Abstract P3-05-08: Steroid receptors and steroidogenic enzymes in human breast cancer: Associations with breast cancer subtypes and clinical outcome
Authors: McNamara KM , Guestini F , Sauer T , Lindstrøm JC , Sasano H , Geisler J 
Published: March 2017

Abstract
Introduction: The majority of breast cancer (BC) cases are believed to be highly steroid dependent. Therefore exploitation of currently untapped steroid pathways could potentially contribute to our search for novel targeted breast cancer therapies. Given the growing understanding of the importance of both intratumoral steroid metabolism and impact of alternate steroid receptors in BC biology, we evaluated selected steroidogenic pathways in a cohort of 140 BC cases from Akershus University Hospital, Norway. In this study we immunolocalized both the androgen receptor (AR) and glucocorticoid receptor (GR) in addition to steroid sulfatase (STS) and 17β hydroxysteroid dehydrogenase 2 (17βHSD2). We also evaluated immunoreactivity of Ki-67 and CYP19/aromatase. We correlated these factors with the occurrence of distant metastasis or local relapse, and survival adjusted by age at surgery. We also examined whether any of these pathways were enriched in the classical breast cancer subtypes (Luminal A, Luminal B, HER-2 positive, triple-negative BC). Logistic and Cox regression analysis was employed to examine interactions between the above factors.
Results: In an analysis looking at possible interactions between recurrence and the factors above, the status of intratumoral STS was significantly inversely associated with distant metastasis (OR=0.17, p&lt;0.001) and local relapses (OR=0.17, p&lt;0.001), while that of 17βHSD2 trended towards correlation with the presence of metastasis (OR=3.47, p=0.055) and relapse (OR=3.14, p=0.07). Interestingly, ER and PR were not correlated with metastasis or relapse, but HER2 status positively correlated with distant metastasis during follow-up (OR=2.15, p=0.02) and trended to be associated with local relapses as well (OR=1.99, p=0.054). When evaluated according to the established breast cancer subtypes the only significant changes detected between subgroups were for AR and STS. AR was positive in a lesser proportion of the cases in the TNBC subgrouping (p=0.01), while STS was depleted in the luminal B and enriched in the HER2 subtypes (p=0.027). In an analysis of survival, STS was the only factor examined that was significantly associated with survival outcomes of the patients. Positive intratumoral STS status was significantly associated with improved survival (HR=0.27, p&lt;0.001). The inverse of this was also noticed for 17βHSD2 but the correlation did not reach statistical significance (HR=2.1, p=0.16).
Discussion and Conclusions: The results of our present study suggest that the intratumoral metabolism of estrogens through STS is associated with significantly lower incidence of relapse and/or distant metastasis and correspondingly a better prognosis. The inverse is also true when evaluating the trends noted with the expression of 17βHSD2 adding consistency to our finding above. The enrichment of STS in the HER2 overexpressing subtype of breast cancer is intriguing, especially given the possible role of HER-2 positivity in endocrine resistance. All in all, our results suggest that extended endocrine information about the intratumoral steroid metabolism of a given tumour may have so far unused prognostic potential and impact on clinical decision making.
Citation Format: McNamara KM, Guestini F, Sauer T, Lindstrøm JC, Sasano H, Geisler J. Steroid receptors and steroidogenic enzymes in human breast cancer: Associations with breast cancer subtypes and clinical outcome [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-05-08.