Abstract P1-09-07: Topical 4-OHT trial in women with DCIS of the breast: report of plasma and breast tissue concentration of tamoxifen metabolites

Background: Earlier studies have shown that 1–2mg of 4-hydroxytamoxifen (4–OHT) gel applied to the breast skin reduced cell proliferation in estrogen receptor (ER) positive invasive cancers to a similar degree as oral tamoxifen (TAM), with significantly lower plasma levels. We now report results of a Phase IIB pre-surgical window trial of women with DCIS, designed to obtain pilot data in early lesions. Our ultimate goal is to develop transdermal 4-OHT as an alternative to oral TAM for women at high risk for breast cancer and those with DCIS. The study was closed early because the manufacturer discontinued the drug supply, but remains blinded until all biomarker analysis is complete. Here we report the plasma and breast adipose tissue concentration of TAM metabolites from the topical 4-OHT gel group (4 mg) in comparison with the oral TAM group (20mg). Methods: Women with DCIS were enrolled, and randomized to 4-OHT gel (4mg/day, 2mg per breast, E: Z isomers = 1:1,) or to oral (Z) TAM (20mg/day) for 4–10 weeks before surgery. Blood was collected on the day of surgery, and breast adipose tissue was collected at surgery. There were a total of 22 patients with matched blood and breast adipose tissue. The concentration of TAM metabolites in plasma and breast tissue was determined with liquid chromatography/tandem mass spectrometry. We assumed that the subjects with detectable N -desmethyl TAM (NDT) in plasma belong to the oral TAM group because NDT is not a product of 4-OHT metabolism. Under this assumption, 13 subjects were categorized into oral TAM group, and 9 subjects into the topical 4-OHT group. Wilcoxon rank-sum test was used for statistical analysis. Results: The results are shown in the table. The concentration is presented as mean ± SD; the lowest quantitation limit (LQL) was 1 ng/mL for plasma, and 3 ng/g for tissue. TAM and its metabolites were found in the plasma of the presumed oral TAM group, with high levels of TAM and NDT. In the presumed 4-OHT gel group, only (Z) 4-OHT was found in the plasma although both (E) and (Z) forms were applied. The mean plasma level of 4-OHT in the gel group was 70% lower than the mean of 4-OHT in the oral TAM group (p = 0.004). In breast tissue, similar amounts of (E) and (Z) forms of 4-OHT were found in the 4-OHT gel group, with the (Z) 4-OHT level being equivalent to that in the oral TAM group (p = 0.48). Endoxifen was only found in the oral TAM group. We saw no evidence of further metabolic transformation of 4-OHT in the breast following topical administration. Conclusions: With 4 mg of 4-OHT gel daily applied to the breasts of DCIS patients, the mean plasma level of 4-OHT was significantly lower and the mean breast tissue level of 4-OHT was similar to that in women taking oral TAM 20 mg daily, thus confirming the results from previous studies. We are still evaluating efficacy of topical 4-OHT in terms of reduction of cell proliferation (Ki67). Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-09-07.