title: Local transdermal therapy to the breast for breast cancer prevention and DCIS therapy: preclinical and clinical evaluation.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Surgery, The Robert H. Lurie Cancer Center of Northwestern University, Chicago, IL, USA.
authors.forename: Oukseub
authors.initials: O
authors.lastname: Lee
authors.affiliation: Department of Surgery, The Robert H. Lurie Cancer Center of Northwestern University, Chicago, IL, USA.
authors.forename: David
authors.initials: D
authors.lastname: Ivancic
authors.affiliation: Department of Surgery, The Robert H. Lurie Cancer Center of Northwestern University, Chicago, IL, USA.|Department of Medicine, The Robert H. Lurie Cancer Center of Northwestern University, Chicago, IL, USA.
authors.forename: Subhashini
authors.initials: S
authors.lastname: Allu
authors.affiliation: Department of Surgery, The Robert H. Lurie Cancer Center of Northwestern University, Chicago, IL, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Shidfar
authors.affiliation: Department of Medicine, The Robert H. Lurie Cancer Center of Northwestern University, Chicago, IL, USA.
authors.forename: Kara
authors.initials: K
authors.lastname: Kenney
authors.affiliation: Department of Preventive Medicine, The Robert H. Lurie Cancer Center of Northwestern University, Chicago, IL, USA.
authors.forename: Irene
authors.initials: I
authors.lastname: Helenowski
authors.affiliation: Department of Pathology, The Robert H. Lurie Cancer Center of Northwestern University, Chicago, IL, USA.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Sullivan
authors.affiliation: Illinois Institute of Technology Research Institute, Chicago, IL, USA.
authors.forename: Miguel
authors.initials: M
authors.lastname: Muzzio
authors.affiliation: Department of Preventive Medicine, The Robert H. Lurie Cancer Center of Northwestern University, Chicago, IL, USA.
authors.forename: Denise
authors.initials: D
authors.lastname: Scholtens
authors.affiliation: Department of Obstetrics and Gynecology, The Robert H. Lurie Cancer Center of Northwestern University, Chicago, IL, USA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Chatterton
authors.affiliation: Department of Surgery, The Robert H. Lurie Cancer Center of Northwestern University, Chicago, IL, USA.|Department of Medicine, The Robert H. Lurie Cancer Center of Northwestern University, Chicago, IL, USA.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Bethke
authors.affiliation: Department of Surgery, The Robert H. Lurie Cancer Center of Northwestern University, Chicago, IL, USA.|Department of Medicine, The Robert H. Lurie Cancer Center of Northwestern University, Chicago, IL, USA.
authors.forename: Nora M
authors.initials: NM
authors.lastname: Hansen
authors.affiliation: Department of Surgery, The Robert H. Lurie Cancer Center of Northwestern University, Chicago, IL, USA. skhan@nmh.org.|Department of Medicine, The Robert H. Lurie Cancer Center of Northwestern University, Chicago, IL, USA. skhan@nmh.org.|Northwestern University Feinberg School of Medicine, 303 E Superior St., Lurie 4-111, Chicago, IL, 60611, USA. skhan@nmh.org.
authors.forename: Seema A
authors.initials: SA
authors.lastname: Khan
mesh_terms: D000279:Administration, Cutaneous; D000284:Administration, Oral; D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001940:Breast / Q000187:drug effects* / Q000473:pathology; D001943:Breast Neoplasms / Q000517:prevention & control*; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000188:drug therapy*; D004008:Diclofenac / Q000008:administration & dosage / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D005782:Gels; D006801:Humans; D008321:Mammary Glands, Animal / Q000187:drug effects; D008875:Middle Aged; D009649:Norpregnadienes / Q000008:administration & dosage / Q000494:pharmacology; D017063:Outcome Assessment, Health Care; D010865:Pilot Projects; D057234:Preoperative Period; D011897:Random Allocation; D011923:Rats, Nude; D013629:Tamoxifen / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D005782:Gels; D009649:Norpregnadienes; D013629:Tamoxifen; D004008:Diclofenac; C016601:afimoxifene; C461063:telapristone acetate; C055492:4-hydroxy-N-desmethyltamoxifen
keywords: 4-Hydroxytamoxifen; Breast; Diclofenac; Endoxifen; Telapristone; Transdermal therapy