A randomized Phase I pre-operative window trial of transdermal endoxifen in women planning mastectomy: Evaluation of dermal safety, intra-mammary drug distribution, and biologic effects.
- 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.
- Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Electronic address: s-khan2@northwestern.edu.
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.