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

Oukseub Lee, Katherine Page, David Ivancic, Irene Helenowski, Vamsi Parini, Megan E. Sullivan, Julie A. Margenthaler, Robert T. Chatterton, 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. JerussRaymond Bergan, Seema A. Khan

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26 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)3672-3682
Number of pages11
JournalClinical Cancer Research
Issue number14
StatePublished - Jul 15 2014


ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Lee, O., Page, K., Ivancic, D., Helenowski, I., Parini, V., Sullivan, M. E., Margenthaler, J. A., Chatterton, R. T., Jovanovic, B., Dunn, B. K., Heckman-Stoddard, B. M., Foster, K., Muzzio, M., Shklovskaya, J., Skripkauskas, S., Kulesza, P., Green, D., Hansen, N. M., Bethke, K. P., ... Khan, S. A. (2014). A randomized phase II presurgical trial of transdermal 4-hydroxytamoxifen gel versus oral tamoxifen in women with ductal carcinoma in Situ of the breast. Clinical Cancer Research, 20(14), 3672-3682. https://doi.org/10.1158/1078-0432.CCR-13-3045