A randomized phase II presurgical trial of transdermal 4-hydroxytamoxifen gel versus oral tamoxifen in women with ductal carcinoma in situ of the breast.

Abstract

PURPOSE:

Local transdermal therapy to the breast may achieve effective target-organ drug delivery, while diminishing systemic effects. We conducted a randomized, double-blind, placebo-controlled phase II trial comparing transdermal 4-hydroxytamoxifen gel (4-OHT) to oral tamoxifen (oral-T) in women with ductal carcinoma in situ (DCIS).

METHODS:

Twenty-seven pre- and postmenopausal women were randomized to 4-OHT (4 mg/day) or oral-T (20 mg/day) for 6 to 10 weeks before surgery. Plasma, nipple aspirate fluid, and breast adipose tissue concentrations of tamoxifen and its major metabolites were determined by liquid chromatography/tandem mass spectrometry. The primary endpoint was Ki67 labeling in DCIS lesions, measured by immunohistochemistry. In plasma, insulin-like growth factor-1 (IGFI), sex hormone-binding globulin (SHBG), and coagulation protein concentrations were determined.

RESULTS:

Posttherapy Ki67 decreased by 3.4% in the 4-OHT and 5.1% in the oral-T group (P ≤ 0.03 in both, between-group P = 0. 99). Mean plasma 4-OHT was 0.2 and 1.1 ng/mL in 4-OHT and oral groups, respectively (P = 0.0003), whereas mean breast adipose tissue concentrations of 4-OHT were 5.8 ng/g in the 4-OHT group and 5.4 ng/g in the oral group (P = 0.88). There were significant increases in plasma SHBG, factor VIII, and von Willebrand factor and a significant decrease in plasma IGFI with oral-T, but not with 4-OHT. The incidence of hot flashes was similar in both groups.

CONCLUSIONS:

The antiproliferative effect of 4-OHT gel applied to breast skin was similar to that of oral-T, but effects on endocrine and coagulation parameters were reduced. These findings support the further evaluation of local transdermal therapy for DCIS and breast cancer prevention.

• Authors: Oukseub Lee, Katherine Page, David Ivancic, Irene Helenowski, Vamsi Parini, Megan E Sullivan, Julie A Margenthaler, Robert T Chatterton Jr, Borko Jovanovic, Barbara K Dunn, Brandy M Heckman-Stoddard, Kathleen Foster, Miguel Muzzio, Julia Shklovskaya, Silvia Skripkauskas, Piotr Kulesza, David Green, Nora M Hansen, Kevin P Bethke, Jacqueline S Jeruss, Raymond Bergan, Seema A Khan
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 20 Issue 14 Pg. 3672-82 (Jul 15 2014) ISSN: 1557-3265 [Electronic] United States
• PMID: 25028506 (Publication Type: Clinical Trial, Phase II, Comparative Study, Journal Article, Randomized Controlled Trial)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents, Hormonal
• Biomarkers, Tumor
• Tamoxifen
• afimoxifene

Topics

• Administration, Cutaneous
• Administration, Oral
• Aged
• Antineoplastic Agents, Hormonal (administration & dosage, pharmacokinetics)
• Biomarkers, Tumor (blood)
• Breast Neoplasms (drug therapy)
• Carcinoma, Intraductal, Noninfiltrating (drug therapy)
• Double-Blind Method
• Female
• Humans
• Middle Aged
• Tamoxifen (administration & dosage, analogs & derivatives, pharmacokinetics)
• Treatment Outcome