Preliminary results on safety and activity of a randomized, double-blind, 2 x 2 trial of low-dose tamoxifen and fenretinide for breast cancer prevention in premenopausal women.
OBJECTIVE
To determine whether low-dose tamoxifen and fenretinide have a synergistic effect on surrogate biomarkers, including circulating insulin-like growth factor I (IGF-I) and mammographic density, in premenopausal women at risk for breast cancer and to study drug safety.


METHODS
Premenopausal women (n = 235) were randomly assigned in a double-blind four-arm trial to receive tamoxifen 5 mg/d, fenretinide 200 mg/d, both agents, or placebo for 2 years. The present analysis refers to preliminary data on safety, IGF-I, and breast cancer events.


RESULTS
Patients were included if they had an excised ductal carcinoma-in-situ (57%), lobular carcinoma-in-situ (13%), minimal invasive breast cancer (7%), or a 5-year Gail risk > or = 1.3% (23%). After a median follow-up of 40 months, there was a reduction of 13%, 2%, 20%, and 1% in IGF-I levels for patients on tamoxifen, fenretinide, tamoxifen plus fenretinide, and placebo, respectively. Recruitment was stopped based on the lack of an interaction on IGF-I levels, which was a primary end point for the study. Thirty-six patients have dropped out of the study, 17 because of adverse events and 19 for various other reasons. One stage I endometrial cancer occurred in a patient on fenretinide, and one optic nerve ischemia and one deep venous thrombosis occurred on tamoxifen. There was no difference in menopausal symptoms, endometrial thickness, polyps, or ovarian cysts among treatment arms. To date, 24 breast cancers have been observed, without differences among arms.


CONCLUSIONS
The combination of low-dose tamoxifen and fenretinide is safe but not synergistic in lowering IGF-I levels in premenopausal women. The clinical implications require further follow-up.
Guerrieri-Gonzaga
Aliana
A
Division of Chemoprevention, European Institute of Oncology, Milan, Italy.
Robertson
Chris
C
Bonanni
Bernardo
B
Serrano
Davide
D
Cazzaniga
Massimiliano
M
Mora
Serena
S
Gulisano
Marcella
M
Johansson
Harriet
H
Formelli
Franca
F
Intra
Mattia
M
Latronico
Antuono
A
Franchi
Dorella
D
Pelosi
Giuseppe
G
Johnson
Karen
K
Decensi
Andrea
A
D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000517:prevention & control*; D004311:Double-Blind Method; D004717:Endometrium / Q000187:drug effects / Q000473:pathology; D005260:Female; D017313:Fenretinide / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D008875:Middle Aged; D017697:Premenopause; D013629:Tamoxifen / Q000008:administration & dosage / Q000009:adverse effects; D014801:Vitamin A / Q000097:blood
D000970:Antineoplastic Agents; D013629:Tamoxifen; D014801:Vitamin A; D017313:Fenretinide; D007334:Insulin-Like Growth Factor I