Abstract P3-05-12: Circulating oxysterol metabolites as potential new surrogate markers for hormonotherapy in patients with hormone receptor-positive breast cancer? A pilot study
Authors: Dalenc Florence , Iuliano Luggi , Filleron Thomas , Voisin Maud , Roché Henri , Silvente-Poirot Sandrine , Poirot Marc 
Published: May 2015

Abstract
Background: Clinicians need new predictive biomarkers of response to hormonal therapy in patients (pts) with hormone receptor-positive (HR+) breast cancer (BC). Current treatments used the selective estrogen receptor modulator tamoxifen (Tam) or aromatase inhibitors (AI). Several data from the literature and our preclinical results indicate that cholesterol metabolism pathway is involved in BC oncogenesis and sensitivity/resistance to Tam. Our team has established that Tam modulates cholesterol oxydative metabolism and modulate oxysterol (OS) levels in vitro and in vivo on BC cell lines. Tam is a potent inhibitor of the cholesterol-5,6-epoxide hydrolase (ChEH), which led to the accumulation of cholesterol epoxides (CEs) and the inhibition formation of cholesterol triol (CT). Importantly, we found that CEs mediated the cytotoxicity of Tam in BC. Therefore, an increase in CEs, and no increase in CT could be markers of the efficacy of Tam reflecting its inhibition of ChEH in pts. On the other hand 27-hydroxycholesterol (27HC), another OS, is an estrogen receptor ligand with tumor promoter properties in BC. The 27HC level could constitute a new risk factor for BC development that has to be measured. The impact of AI on cholesterol metabolism is totally unknown, it is thus important to study its impact on OS levels in pts.
Methods: We have conducted a monocentric, prospective, clinical trial in pts who must received Tam or AI in adjuvant or metastatic setting for a HR+ BC. The primary end point was the feasibility of detection of circulating OS (CEs, CT and 27HC) in the serum of patients before the first administration of hormonal therapy and at 1 month. Key secondary end points were to measure variations in the concentration of OS according to patients and treatments. 12 different OS including CEs, CT and 27HC were quantified by GC/MS.
Results : bCE relative concentration significantly increased in the entire population (p=0.0109) while no increase in CT was measured under HT treatment establishing that Tam inhibited ChEH in pts. It should be noted that an important inter-individual variability in pts was observed according the OS species considered. AI stimulated the accumulation of βCE (p=0.0022) suggesting that they modulate CEs metabolism. We found that AI were not direct inhibitors of ChEH in BC cells suggesting that they modulate CEs level through a different mechanism than Tam. Importantly, we found that letrozol, but not exemestane or Tam, increased the blood level in 27-HC. This suggests that letrozol increased a factor of BC risk since 27HC is a tumor promoter which may be involved in BC recurrence.
Conclusion: This pilot study provides the first evidence that circulating OS could be measured in the blood of pts with BC. The clinical utility of OS as biomarkers of sensibility/resistance to hormone therapy needs further clinical investigations. Based on the present study the CE/27HC ratio should be more specifically investigated. The mechanisms involved in the modulation of OS by AI deserve further studies.
Citation Format: Florence Dalenc, Luggi Iuliano, Thomas Filleron, Maud Voisin, Henri Roché, Sandrine Silvente-Poirot, Marc Poirot. Circulating oxysterol metabolites as potential new surrogate markers for hormonotherapy in patients with hormone receptor-positive breast cancer? A pilot study [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 P3-05-12.