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 27pre and postmenopausal women were randomized to 4-OHT (4mg/day) or oral-T (20mg/day) for 6-10 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 (IGF-1), sex hormone-binding globulin (SHBG), and coagulation protein concentrations were determined. Results Post-therapy Ki-67 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), while 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 IGF-1 with oral-T, but not with 4-OHT. The incidence of hot flashes was similar in both groups. Conclusions The anti-proliferative 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.

Downregulation of microRNA-27b-3p enhances tamoxifen resistance in breast cancer by increasing NR5A2 and CREB1 expression

“…It is found clinically that tamoxifen can significantly improve overall and relapse-free survival rates of all stages of patients with ER-positive breast cancer. 2 Studies showed tamoxifen can reduce the incidence of contralateral breast cancer. 3 Therefore, the drug has been approved as a prophylactic agent to prevent breast tumor.…”

Tamoxifen inhibits cell proliferation by impaired glucose metabolism in gallbladder cancer

“…45 Tamoxifen metabolites 4-hydroxytamoxifen and N-desmethyl-4hydroxytamoxifen, which possess a much stronger ER inhibitory activity, 46 could be secreted in bile and participate in enterohepatic circulation. 45 Tamoxifen metabolites 4-hydroxytamoxifen and N-desmethyl-4hydroxytamoxifen, which possess a much stronger ER inhibitory activity, 46 could be secreted in bile and participate in enterohepatic circulation.…”

Autologous Fat Grafting as a Novel Antiestrogen Vehicle for the Treatment of Breast Cancer

“…For breast cancer, approaches have included implantable hydrogels, wafers, rods, and films that act as depots (12), which are often designed to biodegrade and thus eliminate the need for surgical removal, topical applications that facilitate transdermal delivery (19, 20), intraductal administration (21, 22), and iontophoretic devices that utilize electric fields to drive and direct drug diffusion (23, 24). An adipose depot has several advantages over these other approaches.…”