Abstract P2-08-26: High expression of CYP27A1 in breast cancer is associated with poor tumor pathological features and may differentially predict prognosis depending on menopausal status

Abstract

Background: Pre-clinical and epidemiological data strongly link high cholesterol with breast cancer progression and poor prognosis. It was recently uncovered that the pathogenicity of cholesterol in breast cancer is directly propagated by 27-hydroxycholesterol (27HC), an oxysterol produced when cholesterol is hydroxylated by cytochrome P450, family 27, subfamily A, polypeptide 1 (CYP27A1) during bile acid synthesis. 27HC promotes breast tumor growth and metastasis via interactions with the estrogen receptor (ER) and liver x receptors respectively. Consequently, pharmaceutical approaches that directly interfere with CYP27A1 activity have been proposed to mitigate the adverse impact of 27HC in breast cancer. However, CYP27A1 expression or deregulation in clinical breast cancer is not well characterised. The aim of this study was to comprehensively describe the impact of tumor-specific expression of CYP27A1 protein on clinical breast cancer pathobiology and prognosis. Methods: CYP27A1 expression in tumor cells was evaluated by immunohistochemistry in two independent population based cohorts including female patients with primary invasive breast cancer diagnosed between 1991 and 2010 (cohort 1) and between 2002 and 2012 (cohort 2). Staining was evaluable in 645 and 813 cases in cohort 1 and cohort 2, respectively. Associations between CYP27A1 expression with tumor pathological factors and survival were assessed by using logistic and Cox regression models respectively. Multivariable models adjusted for age at diagnosis, nodal status, histological grade, tumor size, ER and BMI. Results: CYP27A1 was overexpressed in 21% and 28% in cohort 1 and cohort 2 respectively. High CYP27A1 expression was significantly associated with adverse tumor pathological features including negative hormone receptor (ER and PgR) status and histological grade 3 in both cohorts and with larger tumors (>20 mm) in cohort two only (p<0.05, for all comparisons). In multivariable Cox regression analyses, overexpression of CYP27A1 was neither independently prognostic for recurrence-free survival (cohort 2: HR=1.3, 95% CI= 0.88 – 1.9) nor overall survival (cohort 1: HR=1.3, 95% CI= 0.88 – 1.9 and Cohort 2: HR=1.3, 95% CI= 0.81 – 2.0, respectively). Upon stratification for menopausal status using age at diagnosis (< 50 years vs ≥ 50 years) as surrogate, the relationship between CYP27A1 expression and prognosis remained non-significant for older (postmenopausal) patients. Interestingly, among younger (premenopausal) women, elevated CYP27A1 expression was independently prognostic for shorter time to recurrence or death (HR=3.3, 95% CI= 1.5 – 7.4; cohort 2). Conclusions: Collectively, these results indicate that intratumoral CYP27A1 expression supports the notion that 27HC plays an important pathological role in breast cancer progression but tumor cell-specific CYP27A1 expression is not sufficient to independently predict overall survival in postmenopausal patients. Further sufficiently sized studies are needed to clarify the prognostic significance of CYP27A1 in younger and presumably premenopausal patients and evaluate its role as a treatment predictive factor. Citation Format: Kimbung S, Stålhammar T, Inasu M, Nodin B, Elebro K, Tryggvadottir H, Jirström K, Rose C, Ingvar C, Jernström H, Borgquist S. High expression of CYP27A1 in breast cancer is associated with poor tumor pathological features and may differentially predict prognosis depending on menopausal status [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-26.