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IPET study: an FLT-PET window study to assess the activity of the steroid sulfatase inhibitor irosustat in early breast cancer

Title: IPET study: an FLT-PET window study to assess the activity of the steroid sulfatase inhibitor irosustat in early breast cancer
Authors: Palmieri, C
Szydlo, R
Miller, M
Barker, L
Patel, NH
Sasano, H
Barwick, T
Tam, H
Hadjiminas, D
Lee, J
Shaaban, A
Nicholas, H
Coombes, RC
Kenny, LM
Item Type: Journal Article
Abstract: BACKGROUND: Steroid sulfatase (STS) is involved in oestrogen biosynthesis and irosustat is a first generation, irreversible steroid sulfatase inhibitor. A pre-surgical window-of-opportunity study with irosustat was undertaken in estrogen receptor-positive (ER+) breast cancer to assess the effect of irosustat on tumour cell proliferation as measured by 3'-deoxy-3'-[18F] fluorothymidine uptake measured by PET scanning (FLT-PET) and Ki67. METHODS: Postmenopausal women with untreated ER+ early breast cancer were recruited, and imaged with FLT-PET at baseline and after at least 2 weeks treatment with irosustat, 40 mg once daily orally. The primary endpoint was changed in FLT uptake; secondary endpoints included safety and tolerability of irosustat, changes in tumoral Ki67 and steroidogenic enzymes expression and circulating steroid hormone levels. RESULTS: Thirteen women were recruited, and ten started irosustat for 2 weeks, followed by repeat FLT-PET scans in eight. Defining response as decreases of ≥20% in standardized uptake value (SUV) or ≥30% in Ki, 1 (12.5% (95% CI 2-47%, p = 0.001)) and 3 (43% (95% CI 16-75%, p = <0.001) patients, respectively, responded. 6 out of 7 patients had a Ki67 reduction (range = -19.3 to 76.4%), and median percentage difference in Ki67 was 52.3% (p = 0.028). In one patient with a low baseline STS expression, a 19.7% increase in Ki67 was recorded. STS decreases were seen in tumours with high basal STS expression, significant decreases were also noted in aromatase, and 17β-hydroxysteroid dehydrogenase type 1 and 2. Irosustat was generally well tolerated with all adverse event CTCAE Grade ≤2. CONCLUSIONS: Irosustat resulted in a significant reduction in FLT uptake and Ki67, and is well tolerated. These data are the first demonstrating clinical activity of irosustat in early breast cancer. Baseline expression of STS may be a biomarker of sensitivity to irosustat.
Issue Date: 1-Nov-2017
Date of Acceptance: 26-Jul-2017
URI: http://hdl.handle.net/10044/1/64157
DOI: https://dx.doi.org/10.1007/s10549-017-4427-x
ISSN: 0167-6806
Publisher: Springer Verlag
Start Page: 527
End Page: 539
Journal / Book Title: Breast Cancer Research and Treatment
Volume: 166
Issue: 2
Copyright Statement: © The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Sponsor/Funder: Novartis Pharmaceuticals UK Limited
Pfizer Limited
Cancer Research UK
Cancer Research UK
Imperial College Healthcare NHS Trust- BRC Funding
Imperial College Healthcare NHS Trust- BRC Funding
Cancer Research UK
Funder's Grant Number: Neocent Trial
PG281732/GA9001DP
C37/A9356
13392
RD205
RDB01 79560
18078
Keywords: Science & Technology
Life Sciences & Biomedicine
Oncology
Breast Cancer
ER
FLT
PET
Ki67
Sulfatase
Irosustat
POSITRON-EMISSION-TOMOGRAPHY
INDUCED MAMMARY-TUMORS
CELL-PROLIFERATION
17-BETA-HYDROXYSTEROID-DEHYDROGENASE TYPE-1
DEHYDROEPIANDROSTERONE-SULFATE
ENDOCRINE THERAPY
PHASE-I
ESTROGEN
AROMATASE
GROWTH
Aged
Aged, 80 and over
Breast Neoplasms
Early Detection of Cancer
Female
Humans
Middle Aged
Positron-Emission Tomography
Postmenopause
Radiopharmaceuticals
Receptors, Estrogen
Steryl-Sulfatase
Sulfonic Acids
Treatment Outcome
Vascular Endothelial Growth Factor Receptor-1
1112 Oncology And Carcinogenesis
Oncology & Carcinogenesis
Publication Status: Published
Conference Place: Netherlands
Online Publication Date: 2017-08-09
Appears in Collections:Division of Surgery
Division of Cancer
Department of Medicine
Faculty of Medicine



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