A two-by-two factorial trial comparing oral with transdermal estrogen therapy and fenretinide with placebo on breast cancer biomarkers.

Purpose: Oral conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA) increase breast cancer risk, whereas the effect of transdermal estradiol (E2) and MPA is less known. Fenretinide may decrease second breast malignancies in premenopausal women but not in post- menopausal women, suggesting a hormone-sensitizing effect. We compared the 6 and 12-month changes in insulin-like growth factor-I (IGF-I), IGF-binding protein-3 (IGFBP-3), IGF-I:IGFBP-3 ratio, sex-hormone binding-globulin, and computerized mammographic percent density during oral CEE or transdermal E2 with sequential MPA and fenretin- ide or placebo. Experimental Design: A total of 226 recent postmeno- pausal healthy women were randomly assigned in a two-by- two factorial design to either oral CEE 0.625 mg/day (n 111) or transdermal E2, 50 g/day (n 115) and to fen- retinide 100 mg/twice a day (n 112) or placebo (n 114) for 12 months. Treatment effects were investigated by the Kruskall-Wallis test and analysis of covariance. P values were two-sided.Results: After 12 months, oral CEE decreased IGF-I by 26% [95% confidence interval (CI), 22–30%] and increased sex-hormone binding-globulin by 96% (95% CI, 79–112%) relative to baseline, whereas no change occurred with trans- dermal E2 (P < 0.001 between groups). Fenretinide de- creased IGFBP-3 relative to placebo (P 0.04). Percentage of breast density showed an absolute increase of 3.5% (95% CI, 2.5–4.6%) during hormone therapy without differences between groups (P 0.39). Conclusions: Oral CEE has more favorable changes than transdermal E2 on circulating breast cancer risk bi- omarkers but gives similar effects on mammographic den- sity. Fenretinide exerted little modulation on most biomar- kers. The clinical implications of these findings require additional studies.