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

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Abstract

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.

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Acknowledgments

This work was supported by Breast Cancer Research Foundation for telapristone study, Lynn Sage Breast Cancer Research Foundation for diclofenac trial, and Susan G. Komen for the Cure for endoxifen study. We also appreciate Jina Pharmaceuticals, Inc., and Repros Therapeutics, Inc., for providing materials and other supports. The authors had full responsibility for the design of the study, the collection of the data, the analysis and interpretation of the data, the writing of the manuscript, and the decision to submit the manuscript for publication.

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Authors and Affiliations

  1. Department of Surgery, The Robert H. Lurie Cancer Center of Northwestern University, Chicago, IL, USA

    Oukseub Lee, David Ivancic, Subhashini Allu, Ali Shidfar, Kevin P. Bethke, Nora M. Hansen & Seema A. Khan

  2. Department of Pathology, The Robert H. Lurie Cancer Center of Northwestern University, Chicago, IL, USA

    Megan E. Sullivan

  3. Department of Preventive Medicine, The Robert H. Lurie Cancer Center of Northwestern University, Chicago, IL, USA

    Irene Helenowski & Denise Scholtens

  4. Department of Obstetrics and Gynecology, The Robert H. Lurie Cancer Center of Northwestern University, Chicago, IL, USA

    Robert T. Chatterton Jr.

  5. Illinois Institute of Technology Research Institute, Chicago, IL, USA

    Miguel Muzzio

  6. Department of Medicine, The Robert H. Lurie Cancer Center of Northwestern University, Chicago, IL, USA

    Subhashini Allu, Kara Kenney, Kevin P. Bethke, Nora M. Hansen & Seema A. Khan

  7. Northwestern University Feinberg School of Medicine, 303 E Superior St., Lurie 4-111, Chicago, IL, 60611, USA

    Seema A. Khan

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  1. Oukseub Lee
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  2. David Ivancic
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Correspondence to Seema A. Khan.

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Lee, O., Ivancic, D., Allu, S. et al. Local transdermal therapy to the breast for breast cancer prevention and DCIS therapy: preclinical and clinical evaluation. Cancer Chemother Pharmacol 76, 1235–1246 (2015). https://doi.org/10.1007/s00280-015-2848-y

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  • DOI: https://doi.org/10.1007/s00280-015-2848-y

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