Determinants of transdermal drug delivery to the normal and the radiated breast

Project: Research project

Project Details

Description

Duct carcinoma in situ (DCIS) of the breast comprises about 20% of new breast malignancies in mammographically screened populations. Treatment consists of breast conserving surgery (BCS) in about 75% of women, usually followed by post-operative radiotherapy (RT). This halves the risk of ipsilateral new cancer events, with a further 1/3rd reduction through the use of oral endocrine therapy (OET). Additionally, OET reduces risk of new breast cancer by one-half. However, OET is declined by more than half of DCIS patients, given its thromboembolic and uterine risks (selective estrogen receptor modulators), and musculoskeletal effects (aromatase inhibitors). Given the benefits of OET for DCIS patients, drug delivery methods that avoid the adverse effects of these agents will represent a significant advance. Transdermal delivery is well-recognized as an effective alternative to oral delivery. Advantages include low systemic exposure, longer retention in the local tissue, delayed excretion, and avoidance of first-pass hepatic metabolism. Further, the transdermal delivery of active metabolites obviates the potential role of genetic variation in drug metabolism as a barrier to effective therapy. Encouraging preliminary data on local transdermal therapy (LTT) with 4-hydroxytamoxifen (4-OHT) applied to the breast skin have led us to conduct clinical trials aimed at establishing the equivalence of 4-OHT/LTT and OET. If successful, this will be a novel and potentially transformative development for the DCIS population, and for women at high risk for breast cancer. However, there are significant knowledge gaps regarding the determinants of individual variations in dermal permeation and the dynamics of drug retention in the breast. Furthermore, current studies exclude women who have undergone breast RT because this may alter dermal permeation and/or distribution through the breast. Since DCIS patients who receive RT to the affected breast derive additional protection for both b
StatusActive
Effective start/end date2/5/191/31/26

Funding

  • National Cancer Institute (5R01CA235647-05 Revised)

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