except height, in all subgroups of the population. CONCLUSION The significant inverse associations of BMI with IGF-1 levels and of all anthropometric variables, except height, with the IGF-1:IGFBP-3 molar ratio in all subgroups do not support existing hypotheses that associations of excess weight with negative health outcomes, such as specific cancer diagnoses, are mediated through high IGF-1 levels.

Prolactin serum levels and breast cancer: relationships with risk factors and tumour characteristics among pre- and postmenopausal women in a population-based case-control study from Poland

Background:Previous prospective studies have found an association between prolactin (PRL) levels and increased risk of breast cancer. Using data from a population-based breast cancer case–control study conducted in two cities in Poland (2000–2003), we examined the association of PRL levels with breast cancer risk factors among controls and with tumour characteristics among the cases.Methods:We analysed PRL serum levels among 773 controls without breast cancer matched on age and residence to 776 invasive breast cancer cases with available pretreatment serum. Tumours were centrally reviewed and prepared as tissue microarrays for immunohistochemical analysis. Breast cancer risk factors, assessed by interview, were related to serum PRL levels among controls using analysis of variance. Mean serum PRL levels by tumour characteristics are reported. These associations also were evaluated using polytomous logistic regression.Results:Prolactin levels were associated with nulliparity in premenopausal (P=0.05) but not in postmenopausal women. Associations in postmenopausal women included an inverse association with increasing body mass index (P=0.0008) and direct association with use of recent/current hormone therapy (P=0.0006). In case-only analyses, higher PRL levels were more strongly associated with lobular compared with ductal carcinoma among postmenopausal women (P=0.02). Levels were not different by tumour size, grade, node involvement or oestrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2 status.Conclusions:Our analysis demonstrates that PRL levels are higher among premenopausal nulliparous as compared with parous women. Among postmenopausal women, levels were higher among hormone users and lower among obese women. These results may have value in understanding the mechanisms underlying several breast cancer risk factor associations.

Alumni Perspectives on Career Preparation during a Postdoctoral Training Program: A Qualitative Study

This article features qualitative data from in-depth interviews of alumni from a long-standing, structured, postdoctoral research training program. Alumni from diverse scientific disciplines and representing 25 years of the program’s history reflected on the training curriculum and career preparation as it relates to their current career path.

Cluster analysis of placental inflammatory proteins can distinguish preeclampsia from preterm labor and premature membrane rupture in singleton deliveries less than 28 weeks of gestation.

Citation Faupel‐Badger JM, Fichorova RN, Allred EN, Hecht JL, Dammann O, Leviton A, McElrath TF. Cluster analysis of placental inflammatory proteins can distinguish preeclampsia from preterm labor and premature membrane rupture in singleton deliveries less than 28 weeks of gestation. Am J Reprod Immunol 2011; 66: 488–494

Maternal Angiogenic Profile in Pregnancies that Remain Normotensive

OBJECTIVE We sought to determine if maternal characteristics are associated with angiogenic profile in the first and second trimester of normotensive pregnancies. STUDY DESIGN Circulating levels of maternal placental like growth factor (PlGF), soluble fms-like tyrosine kinase receptor (sFlt1), and soluble endoglin (sEng) were measured in serum samples collected during the first (median 11.3 weeks) and second trimester (median 17.1 weeks) of 182 normotensive pregnancies. Diastolic blood pressure (DBP), systolic blood pressure (SBP), and mean arterial pressure (MAP) were measured at the same visits when samples were collected to measure angiogenic factors. Linear regression analysis was used to examine associations of the angiogenic measures with maternal characteristics. The association between blood pressure measures and concentrations of angiogenic factors was evaluated using Spearman correlation and linear regression analysis. RESULTS In adjusted analyses, nulliparous women had higher sFlt1 concentrations in both first (p=0.06) and second (p=0.001) trimester. Higher BMI was associated with greater sFlt1 concentrations in both the first (p=0.004) and second trimester (p=0.008), but significantly lower sEng concentrations in both trimesters (p=0.002 for first trimester and p=0.0009 for second). Nulliparity and higher BMI also were associated with higher sFlt1/PLGF anti-angiogenic ratios in both first (p=0.05 and p=0.007, respectively) and second trimesters (p=0.003 and p=0.02, respectively). First trimester sFlt1 levels were weakly correlated with first trimester SBP (r(s)=0.18, p=0.03) and MAP (r(s)=0.16, p=0.04). Second trimester sEng levels were inversely associated with second trimester MAP (r(s)=-0.17, p=0.05). Including blood pressure measures in the linear regression models did not change the reported associations of angiogenic factors with maternal characteristics. CONCLUSIONS These results demonstrate that even early in normotensive pregnancies maternal characteristics are associated with variations in angiogenic profile across this population.