The effect of transdermal estradiol or oral conjugated oestrogen and fenretinide versus placebo on haemostasis and cardiovascular risk biomarkers in a randomised breast cancer chemoprevention trial

Abstract

Background:We have previously reported the favourable effect of transdermal estradiol (E2), relative to oral conjugated equine oestrogen (CEE), on ultrasensitive C-reactive protein after 12 months of treatment in a retinoid-placebo controlled two-by-two randomized breast cancer prevention trial (Decensi A et al (2002) Circulation 106 10 1224–8). Here, we investigate the changes in lipids and clotting profile in patients of the same trial.Methods and results:Recent post-menopausal women were randomised to either oral CEE 0.625 mg/day and placebo (n = 55), CEE and fenretinide 200 mg/day (n = 56), transdermal E2 50 mg/day and placebo (n = 59) or E2 and fenretinide 200 mg/day (n = 56). Sequential medroxyprogesterone acetate 10 mg/day was given in each group. After 12 months, there was a statistically significant effect of the route of administration of hormone replacement therapy (HRT) on fibrinogen levels; the median percentage change being −5.7% with CEE and −1.1% with E2 (p = 0.012). Total cholesterol decreased in all arms (p < 0.0001). HDL-C decreased significantly with transdermal E2 (p = 0.006) compared to oral CEE and with fenretinide relative to placebo (p<0.001). Triglycerides exhibited an opposite modulation in the HRT route, with a 21.4% median increase with oral CEE and an 8.6% reduction with transdermal E2 (p < 0.0001). Antithrombin-III showed a 4% borderline significant reduction in the fenretinide arm relative to placebo, irrespective of the HRT administration route (p = 0.055).Conclusions:Our data indicate that transdermal E2 may be preferable to oral CEE based on its safer cardiovascular risk profile. Fenretinide modified some cardiovascular risk biomarkers and confirmed a safer profile compared to other retinoids.

Association of Serum Retinol Binding Protein 4 with Atherogenic Dyslipidemia in Morbid Obese Patients

“…RBP4 has been shown to alter lipid profile in several clinical trials with fenretinide, a synthetic retinoid designed for cancer therapy that increases renal clearance of RBP4. Lazzeroni and colleagues reported a statistically significant increase in HDLc between fenretinide- and placebo-treated post-menopausal healthy women [44] , in line with previous results obtained in metastatic breast cancer patients [45] . Moreover, fenretinide prevented the increase in triglyceride levels associated with augmented HOMA in premenopausal women with a high risk of developing breast cancer [46] .…”