Abstract 589: Circulating progesterone is associated with increased postmenopausal breast cancer risk: B~FIT cohort
Authors: Trabert Britton , Bauer Doug C. , Brinton Louise A. , Buist Diane S. , Cauley Jane A. , Dallal Cher M. , Gierach Gretchen L. , Falk Roni T. , Hue Trisha F. , Lacey James V. , LaCroix Andrea Z. , Tice Jeffrey A. , Xu Xia 
Published: August 2019

Abstract
BACKGROUND: Epidemiologic data provide compelling evidence of the association between elevated endogenous estrogens and androgens and increased postmenopausal breast cancer risk. However, the role of progesterone remains largely unexplored, primarily due to limitations in assay sensitivity and precision of progesterone measurements at low concentrations in postmenopausal women. Recently identified progesterone metabolites may provide etiologic insights as experimental data suggest that relative changes in concentrations of 5-α dihydroprogesterone (5αP) and 3-α dihydroprogesterone (3αHP) reflect cancer promoting and cancer inhibiting properties, respectively.
METHODS: We developed a sensitive and reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay and quantified prediagnostic levels of progesterone/progesterone metabolites in a case-cohort study within the Breast and Bone Follow-up to the Fracture Intervention Trial (B~FIT) including 405 breast cancer cases diagnosed during follow-up and a subcohort of 495 postmenopausal women not using exogenous hormones at blood draw. Multivariable adjusted hazard ratios (HR) and 95% confidence intervals (CIs) were estimated using Cox regression and linearity was assessed using splines.
RESULTS: Hormone concentrations among women in the subcohort were on average 4.6 pg/mL (range 2.3-21.6) for progesterone; all measured values were above the assay detection limit. Women with higher circulating progesterone levels had an elevated postmenopausal breast cancer risk [HR (95% CI) per 10 pg/mL increase in progesterone: 1.18 (0.99-1.41)]. This association was linear in a 5-knot spline and strengthened [1.24 (1.03-1.49)] in models excluding women who reported current use of tamoxifen/raloxifene. Higher levels of 5αP relative to 3αHP were associated with a 4% increased postmenopausal breast cancer risk [per unit increase in ratio: 1.04 (1.00-1.07)]. For the individual metabolites, higher levels of both 5αP [per 10 pg/mL increase: 1.04 (0.93-1.18) and 3αHP [per 3 pg/mL increase: 1.11 (0.999-1.24)] were associated with elevated risk. All associations remained after adjustment for circulating estrogen levels.
CONCLUSIONS: Our prospective data suggest that postmenopausal women with increased serum progesterone concentrations, measured using a highly sensitive LC-MS/MS assay, are at increased risk of breast cancer. Consistent with experimental studies, higher levels of 5αP relative to 3αHP were indicative of increased breast cancer risk. Unlike experimental studies, our data do not suggest that endogenous concentrations of 3αHP are associated with reduced breast cancer risk; instead both metabolites were associated with elevated risk. The identification of these risk-related progesterone metabolites supports the need for additional research regarding their role in the etiology of breast cancer.
Citation Format: Britton Trabert, Doug C. Bauer, Louise A. Brinton, Diane S. Buist, Jane A. Cauley, Cher M. Dallal, Gretchen L. Gierach, Roni T. Falk, Trisha F. Hue, James V. Lacey, Andrea Z. LaCroix, Jeffrey A. Tice, Xia Xu. Circulating progesterone is associated with increased postmenopausal breast cancer risk: B~FIT cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 589.