Randomized dose-ranging trial of tamoxifen at low doses in hormone replacement therapy users.
OBJECTIVE
The combination of hormone replacement therapy (HRT) and low-dose tamoxifen may retain the benefits while reducing the risks of either agent. We assessed the optimal biologic dose and schedule of tamoxifen in HRT users using surrogate end point biomarkers and menopausal symptoms.


METHODS
Two hundred ten current or de novo HRT users were randomly assigned to one of the following four arms: tamoxifen 1 mg/day and placebo/week, placebo/day and tamoxifen 10 mg/week, tamoxifen 5 mg/day and placebo/week, or both placebos for 12 months. The primary end point was the change of plasma insulinlike growth factor 1 (IGF-I) through 12 months, and secondary end points were IGF-I/IGF binding protein-3 (IGFBP-3) ratio, fibrinogen, antithrombin III, C reactive protein, C-telopeptide, mammographic percent density, and endometrial thickness. Endometrial proliferation was assessed by Pipelle biopsy in superficial, deep glandular, and stromal compartments after 12 months.


RESULTS
Compared with placebo, IGF-I declined in all tamoxifen arms (P = .005), with a greater change on 5 mg/day (P = .019 v 10 mg/week or 1 mg/day). Tamoxifen increased IGFBP-3 and lowered antithrombin-III, C reactive protein, and mammographic density, with greater effects of 5 mg/day. Tamoxifen increased endometrial thickness but not Ki-67 expression, which was lower on 5 mg/day among the three doses. Menopausal symptoms were not significantly worsened by tamoxifen.


CONCLUSIONS
Doses of tamoxifen < or = 5 mg/day modulate favorably biomarkers of breast carcinogenesis and cardiovascular risk in HRT users with no increase of endometrial proliferation and menopausal symptoms. A dose of 5 mg/day was the most effective and has been selected for a phase III trial in HRT users.
Decensi
Andrea
A
Division of Chemoprevention, European Institute of Oncology, Milan, Italy. andrea.decensi@galliera.it
Gandini
Sara
S
Serrano
Davide
D
Cazzaniga
Massimiliano
M
Pizzamiglio
Maria
M
Maffini
Fausto
F
Pelosi
Giuseppe
G
Daldoss
Cristina
C
Omodei
Umberto
U
Johansson
Harriet
H
Macis
Debora
D
Lazzeroni
Matteo
M
Penotti
Mauro
M
Sironi
Laura
L
Moroni
Simona
S
Bianco
Vanda
V
Rondanina
Gabriella
G
Gjerde
Jennifer
J
Guerrieri-Gonzaga
Aliana
A
Bonanni
Bernardo
B
D000328:Adult; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage*; D014408:Biomarkers, Tumor; D002097:C-Reactive Protein / Q000378:metabolism; D049109:Cell Proliferation; D004334:Drug Administration Schedule; D004717:Endometrium / Q000378:metabolism; D005260:Female; D020249:Hormone Replacement Therapy / Q000379:methods*; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis; D008875:Middle Aged; D010919:Placebos; D013629:Tamoxifen / Q000008:administration & dosage*
D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D018972:Insulin-Like Growth Factor Binding Protein 3; D010919:Placebos; D013629:Tamoxifen; D007334:Insulin-Like Growth Factor I; D002097:C-Reactive Protein