• Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Electronic address: o-lee@northwestern.edu.
• Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
• Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
• Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
• Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
• Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
• Saul and Joyce Brandman Breast Center, Cedars-Sinai Medical Center, West Hollywood, CA, USA.
• Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
• Hormone Laboratory, Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, Bergen, Norway; Department of Clinical Science, University of Bergen, Bergen, Norway.
• Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA.

Breast cancer prevention only requires local exposure of the breast to active drug. However, oral preventive agents entail systemic exposure, causing adverse effects that limit acceptance by high-risk women. Drug-delivery through the breast skin is an attractive option, but requires demonstration of dermal safety and drug distribution throughout the breast. We formulated the tamoxifen metabolite (E/Z)-endoxifen for transdermal delivery and tested it in a placebo-controlled, double-blinded Phase I trial with dose escalation from 10 to 20 mg daily. The primary endpoint was dermal toxicity. Thirty-two women planning mastectomy were randomized (2:1) to endoxifen-gel or placebo-gel applied to both breasts for 3-5 weeks. Both doses of endoxifen-gel incurred no dermal or systemic toxicity compared to placebo. All endoxifen-treated breasts contained the drug at each of five sampling locations; the median per-person tissue concentration in the treated participants was 0.6 ng/g (IQR 0.4-1.6), significantly higher (p < 0.001) than the median plasma concentration (0.2 ng/mL, IQR 0.2-0.2). The median ratio of the more potent (Z)-isomer to (E)-isomer at each breast location was 1.50 (IQR 0.96-2.54, p < 0.05). No discernible effects of breast size or adiposity on tissue concentrations were observed. At the endoxifen doses and duration used, and the tissue concentration achieved, we observed a non-significant overall reduction of tumor proliferation (Ki67 LI) and significant downregulation of gene signatures known to promote cancer invasion (FN1, SERPINH1, PLOD2, PDGFA, ITGAV) (p = 0.03). Transdermal endoxifen is an important potential breast cancer prevention agent but formulations with better dermal penetration are needed.