Regina Ziegler

PhD, MPH

National Cancer Institute

Senior Investigator

PLCO (Learn more about this study)

2017-0029

Jun 29, 2017

Circulating Estrogens, Androgens, and Progestogens and Risk of Breast Cancer in the PLCO Cohort

Postmenopausal breast cancer is strongly and positively associated with circulating levels of the parent estrogens, estrone and estradiol, and androgens, including dehydoepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), androstenedione, and testosterone. Somewhat stronger associations have been reported for the androgens although this may simply result from more accurate assays for the androgens than the estrogens. The interrelationships of estrogens and androgens with breast cancer risk, including independent, joint, and mediating effects, are not well understood, partly because of the limited accuracy, specificity, and sensitivity of many steroid hormone assays at the low concentrations characteristic of postmenopausal women and partly because of the limited number of studies that have carefully measured androgens and estrogens in the same blood samples. In addition, few studies of postmenopausal breast cancer have evaluated circulating progesterone (less than 500 cases in all studies combined); and the accuracy of progesterone assays has historically been poor. However, preliminary results from pooled analyses of these limited data suggest progesterone is also positively associated with risk of postmenopausal breast cancer.
In a nested case-control study of breast cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) cohort, restricted to women postmenopausal and not on menopausal hormone therapy at study entry, we propose to use a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay recently developed by the Centers for Disease Control and Prevention (CDC) that concurrently measures estrone sulfate, estrone, estradiol, DHEAS, androstenedione, testosterone, progesterone and several other steroid hormones in a single serum sample (~0.3 mL). The absolute hormone concentrations will be unusually accurate since the lab is participating in the Hormone Standardization Programs for estradiol and testosterone and College of American Pathologists external evaluations; using certified and/or purified standards; and rigorously investigating interfering compounds, peak baseline resolution, and absolute recovery. Laboratory coefficients of variation for each steroid, at the concentrations characteristic of postmenopausal women, are less than 10%. Our nested case-control study in PLCO will be the first epidemiologic study to utilize this CDC platform for multiple steroid hormones. To estimate bioavailable and free estradiol and testosterone, believed to be the best measures of hormone bioactivity, we will also measure sex-hormone binding globulin (SHBG).
We will include in this study all the invasive breast cancer cases (~290) and frequency matched controls (~440) previously identified for a series of prospective studies of circulating biomarkers and risk of breast cancer in the PLCO cohort. Therefore, we will be able to integrate the estrogen metabolism profile (15 estrogens/estrogen metabolites), prolactin, insulin-like growth factor (IGF-1, IGFBP-3), and vitamin D metabolites data previously obtained for these cases and controls and examine independent and joint effects with the androgens, estrogens, and progesterone. In addition, we will expand this study by including the additional incident invasive breast cancer cases that have been diagnosed since the earlier study among women postmenopausal and not using menopausal hormone therapy at study baseline. One control per case will be selected by incidence density sampling with individual matching on attained age.