Investigation Of 27-Hydroxycholesterol As A Biomarker For Aggressive Endometrial Cancer

Background: Strong risk factors for the most common (endometrioid) type of endometrial cancer (EC) include obesity and exposure to high estrogen levels. While EC has a favorable prognosis overall, one third of women present with advanced stage disease at diagnosis which has high recurrence and mortality rates. Given the estrogen-mediated etiology of EC, the current study focuses on the selective estrogen receptor modulator (SERM) 27-hydroxycholesterol (27HC) pathway. SERMs like 27HC can mimic estrogenic actions, and experimental work indicates 27HC exposure leads to continuous estrogenic stimulation and increases proliferation in the endometrium. Objective: to identify biomarkers for more aggressive disease, particularly markers present in early stages of carcinogenesis, to help guide decisions regarding treatment options. Methods: We conducted immunohistochemical staining on two tissue microarrays (TMAs) representing EC and its precursor endometrial intraepithelial neoplasia (EIN) tissues to measure protein levels of the enzymes that metabolize cholesterol into 27HC (CYP27A1) and 27HC into bile acids (CYP7B1), the receptors that bind 27HC (Estrogen Receptor [ER])-alpha, ER-beta as well as Liver Receptor X [LXR]-alpha and LXR-beta) and progesterone receptor (PR). We will use Fisher9s exact test to evaluate 27HC associated biomarkers (categories split at the median) in relation to the presence of myometrial invasion (MI) and final diagnosis (EC or not) in the EIN TMA, and to assess clinico-pathologic factors including disease stage and grade in the EC TMA. Results: We created a new EIN TMA using formalin-fixed paraffin-embedded endometrial curettage or Pipelle endometrial biopsies from 144 EIN cases of diverse racial/ethnic backgrounds (Japanese, Hawaiian, White, Filipino and Asian/Pacific Islander) who were treated between 2007-16 in the Hawaii Pacific Health System. The EIN TMA contains both abnormal EIN tissues and neighboring benign/non-atypical tissues. In total, 50% of the EIN cases had no EC, 30% had cancer with no myometrial invasion (MI) and 20% had cancer with myometrial invasion. We are concurrently evaluating 27HC pathway markers in a TMA representing EC tumors from 96 cases who were treated in the same hospitals between 2001-07. The EC TMA represents diverse racial/ethnic groups including 28% Japanese American, 25% Native Hawaiian and 23% white cases (24% other). The EC TMA contains representative tissues from 91% endometrioid histotype cases and 72% localized and 28% regional/distant stage cases. We will examine associations between 27HC pathway biomarkers and clinico-pathologic characteristics of EC and EIN and will present our findings at the meeting. Conclusions: This study provides new data to determine whether 27HC pathway biomarkers may relate to characteristics of aggressive EC, such as the presence of myometrial invasion and higher stage and grade at diagnosis. Citation Format: Danja Sarink, Lenora W. Loo, Jeffrey Killeen, Brenda Y. Hernandez, Owen T. Chan, Melissa A. Merrit. Investigation of 27-hydroxycholesterol as a biomarker for aggressive endometrial cancer [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 3490.