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

• Published in: Journal of clinical oncology Vol. 23; no. 13; pp. 2980 - 2987
• Main Authors: ROUANET, Philippe, LINARES-CRUZ, Gustavo, MAUDELONDE, Thierry, DRAVET, Francois, PONJOL, Sylvain, GOURGOU, Sophie, SIMONY-LAFONTAINE, Joelle, GRENIER, Jean, KRAMAR, Andrew, GIRAULT, Jean, LE NESTOUR, Elisabeth
• Format: Journal Article
• Language: English
• Published: Baltimore, MD American Society of Clinical Oncology 01.05.2005; Lippincott Williams & Wilkins
• Subjects: Administration, Cutaneous; Administration, Oral; Administration, Topical; Adult; Aged; Antineoplastic Agents, Hormonal - administration & dosage; Antineoplastic Agents, Hormonal - adverse effects; Antineoplastic Agents, Hormonal - therapeutic use; Apoptosis; Biological and medical sciences; Biopsy; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Cell Proliferation; Dose-Response Relationship, Drug; Estrogen Antagonists - administration & dosage; Estrogen Antagonists - adverse effects; Estrogen Antagonists - therapeutic use; Female; Humans; Medical sciences; Middle Aged; Neoadjuvant Therapy; Postmenopause; Receptors, Estrogen - agonists; Receptors, Estrogen - analysis; Tamoxifen - administration & dosage; Tamoxifen - adverse effects; Tamoxifen - analogs & derivatives; Tamoxifen - therapeutic use; Tumors; Antineoplastic agent; Cell proliferation; Antiestrogen; Oral administration; Antihormone; Tamoxifene; Percutaneous route; Prospective; Randomization; Cancerology; Tumor; Mammary gland; Non steroid compound; Dose; Comparative study
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2005.06.064

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. 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. Administration of 4-OHT gel resulted in reductions in tumor tissue proliferation indexes (Ki-67 and PCNA), with approximate equivalence between the 1.0 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. Percutaneous 4-OHT gel has a local impact on tumor proliferation. It could be tested in future prospective trials of chemoprevention or ductal carcinoma in situ adjuvant hormonotherapy.