Local transdermal therapy to the breast for breast cancer prevention and DCIS therapy: preclinical and clinical evaluation

• Published in: Cancer chemotherapy and pharmacology 2015-12, Vol.76 (6), p.1235-1246
• Main Authors: Lee, Oukseub, Ivancic, David, Allu, Subhashini, Shidfar, Ali, Kenney, Kara, Helenowski, Irene, Sullivan, Megan E., Muzzio, Miguel, Scholtens, Denise, Chatterton, Robert T., Bethke, Kevin P., Hansen, Nora M., Khan, Seema A.
• Format: Article
• Language: English
• Subjects: Administration, Cutaneous; Administration, Oral; Adult; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - therapeutic use; Breast - drug effects; Breast - pathology; Breast Neoplasms - prevention & control; Cancer Research; Carcinoma, Intraductal, Noninfiltrating - drug therapy; Diclofenac - administration & dosage; Diclofenac - therapeutic use; Drug Evaluation, Preclinical - methods; Female; Gels; Humans; Mammary Glands, Animal - drug effects; Medicine; Medicine & Public Health; Middle Aged; Norpregnadienes - administration & dosage; Norpregnadienes - pharmacology; Oncology; Original Article; Outcome Assessment (Health Care); Pharmacology/Toxicology; Pilot Projects; Preoperative Period; Random Allocation; Rats, Nude; Tamoxifen - administration & dosage; Tamoxifen - analogs & derivatives; Tamoxifen - pharmacology
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-015-2848-y

Purpose Women at high risk of breast cancer and those with carcinoma in situ need non-toxic, well-tolerated preventive interventions. One promising approach is drug delivery through the breast skin (local transdermal therapy, LTT). Our goal was to test novel drugs for LTT, to establish that LTT is applicable to non-steroidal drugs. Methods Athymic nude rats were treated with oral tamoxifen, transdermal 4-hydroxytamoxifen (4-OHT) or endoxifen gel applied daily to the axillary mammary gland for 6 weeks (Study 1). Study 2 was identical to Study 1, testing transdermal telapristone acetate (telapristone) gel versus subcutaneous implant. At euthanasia, mammary glands and blood were collected. In Study 3, consenting women requiring mastectomy were randomized to diclofenac patch applied to the abdomen or the breast for 3 days preoperatively. At surgery, eight tissue samples per breast were collected from predetermined locations, along with venous blood. Drug concentrations were measured using liquid chromatography–tandem mass spectroscopy. Results Mammary tissue concentrations of 4-OHT, endoxifen, and telapristone were significantly higher in the axillary glands of the gel-treated animals, compared to inguinal glands or to systemically treated animals. Plasma concentrations were similar in gel and systemically treated animals. The clinical trial showed significantly higher mammary concentrations when diclofenac was applied to the breast skin versus the abdominal skin, but concentrations were variable. Conclusions These results demonstrate that lipophilic drugs can be developed for LTT; although the nude rat is suitable for testing drug permeability, delivery is systemic. In human, however, transdermal application to the breast skin provides local delivery.