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


METHODS
A total of 226 recent postmenopausal 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 microg/day (n = 115) and to fenretinide 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 transdermal E2 (P < 0.001 between groups). Fenretinide decreased 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 biomarkers but gives similar effects on mammographic density. Fenretinide exerted little modulation on most biomarkers. The clinical implications of these findings require additional studies.
Decensi
Andrea
A
Divisions of Chemoprevention, Epidemiology and Biostatistics, Laboratory Medicine, Radiology, and Gynecology, European Institute of Oncology, Milan, Italy. andrea.decensi@ieo.it
Bonanni
Bernardo
B
Baglietto
Laura
L
Guerrieri-Gonzaga
Aliana
A
Ramazzotto
Francesca
F
Johansson
Harriet
H
Robertson
Chris
C
Marinucci
Irene
I
Mariette
Frederique
F
Sandri
Maria Teresa
MT
Daldoss
Cristina
C
Bianco
Vanda
V
Buttarelli
Marco
M
Cazzaniga
Massimiliano
M
Franchi
Dorella
D
Cassano
Enrico
E
Omodei
Umberto
U
D000279:Administration, Cutaneous; D000284:Administration, Oral; D000328:Adult; D000568:Amenorrhea / Q000378:metabolism; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy*; D015536:Down-Regulation; D004492:Edetic Acid / Q000494:pharmacology; D004967:Estrogens / Q000008:administration & dosage*; D005260:Female; D017313:Fenretinide / Q000008:administration & dosage*; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008327:Mammography; D008875:Middle Aged; D010919:Placebos; D017698:Postmenopause; D012107:Research Design; D012306:Risk; D012738:Sex Hormone-Binding Globulin / Q000378:metabolism; D013997:Time Factors
D014408:Biomarkers, Tumor; D004967:Estrogens; D018972:Insulin-Like Growth Factor Binding Protein 3; D010919:Placebos; D012738:Sex Hormone-Binding Globulin; D017313:Fenretinide; D007334:Insulin-Like Growth Factor I; D004492:Edetic Acid