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

Clin Cancer Res. 2014 Jul 15;20(14):3672-82. doi: 10.1158/1078-0432.CCR-13-3045.


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.

Publication types

  • Clinical Trial, Phase II
  • Comparative Study
  • Randomized Controlled Trial

MeSH terms

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


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