Abstract 2359: Endogenous progestogens and colorectal cancer risk among postmenopausal women
Authors: Michels Kara A. , Falk Roni T. , Geczik Ashley M. , Bauer Doug C. , Buist Diana S. , Cauley Jane A. , Dallal Cher M. , Hue Trisha F. , Lacey James V. , LaCroix Andrea Z. , Tice Jeffrey A. , Xu Xia , Brinton Louise A. , Trabert Britton 
Published: September 2020

Abstract
Progestogens are sex steroid hormones that serve as precursors to androgens, estrogens, and corticosteroids. While known to influence breast and endometrial cancer risk, the exact roles progestogens play in cancer development are poorly characterized–especially for colorectal cancer. Nor have we been able to determine the utility of measuring circulating progestogens for cancer risk prediction in epidemiologic studies and clinical settings. These gaps in knowledge are largely attributable to the difficulty in measuring hormones among postmenopausal women, when concentrations are low. To address this problem, we developed a highly sensitive and reliable liquid chromatography-tandem mass spectrometry assay to measure concentrations of seven markers of endogenous progestogen metabolism: pregnenolone (a progestogen precursor), progesterone, the two 17-alpha-hydroxy (17OH) forms of these hormones (which are androgen precursors), and three progesterone metabolites. These markers were measured in prediagnostic serum collected from women in a case-cohort study within the Breast and Bone Follow-up to the Fracture Intervention Trial (B~FIT). From the 15,595 postmenopausal women in B~FIT, we followed women not using exogenous hormones at baseline (1992-1993) for up to twelve years: 187 women with incident colorectal cancer diagnosed during follow-up and a subcohort of 495 women selected on strata of age (10-year windows) and clinical center. We used Cox regression models to estimate risk for colorectal cancer (hazard ratios [HR], 95% confidence intervals [CI]); models were adjusted for age, body mass index, clinic site, and enrollment arm from the original clinical trial. High concentrations of progestogens were not associated with colorectal cancer risk (quintile(Q)5 vs. Q1: pregnenolone HR 0.71, CI 0.40-1.25; progesterone HR 1.25, CI 0.71, 2.22). A trend of increasing risk was suggested, but imprecise across quintiles of 17OH-pregnenolone (Q2 to Q5 HRs 0.75 to 1.44, p-trend 0.06), but no association was noted with 17OH-progesterone. Using 5-knot splines, we identified non-linear risk relationships with several of the progestogens–indicating that biologic mechanisms unique to each hormone may exist. However, circulating progestogens were generally unrelated to colorectal cancer risk in postmenopausal women, which is in line with prior work indicating that circulating estrogen metabolites are also not associated with risk.
Citation Format: Kara A. Michels, Roni T. Falk, Ashley M. Geczik, Doug C. Bauer, Diana S. Buist, Jane A. Cauley, Cher M. Dallal, Trisha F. Hue, James V. Lacey, Andrea Z. LaCroix, Jeffrey A. Tice, Xia Xu, Louise A. Brinton, Britton Trabert. Endogenous progestogens and colorectal cancer risk among postmenopausal women [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 2359.