Neoadjuvant percutaneous 4-hydroxytamoxifen decreases breast tumoral cell proliferation: a prospective controlled randomized study comparing three doses of 4-hydroxytamoxifen gel to oral tamoxifen.
OBJECTIVE
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.


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 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.


CONCLUSIONS
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.
Rouanet
Philippe
P
Centre Val d'Aurelle, 34298 Montpellier, France. PRouanet@valdorel.fnclcc.fr
Linares-Cruz
Gustavo
G
Dravet
François
F
Poujol
Sylvain
S
Gourgou
Sophie
S
Simony-Lafontaine
Joelle
J
Grenier
Jean
J
Kramar
Andrew
A
Girault
Jean
J
Le Nestour
Elisabeth
E
Maudelonde
Thierry
T
D000279:Administration, Cutaneous; D000284:Administration, Oral; D000287:Administration, Topical; D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D017209:Apoptosis; D001706:Biopsy; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D004965:Estrogen Antagonists / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D017698:Postmenopause; D011960:Receptors, Estrogen / Q000819:agonists / Q000032:analysis; D013629:Tamoxifen / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use*
D018931:Antineoplastic Agents, Hormonal; D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D013629:Tamoxifen; C016601:afimoxifene