Originally published as JCO Early Release 10.1200/JCO.2006.09.4318 on August 20 2007

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Randomized Dose-Ranging Trial of Tamoxifen at Low Doses in Hormone Replacement Therapy Users

Andrea Decensi, Sara Gandini, Davide Serrano, Massimiliano Cazzaniga, Maria Pizzamiglio, Fausto Maffini, Giuseppe Pelosi, Cristina Daldoss, Umberto Omodei, Harriet Johansson, Debora Macis, Matteo Lazzeroni, Mauro Penotti, Laura Sironi, Simona Moroni, Vanda Bianco, Gabriella Rondanina, Jennifer Gjerde, Aliana Guerrieri-Gonzaga, Bernardo Bonanni

From the Divisions of Chemoprevention, Epidemiology and Biostatistics, Radiology, Pathology, Laboratory Medicine, Preventive Gynecology, European Institute of Oncology; Mangiagalli Clinic; Buzzi Hospital, Milan; Division of Gynecology, University of Brescia, Brescia; Division of Medical Oncology, Galliera Hospital, Genoa, Italy; Hormone Laboratory, Haukeland Hospital, University of Bergen; and the Section for Endocrinology, Institute of Medicine, University of Bergen, Bergen, Norway

Address reprint requests to Andrea Decensi, MD, Division of Medical Oncology, Ospedali Galliera, Mura Le capuccine 10, 16128 Genoa, Italy; e-mail: andrea.decensi{at}galliera.it

Purpose 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.

Subjects and 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.

Conclusion Doses of tamoxifen 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.

published online ahead of print at www.jco.org on August 20, 2007.

Supported by grant No. BCTR01-00537 from the S. Komen Breast Cancer Foundation and the Italian Health Ministry (Ricerca Finalizzata); a fellowship from Gruppo Bancario Credito Valtellinese and the European School of Oncology; and a contract from the Italian Foundation for Cancer Research.

Presented in part at the American Association for Cancer Research Frontiers in Cancer Prevention Research conference, Baltimore, MD, October 29 to November 3, 2005.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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