Abstract P3-08-21: High CYP27A1 expression at protein and transcript level predicts favorable outcome in node negative, premenopausal breast cancer
Authors: Inasu Maria , Bendahl Pär Ola , Fernö Mårten , Malmström Per , Borgquist Signe , Kimbung Siker 
Published: March 2020

Background: Experimental evidence suggests that pathogenicity caused by cholesterol in breast cancer is partly elicited by 27-hydroxycholesterol (27HC), a primary cholesterol metabolite produced by the sterol 27-hydroxylase cytochrome p450 27A1 (CYP27A1). Targeting CYP27A1 abrogated the adverse effects of cholesterol and 27HC in preclinical studies. The prognostic relevance of CYP27A1 expression in patients with breast cancer is however not clearly defined. Previous studies suggest that the intratumoral expression of CYP27A1 might have diverse effects on prognosis depending on menopausal status. The aim of this study was to comprehensively evaluate the impact of both CYP27A1 protein and mRNA expression on tumor pathobiology and prognosis in pre-menopausal, node-negative breast cancer.

Materials and Methods: CYP27A1 expression at the protein and transcript level was evaluated in a prospective cohort of 237 premenopausal women with node-negative, primary invasive breast cancer. Protein and mRNA expression were assessed by immunohistochemistry (IHC) and in situ hybridization technique-RNAscope, respectively. Associations of CYP27A1 expression with tumor pathological features and prognosis were assessed with chi-square test and Cox regression models, respectively. Multivariable models were adjusted for age, hormone receptor status, Ki67, and histological grade.

Results: CYP27A1 protein was overexpressed in 28% and CYP27A1 mRNA in 23% of the tumors. The concordance between CYP27A1 protein and mRNA expression was 77.8% (rs=0.430). Among the discordant cases, 13.9% were only positive by IHC. Elevated expression of both protein and mRNA was significantly associated with aggressive tumor pathological features like high histological grade and high Ki67 expression (P&lt;0.001). In multivariable Cox regression analyses, overexpression of CYP27A1 protein was independently prognostic for more than a factor-two reduced risk of disease recurrence (Recurrence-Free Survival (RFS): HR=0.40, 95% CI=0.23-0.86; Distant Recurrence-Free Survival (DRFS): HR=0.40, 95% CI=0.16-0.95). High CYP27A1 expression conferred even stronger protective effect for patients with estrogen receptor (ER) positive tumors when the analyses were stratified by ER status (RFS: HR=0.18, 95% CI=0.06-0.55; DRFS: HR=0.20, 95% CI=0.06-0.81). Likewise, high CYP27A1 mRNA expression was also independently prognostic for a longer RFS (HR=0.40, 95% CI=0.2-0.8), DRFS (HR=0.28; 95%CI=0.1-0.7) and in addition better overall survival (OS) (HR=0.20, 95% CI=0.08-0.60) in the overall population and in the subgroup of patients with ER positive tumors (OS: HR=0.14; 95% CI=0.03-0.65; RFS: HR= 0.22; 95% CI= 0.07-0.68; DRFS: HR=0.16; 95% CI=0.03-0.73).

Conclusion: These results indicate that high intratumoral expression of CYP27A1 is a strong indicator for an extensive recurrence-free interval and overall survival in premenopausal women with ER positive, lymph node-negative breast cancer. CYP27A1 transcript expression may serve as an even more sensitive prognostic biomarker.

Citation Format: Maria Inasu, Pär Ola Bendahl, Mårten Fernö, Per Malmström, Signe Borgquist, Siker Kimbung. High CYP27A1 expression at protein and transcript level predicts favorable outcome in node negative, premenopausal breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-21.