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Neoadjuvant Percutaneous 4-Hydroxytamoxifen Decreases Breast Tumoral Cell Proliferation: A Prospective Controlled Randomized Study Comparing Three Doses of 4-Hydroxytamoxifen Gel to Oral Tamoxifen

From the Centre Val d'Aurelle; U 450 INSERM, CHU, Montpellier; Centre rené Gauducheau, Nantes; Laboratoires Besins-International; Lab Pharmacologie, IFR Saint-Louis, Paris

Address reprint requests to Philippe Rouanet, MD, Centre Val d'Aurelle, 34298 Montpellier, France; e-mail: PRouanet{at}valdorel.fnclcc.fr

PURPOSE: Two chemoprevention randomized studies using tamoxifen showed drug efficacy; however, adverse effects such as hot flushes, endometrial cancer, and above all, thromboembolism, remain a problem. 4 hydroxytamoxifen (4-OHT) is a very active metabolite of tamoxifen. This randomized study was designed to analyze if 4-OHT gel, administered percutaneously on the breast skin, can inhibit the proliferation of malignant breast cells to the same extent as orally administered tamoxifen.

PATIENTS AND METHODS: Fifty-five postmenopausal women with an invasive estrogen receptor–positive breast cancer were randomly assigned to receive (for 2 to 3 weeks) either 4-OHT gel (0.5, 1, or 2 mg/d) or oral tamoxifen (20 mg/d) or no treatment. Response was evaluated using proliferation markers (Ki-67, proliferating cell nuclear antigen) and apoptosis markers in tissue samples obtained by Tru-cut biopsy before treatment, and at surgery after treatment.

RESULTS: Administration of 4-OHT gel resulted in reductions in tumor tissue proliferation indexes (Ki-67 and PCNA), with approximate equivalence between the1.0 mg/d or 2.0 mg/d 4-OHT dose, and oral tamoxifen, but had no effect on apoptotic markers. Plasma levels of 4-OHT were consistently higher in the oral tamoxifen group than in the gel groups. No dose-related pattern was shown for estrogen or progesterone receptor levels, and topical 4-OHT gel appeared to be generally well tolerated. Hot flushes are as common in the two higher gel doses as with tamoxifen.

CONCLUSION: Percutaneous 4-OHT gel has a local impact on tumor proliferation. It could be tested in future propective trials of chemoprevention or ductal carcinoma in situ adjuvant hormonotherapy.

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

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