title: Circulating oxysterol metabolites as potential new surrogate markers in patients with hormone receptor-positive breast cancer: Results of the OXYTAM study.
abstract: Accumulating evidence indicates that cholesterol oxygenation products, also known as oxysterols (OS), are involved in breast cancer (BC) promotion. The impact of Tam, as well as aromatase inhibitors (AI), an alternative BC endocrine therapy (ET), on OS metabolism in patients is currently unknown. We conducted a prospective clinical study in BC patients receiving Tam (n=15) or AI (n=14) in adjuvant or in metastatic settings. The primary end point was the feasibility of detecting and quantifying 11 different OS in the circulation of patients before and after 28days of treatment with Tam or AI. Key secondary end points were the measurements of variations in the concentrations of OS according to differences between patients and treatments. OS profiling in the serum of patients was determined by gas chromatography coupled to mass spectrometry. OS profiling was conducted in all patients both at baseline and during treatment regimens. An important inter-individual variability was observed for each OS. Interestingly 5,6β-epoxycholesterol relative concentrations significantly increased in the entire population (p=0.0109), while no increase in Cholestane-triol (CT) levels was measured. Interestingly, we found that, in contrast to AI, Tam therapy significantly decreased blood levels of 24-hydroxycholesterol (24-HC), 7α-HC and 25-HC (a tumor promoter) (p=0.0007, p=0.0231 and p=0.0231, respectively), whereas 4β-HC levels increased (p=0.0010). Interestingly, levels of 27-HC (a tumor promoter) significantly increased in response to AI (p=0.0342), but not Tam treatment. According to these results, specific OS are promising candidate markers of Tam and AI efficacy. Thus, further clinical investigations are needed to confirm the use of oxysterols as biomarkers of both prognosis and/or the efficacy of ET.
authors.affiliation: Department of Medical Oncology, Institut Claudius Regaud, IUCT-Oncopole, Toulouse, France; Inserm UMR 1037, Team "Cholesterol metabolism and therapeutic innovations", Cancer Research Center of Toulouse, Toulouse, France. Electronic address: dalenc.florence@iuct-oncople.fr.
authors.forename: Florence
authors.initials: F
authors.lastname: Dalenc
authors.affiliation: Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy.
authors.forename: Luiggi
authors.initials: L
authors.lastname: Iuliano
authors.affiliation: Department of Biostatistics, Institut Claudius Regaud, IUCT-Oncopole, Toulouse, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Filleron
authors.affiliation: Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Zerbinati
authors.affiliation: Department of Medical Oncology, Institut Claudius Regaud, IUCT-Oncopole, Toulouse, France; Inserm UMR 1037, Team "Cholesterol metabolism and therapeutic innovations", Cancer Research Center of Toulouse, Toulouse, France; University of Toulouse III, Toulouse France.
authors.forename: Maud
authors.initials: M
authors.lastname: Voisin
authors.affiliation: Institut Claudius-Regaud, IUCT-Oncopole and EA4553 University of Toulouse III Paul-Sabatier, Toulouse, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Arellano
authors.affiliation: Institut Claudius-Regaud, IUCT-Oncopole and EA4553 University of Toulouse III Paul-Sabatier, Toulouse, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Chatelut
authors.affiliation: CHU Limoges, University of Limoges, U850 INSERM, Limoges, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Marquet
authors.affiliation: LCPMC-A2, ICPM, Département de Chimie, University of Lorraine, Metz, France.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Samadi
authors.affiliation: Department of Medical Oncology, Institut Claudius Regaud, IUCT-Oncopole, Toulouse, France.
authors.forename: Henri
authors.initials: H
authors.lastname: Roché
authors.affiliation: Inserm UMR 1037, Team "Cholesterol metabolism and therapeutic innovations", Cancer Research Center of Toulouse, Toulouse, France; University of Toulouse III, Toulouse France. Electronic address: marc.poirot@inserm.fr.
authors.forename: Marc
authors.initials: M
authors.lastname: Poirot
authors.affiliation: Inserm UMR 1037, Team "Cholesterol metabolism and therapeutic innovations", Cancer Research Center of Toulouse, Toulouse, France; University of Toulouse III, Toulouse France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Silvente-Poirot
mesh_terms: D000328:Adult; D000368:Aged; D000730:Androstadienes / Q000627:therapeutic use; D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D015992:Body Mass Index; D001943:Breast Neoplasms / Q000097:blood* / Q000378:metabolism; D002776:Cholestanes / Q000097:blood; D002784:Cholesterol / Q000031:analogs & derivatives / Q000378:metabolism; D005240:Feasibility Studies; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006728:Hormones / Q000737:chemistry; D006801:Humans; D000077289:Letrozole; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009570:Nitriles / Q000627:therapeutic use; D018384:Oxidative Stress; D000072376:Oxysterols / Q000097:blood / Q000378:metabolism*; D010865:Pilot Projects; D011379:Prognosis; D011446:Prospective Studies; D015203:Reproducibility of Results; D015398:Signal Transduction; D013629:Tamoxifen / Q000627:therapeutic use; D014230:Triazoles / Q000627:therapeutic use
chemical_list: C119784:5,6-epoxycholesterol; D000730:Androstadienes; D047072:Aromatase Inhibitors; D015415:Biomarkers; D002776:Cholestanes; D006728:Hormones; D009570:Nitriles; D000072376:Oxysterols; D014230:Triazoles; D013629:Tamoxifen; D000077289:Letrozole; D002784:Cholesterol; D001141:Aromatase; C056516:exemestane
keywords: Aromatase inhibitor; Biomarkers; Breast cancer; Circulating oxysterols; Endocrine therapy; Tamoxifen