• Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
• Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
• Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
• Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
• Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
• Analytical Chemistry Division, Illinois Institute of Technology Research Institute, Chicago, Illinois, USA.
• Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA.
• National Cancer Institute Division of Cancer Prevention, Bethesda, Maryland, USA.

Oral breast cancer prevention medications entail systemic exposure, limiting acceptance by high-risk women. Delivery through the breast skin, although an attractive alternative, requires demonstration of drug distribution throughout the breast. We conducted a randomized double-blind, placebo-controlled phase II clinical trial comparing telapristone acetate, a progesterone receptor antagonist, administered orally (12 mg/day) or transdermally (12 mg/breast) for 4 ± 1 weeks to women planning mastectomy. Plasma and tissue concentrations, measured at five locations in the mastectomy specimen using liquid chromatography tandem mass spectrometry were compared. In 60 evaluable subjects, median drug concentration (ng/g tissue) was 103 (interquartile range (IQR): 46.3-336) in the oral vs. 2.82 (IQR: 1.4-5.5) in the transdermal group. Despite poor dermal permeation, within-breast drug distribution pattern was identical in both groups (R²  = 0.88, P = 0.006), demonstrating that transdermally and orally delivered drug is distributed similarly through the breast, and is strongly influenced by tissue adiposity (P < 0.0001). Other skin-penetrant drugs should be tested for breast cancer prevention.