Circulating Oxysterols and Survival Following Breast Cancer: A Molecular Epidemiology Study
Abstract
Oxysterols are normal byproducts of cholesterol metabolism in our bodies. Cholesterol is necessary for many processes in the body and is one of the building blocks for sex steroid hormones such as estrogens and androgens. The cholesterol that does not eventually become a sex steroid hormone is broken down into oxysterols including 27-hydroxycholesterol (27HC) and 25-hydroxycholesterol (25HC). Experiments show that 27HC and 25HC communicate with breast cancer cells through the estrogen receptor (ER), as so-called ER modulators, and 27HC was discovered to be a selective ER modulator, or SERM. The specific action of a SERM depends on how it interacts with a given target tissue, for example, the well-known SERM tamoxifen blocks estrogen-induced cancer growth in the breast, but has cancer growth-promoting action in the uterus. Recent data from our Department of Defense-funded research suggests that relatively high postmenopausal concentrations of 27HC — in samples collected years prior to diagnosis — are associated with lower risk of breast cancer in women, especially in women not using postmenopausal hormones. To date, very little is known about oxysterols and breast cancer in humans. Given our observation of lower breast cancer risk with higher 27HC concentrations, we propose the first-ever investigation on oxysterols and prognosis following a breast cancer diagnosis, expanding our line of study to the outcomes of recurrence and survival. Further, our initial study on breast cancer risk focused on 27HC alone. In the proposed study on survival, we will consider both 27HC and 25HC as primary exposures, and other oxysterols in an exploratory aim, to provide urgently needed data on these blood-based biomarkers and breast cancer prognosis. We hypothesize that relatively high concentrations of 27HC and 25HC are associated with better prognosis following a breast cancer diagnosis. The specific aims of this study are to: (1) Evaluate circulating 27HC and 25HC and the outcomes of recurrence and survival (overall and disease-specific) following a breast cancer diagnosis overall. (a) Evaluate recurrence and survival by clinically measured hormone receptor subtype (ER, ER/PR). (b) Investigate effect modification by circulating estradiol concentrations, and SERM and AI use. (c) Characterize potential differences in the associations between oxysterols and breast cancer recurrence and survival by other clinical characteristics including stage at diagnosis. (2) Evaluate cross-sectional associations between oxysterol concentrations. (a) Prognostic, treatment, and case characteristics (available from medical record review). (b) Tumor molecular phenotype (luminal subtypes, HER2-type, triple-negative) and individual tumor tissue immunohistochemistry (IHC) markers including Ki67, Bcl2, CK5/6, EGFR, and p53. (c) Reproductive and lifestyle characteristics (e.g., parity, BMI, physical activity, and alcohol consumption). (3) Exploratory Aim: Investigate a broader panel of analytes included on the oxysterol panel (including 7aHC, 24S-HC, lanosterol) with respect to breast cancer prognosis and in cross-sectional analyses. These aims will be investigated in the MARIE Study, a well-characterized cohort of breast cancer patients. These women were recruited between 2001-2005 in two areas of Germany (Rhein–Neckar–Karlsruhe and the city of Hamburg) and they have been followed-up since for outcomes including recurrence and survival. The cohort includes 2,289 invasive breast cancer patients (stage I-IIIa at diagnosis) with ER status data available, including 438 deaths (n=319 among ER+ cases), and 234 breast cancer-specific deaths (n=158 among ER+ cases), after median 11 years of follow-up. Oxysterols and estradiol will be measured in post-diagnostic plasma samples. We will estimate whether the risk of death is lower among women with relatively high oxysterol concentrations using statistical models. This project addresses
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910786
Entities
People
- S. Renee Turzanski Fortner
Organizations
- German Cancer Research Center
- United States Army