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J Clin Oncol ; 27(23): 3749-56, 2009 Aug 10.
Article in English | MEDLINE | ID: mdl-19597031

ABSTRACT

PURPOSE: Tamoxifen and fenretinide are active in reducing premenopausal breast cancer risk and work synergistically in preclinical models. The authors assessed their combination in a two-by-two biomarker trial. PATIENTS AND METHODS: A total of 235 premenopausal women with pT1mic/pT1a breast cancer (n = 21), or intraepithelial neoplasia (IEN, n = 160), or 5-year Gail risk > or = 1.3% (n = 54) were randomly allocated to either tamoxifen 5 mg/d, fenretinide 200 mg/d, their combination, or placebo. We report data for plasma insulin-like growth factor I (IGF-I), mammographic density, uterine effects, and breast neoplastic events after 5.5 years. RESULTS: During the 2-year intervention, tamoxifen significantly lowered IGF-I and mammographic density by 12% and 20%, respectively, fenretinide by 4% and 10% (not significantly), their combination by 20% and 22%, with no evidence for a synergistic interaction. Tamoxifen increased endometrial thickness principally in women becoming postmenopausal, whereas fenretinide decreased endometrial thickness significantly. The annual rate of breast neoplasms (n = 48) was 3.5% +/- 1.0%, 2.1% +/- 0.8%, 4.7% +/- 1.3%, and 5.2% +/- 1.3% in the tamoxifen, fenretinide, combination, and placebo arms, respectively, with hazard ratios (HRs) of 0.70 (95% CI, 0.32 to 1.52), 0.38 (95% CI, 0.15 to 0.90), and 0.96 (95% CI, 0.46 to 1.99) relative to placebo (tamoxifen x fenretinide adverse interaction P = .03). There was no clear association with tumor receptor type. Baseline IGF-I and mammographic density did not predict breast neoplastic events, nor did change in mammographic density. CONCLUSION: Despite favorable effects on plasma IGF-I levels and mammographic density, the combination of low-dose tamoxifen plus fenretinide did not reduce breast neoplastic events compared to placebo, whereas both single agents, particularly fenretinide, showed numerical reduction in annual odds of breast neoplasms. Further follow-up is indicated.


Subject(s)
Anticarcinogenic Agents/therapeutic use , Antineoplastic Agents, Hormonal/therapeutic use , Biomarkers, Tumor/blood , Breast Neoplasms/pathology , Breast Neoplasms/prevention & control , Fenretinide/therapeutic use , Insulin-Like Growth Factor I/metabolism , Mammography , Premenopause , Tamoxifen/therapeutic use , Adult , Anticarcinogenic Agents/administration & dosage , Anticarcinogenic Agents/adverse effects , Anticarcinogenic Agents/blood , Antineoplastic Agents, Hormonal/administration & dosage , Antineoplastic Agents, Hormonal/adverse effects , Antineoplastic Agents, Hormonal/blood , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/blood , Breast Neoplasms/diagnostic imaging , Carcinoma, Intraductal, Noninfiltrating/prevention & control , Carcinoma, Lobular/prevention & control , Double-Blind Method , Drug Administration Schedule , Drug Synergism , Female , Fenretinide/administration & dosage , Fenretinide/adverse effects , Fenretinide/blood , Humans , Incidence , Insulin-Like Growth Factor Binding Protein 3/blood , Middle Aged , Multivariate Analysis , Odds Ratio , Premenopause/blood , Proportional Hazards Models , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Selective Estrogen Receptor Modulators/therapeutic use , Tamoxifen/administration & dosage , Tamoxifen/adverse effects , Tamoxifen/analogs & derivatives , Tamoxifen/blood , Treatment Outcome , Vitamin A/blood
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