Transdermal drug delivery to the normal and the radiated breast: Determinants of individual variation in skin permeation.

10570 Background: Primary prevention of breast cancer with oral drugs causes systemic effects which are unacceptable to 85% of high-risk women. Transdermal delivery through breast skin can minimize systemic exposure, but individual variation of permeation, the effects of breast radiation, or increased dose have not been studied. We report a prospective single-arm trial addressing these aspects, using 4-hydroxytamoxifen (4-OHT) an active metabolite of oral tamoxifen. Methods: Women with unilateral breast cancer treated with breast conservation and radiotherapy applied 4-OHT gel to both breasts for 4±1 weeks. In Cohort 1 (2 mg/breast/day) we evaluated inter-individual variation of 4-OHT skin permeation in the non-radiated breast based on demographic and skin characteristics. In Cohort 2 (4 mg/breast/day) we evaluated the effect of increased dose. All participants underwent bilateral post-intervention dermal punch and core needle breast biopsy. Drug concentration in tissue and plasma was measured using liquid chromatography-mass spectroscopy. Multivariable linear regression was used to examine the predictors of drug concentration in tissue and plasma. Stepwise model selection was conducted using AIC criteria, with multicollinearity assessed via variance inflation factor (VIF). Results: Of 156 consented women, 120 completed intervention and were evaluable for the primary endpoint (breast tissue drug concentration). On multivariable analysis, breast tissue 4-OHT concentration increased with age and White race. Drug concentration was equivalent in the radiated and the non-radiated breasts and was two-fold higher in Cohort 2 (4 mg/breast/day) compared to Cohort 1 (2 mg/breast/day), (p = 0.001). Plasma drug concentrations were low in both cohorts; 0.27ng/mL in Cohort 1 and 0.15ng/mL in Cohort 2, (p = < 0.001). Conclusions: Transdermal delivery of breast cancer prevention drugs is a viable strategy, with higher dose achieving proportional increase in tissue concentration, without increased leakage into the circulation. Further work should pursue formulations of highly active drug metabolites with excellent permeation. Clinical trial information: NCT04009044 .