Abstract
BackgroundSteroid 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.MethodsPostmenopausal 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.ResultsThirteen 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.ConclusionsIrosustat 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.
Highlights
The estrogen receptor (ER) is key therapeutic target in breast cancer, with over 70% of breast cancers expressing ER
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 30-deoxy-30-[18F] fluorothymidine uptake measured by PET scanning (FLT-PET) and Ki67
Of the patients recruited into the study, there were two baseline FLT production failures, one declined on day 1 to enter, another was withdrawn after days due to an abnormal ECG and in one case an FLT production failure prevented the on treatment PET 8 paired FLT-PET scans were performed (Fig. 2)
Summary
The estrogen receptor (ER) is key therapeutic target in breast cancer, with over 70% of breast cancers expressing ER. Endocrine therapy (ET) is a key treatment modality in the treatment of such estrogen receptor-positive breast cancers and the disruption of the process of estrogen production by inhibition of the peripheral aromatisation (aromatase inhibitors) is a key form of ET [1], Fig. 1. 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 30-deoxy-30-[18F] fluorothymidine uptake measured by PET scanning (FLT-PET) and Ki67. Radiological Sciences Unit and Department of Nuclear Medicine, Imperial College Healthcare NHS Trust, London W6 8RF, UK 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
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