1 3 Cancer Chemother Pharmacol (2015) 76:1235–1246 DOI 10.1007/s00280-015-2848-y ORIGINAL ARTICLE Local transdermal therapy to the breast for breast cancer prevention and DCIS therapy: preclinical and clinical evaluation Oukseub Lee 1 · David Ivancic 1 · Subhashini Allu 1,6 · Ali Shidfar 1 · Kara Kenney 6 · Irene Helenowski 3 · Megan E. Sullivan 2 · Miguel Muzzio 5 · Denise Scholtens 3 · Robert T. Chatterton Jr. 4 · Kevin P. Bethke 1,6 · Nora M. Hansen 1,6 · Seema A. Khan 1,6,7 Received: 18 December 2014 / Accepted: 13 August 2015 / Published online: 11 November 2015 © Springer-Verlag Berlin Heidelberg 2015 and blood were collected. In Study 3, consenting women requiring mastectomy were randomized to diclofenac patch applied to the abdomen or the breast for 3 days preopera- tively. At surgery, eight tissue samples per breast were col- lected from predetermined locations, along with venous blood. Drug concentrations were measured using liquid chromatography–tandem mass spectroscopy. Results Mammary tissue concentrations of 4-OHT, endoxifen, and telapristone were significantly higher in the axillary glands of the gel-treated animals, compared to inguinal glands or to systemically treated animals. Plasma concentrations were similar in gel and systemically treated animals. The clinical trial showed significantly higher mammary concentrations when diclofenac was applied to the breast skin versus the abdominal skin, but concentra- tions were variable. Conclusions These results demonstrate that lipophilic drugs can be developed for LTT; although the nude rat is suitable for testing drug permeability, delivery is systemic. In human, however, transdermal application to the breast skin provides local delivery. Keywords Transdermal therapy · Breast · 4-Hydroxytamoxifen · Endoxifen · Telapristone · Diclofenac Introduction Despite successful breast cancer prevention trials that established the efficacy of selective estrogen receptor modulators [1] and aromatase inhibitors [2, 3], the accept- ance of these drugs by women at high risk of breast can- cer has been low. Reasons include quality-of-life impair- ments, the possibility of more serious side effects, and Abstract Purpose Women at high risk of breast cancer and those with carcinoma in situ need non-toxic, well-tolerated pre- ventive interventions. One promising approach is drug delivery through the breast skin (local transdermal therapy, LTT). Our goal was to test novel drugs for LTT, to establish that LTT is applicable to non-steroidal drugs. Methods Athymic nude rats were treated with oral tamox- ifen, transdermal 4-hydroxytamoxifen (4-OHT) or endox- ifen gel applied daily to the axillary mammary gland for 6 weeks (Study 1). Study 2 was identical to Study 1, test- ing transdermal telapristone acetate (telapristone) gel ver- sus subcutaneous implant. At euthanasia, mammary glands Electronic supplementary material The online version of this article (doi:10.1007/s00280-015-2848-y) contains supplementary material, which is available to authorized users. * Seema A. Khan skhan@nmh.org 1 Department of Surgery, The Robert H. Lurie Cancer Center of Northwestern University, Chicago, IL, USA 2 Department of Pathology, The Robert H. Lurie Cancer Center of Northwestern University, Chicago, IL, USA 3 Department of Preventive Medicine, The Robert H. Lurie Cancer Center of Northwestern University, Chicago, IL, USA 4 Department of Obstetrics and Gynecology, The Robert H. Lurie Cancer Center of Northwestern University, Chicago, IL, USA 5 Illinois Institute of Technology Research Institute, Chicago, IL, USA 6 Department of Medicine, The Robert H. Lurie Cancer Center of Northwestern University, Chicago, IL, USA 7 Northwestern University Feinberg School of Medicine, 303 E Superior St., Lurie 4-111, Chicago, IL 60611, USA