Abstract P6-01-18: 2-Hydroxyestrone is associated with breast density measured by mammography and fat:water ratio magnetic resonance imaging in women taking tamoxifen
Authors: Thomson Cynthia A , Thompson Patricia A , Wertheim Betsy C , Roe Denise , Marron Marilyn T , Galons John-Phillipe , Kupinski Matthew A , Altbach Maria I , Maskarinec Gertraud , Stopeck Alison 
Published: May 2015

Abstract
Research Objectives and Rationale. Tamoxifen (TAM) use has been shown to reduce breast cancer recurrence with the benefit greater in patients who experience a TAM-associated decrease in percent mammographic density(PMD); findings that support PMD as a biomarker of response to TAM. PMD is a radiographic phenomenon of breast fibroglandular tissue that is associated with breast cancer risk. PMD is inversely associated with body mass index (BMI) and sparse data have shown a weak positive association with the sex hormone levels. Limited data exist evaluating the relationship between TAM, 2OHE1:16 a-OHE1 ratio (concentrations previously hypothesized to be associated with a reduced risk of breast cancer) and PBD.
Methods. Using cross-sectional baseline breast density (BD) from an ongoing prevention trial of diindolylmethane (DIM) in 121 women receiving TAM, we evaluated BD in relation to circulating TAM metabolites [TAM, endoxifen, 4-OH TAM, ND TAM], estradiol (E2), sex hormone-binding globulin (SHBG) and urinary 2-OHE1 and 16α-OHE1. PMD was assessed by mammography (n=65; 54%) and also a novel, non-radiative, non-contrast magnetic resonance imaging-derived fat-water ratio (FWR-MRI) as the fat fraction (Fra)50 and 80 (n=53; 44%) developed for repeat BD assessment in short intervals. This is our first report that BD using digitized mammograms is correlated with FWR-MRI-derived measures designated Fra50 and Fra80; Spearman ρ = 0.90 and 0.86, respectively, p &lt; 0.001.
Results. As previously demonstrated, BMI was inversely correlated with all measures of BD. No association was shown between TAM and TAM metabolites and BD or urinary 2OHE1. Further, we found no relationship between circulating E2 or SHBG concentrations and BD. In contrast, urinary 2OHE1 levels were positively correlated with BD across all measures of density; 2OHE1 levels were most strongly correlated with BD measured by FW-MRI using Fra80 (Spearman ρFra80=0.483; p=0.001 compared to ρFra50 =0.431; p = 0.004 and ρPD=0.400; p=0.003). A significant, but weaker, correlation was observed for the 2OHE1:16OHE1 ratio and BD (ρ values 0.34-0.38). The magnitude of the relationship between 2OHE1 and BD was similar in pre and post-menopausal women despite lower PBD after menopause.
Conclusions. Our results replicate earlier work from Maskarinec et al. wherein excreted 2OHE1 was an independent determinant of BD. These data challenge the hypothesis proposed by Yager and Liehr that higher urinary 2OHE1 to 16OHE1 ratio would be indicative of reduced hormone tumorigenesis. These results suggest a possible comparable binding affinity for the estrogen receptor that may modify endogenous steroid hormones and their effects on BD. Our findings strengthen the arguments favoring a better mechanistic understanding of BD, the biological determinants and their relationship to breast cancer. This is particularly timely given new mandates to provide BD measures to all women undergoing mammography and recent findings that while BD is associated with breast cancer risk high BD is not associated with greater breast cancer mortality.
Citation Format: Cynthia A Thomson, Patricia A Thompson, Betsy C Wertheim, Denise Roe, Marilyn T Marron, John-Phillipe Galons, Matthew A Kupinski, Maria I Altbach, Gertraud Maskarinec, Alison Stopeck. 2-Hydroxyestrone is associated with breast density measured by mammography and fat:water ratio magnetic resonance imaging in women taking tamoxifen [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-01-18.