Abstract 1143: Circulating 27-hydroxycholesterol and risk of metachronous colorectal adenomas

Purpose: Oxysterols are cholesterol metabolites thought to play a role in basic carcinogenic mechanisms. One of the most abundant oxysterols in circulation is 27-hydroxycholesterol (27HC), which has been shown to be an endogenous selective estrogen receptor modulator and implicated in breast cancer etiology. 27HC is a ligand for liver X receptors expressed in the liver, gut, adipose tissue, and macrophages. In the colorectum, expression of these receptors suppresses cellular proliferation. It is unknown whether circulating 27HC is associated with the risk of developing colorectal neoplasia. Methods: Circulating 27HC was measured in plasma collected at baseline from participants of the Vitamin D/Calcium Polyp Prevention Study, a completed placebo-controlled randomized clinical trial of daily supplementation with vitamin D, calcium, or both for the prevention of colorectal adenomas. Participants were 2,259 men and women, 45-75 years old, diagnosed with ≥1 colorectal adenoma within 120 days prior to enrollment. Each was followed for new colorectal adenomas during a 3- or 5-year colonoscopy surveillance interval. 27HC concentrations were quantified using high-performance liquid chromatography/mass spectrometry for those who reported fasting ≥8 hours at the time of blood draw. Premenopausal women and postmenopausal women currently using hormone therapy were excluded from analyses. Risk ratios (RR) and 95% confidence intervals (CI) were estimated from log-linear regression models with adjustment for sex, age, race/ethnicity, body mass index, smoking status, family history of colorectal cancer, aspirin use, nonsteroidal anti-inflammatory drug use, and former use of postmenopausal hormone therapy. High-risk colorectal adenoma findings were defined as ≥1 advanced adenoma (≥1 cm in diameter, with 25% villous components, high-grade dysplasia, or adenocarcinoma) or ≥3 synchronous adenomas of any type. Secondary analyses considered results stratified by sex and anatomic location of lesions (proximal colon vs. distal colon/rectum). Results: In total, 27HC was measured for 1,246 participants (894 men and 352 women). Circulating 27HC was higher among men (mean, 181 ng/mL; standard deviation, SD, 49 ng/mL) than among postmenopausal women (mean, 154 ng/mL; SD, 46 ng/mL). During follow-up, 596 (46%) participants were diagnosed with ≥1 new colorectal adenoma. Circulating 27HC was associated with 9% higher risk of any colorectal adenoma per SD increase (RR, 1.09; 95% CI, 1.02-1.15; P=0.008) and 19% higher risk of high-risk colorectal adenoma findings per SD increase (RR, 1.19; 95% CI, 1.07-1.33; P=0.002). Sex-stratified results were of similar magnitude, and there were no meaningful differences according to anatomic location of adenomas. Conclusions: Circulating 27HC concentration may be a novel risk factor for metachronous colorectal adenomas. Citation Format: Michael N. Passarelli, Bonne M. Thompson, Jeffrey G. McDonald, Thomas J. Palys, Judy R. Rees, Elizabeth L. Barry, John A. Baron. Circulating 27-hydroxycholesterol and risk of metachronous colorectal adenomas [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1143.