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

Lee, Oukseub; Ivancic, David; Allu, Subhashini; Shidfar, Ali; Kenney, Kara; Helenowski, Irene; Sullivan, Megan; Muzzio, Miguel; Scholtens, Denise M.; Chatterton, Robert T.; Bethke, Kevin P.; Hansen, Nora M.; Khan, Seema A.

doi:10.1007/s00280-015-2848-y

Cited by 37 publications

(25 citation statements)

References 26 publications

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“…However, this was not available at the time and future availability was unclear. We therefore turned to a plausible alternative that appeared to have good permeability in preclinical testing, both in vitro experiments using human skin, 33 and using animal models that have been shown to be predictive of permeation through human skin (nude rat and minipig) 8,34,35 . Thus, the poor permeation of the modified transdermal formulation tested in our trial was surprising, and points to the need for planned interim analyses and Bayesian adaptive design in trials of novel agents to confirm permeation even when preclinical data are encouraging.…”

Section: Discussionmentioning

confidence: 94%

“…We evaluated the dermal permeation of TPA using human skin in vitro , with oleic acid as a permeation enhancer, 24 and then in nude rats in vivo , where application of the TPA gel to the mammary skin produced significantly higher concentrations in the treated mammary glands than in untreated mammary glands and plasma 8 . Based on these results, Repros Therapeutics agreed to formulate a hydroalcoholic TPA gel formulation, and perform preclinical testing.…”

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confidence: 99%

“…6,7 Prevention strategies that target the breast locally, with low systemic exposure and minimal systemic toxicity, may overcome these barriers. Proposed methods of local therapy to the breast include local transdermal delivery through the breast skin, 8 and intraductal delivery through a catheter cannulating the ductal orifice. 9,10 Of these, the far simpler alternative is transdermal delivery of drugs through the breast skin; this avoids fast hepatic metabolism, is noninvasive, and self-administered, without costly devices.…”

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confidence: 99%

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Local Transdermal Delivery of Telapristone Acetate Through Breast Skin, Compared With Oral Treatment: A Randomized Double‐Blind, Placebo‐Controlled Phase II Trial

Lee

Pilewskie

Karlan

et al. 2020

Clin Pharma and Therapeutics

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Oral breast cancer prevention medications entail systemic exposure, limiting acceptance by high‐risk women. Delivery through the breast skin, although an attractive alternative, requires demonstration of drug distribution throughout the breast. We conducted a randomized double‐blind, placebo‐controlled phase II clinical trial comparing telapristone acetate, a progesterone receptor antagonist, administered orally (12 mg/day) or transdermally (12 mg/breast) for 4 ± 1 weeks to women planning mastectomy. Plasma and tissue concentrations, measured at five locations in the mastectomy specimen using liquid chromatography tandem mass spectrometry were compared. In 60 evaluable subjects, median drug concentration (ng/g tissue) was 103 (interquartile range (IQR): 46.3–336) in the oral vs. 2.82 (IQR: 1.4–5.5) in the transdermal group. Despite poor dermal permeation, within‐breast drug distribution pattern was identical in both groups (R2 = 0.88, P = 0.006), demonstrating that transdermally and orally delivered drug is distributed similarly through the breast, and is strongly influenced by tissue adiposity (P < 0.0001). Other skin‐penetrant drugs should be tested for breast cancer prevention.

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Section: Discussionmentioning

confidence: 94%

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confidence: 99%

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confidence: 99%

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Local Transdermal Delivery of Telapristone Acetate Through Breast Skin, Compared With Oral Treatment: A Randomized Double‐Blind, Placebo‐Controlled Phase II Trial

Lee

Pilewskie

Karlan

et al. 2020

Clin Pharma and Therapeutics

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“…As a SPRM, telapristone leads to progesterone receptor blockade leading to changes in gene expression and deceasing progression of a mutated cell through the cell-cycle progression (69). In preclinical testing, topical telapristone has been studied in comparison with systemic telapristone delivered subcutaneously in a multi-arm trial involving athymic nude rats with primary focus on tissue and plasma concentrations (70). Mammary tissue concentrations were significantly higher in those rats receiving topical preparations compared with recipients of systemic telapristone.…”

Section: Approach To Prevention: Local Transdermal Therapymentioning

confidence: 99%

A Way Forward for Cancer Chemoprevention: Think Local

Rabadi

Bergan

2017

Cancer Prevention Research

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As cells progress through carcinogenesis, the associated exponential expansion of genetic and molecular aberrations and resultant heterogeneity make therapeutic success increasingly unattainable. Therapeutic intervention at early stages of carcinogenesis that occurs within the primary organ and in the face of a lower burden of molecular aberrations, constitutes a basic tenet of cancer chemoprevention, and provides a situation that favors a greater degree of therapeutic efficacy compared with that of advanced cancer. A longstanding barrier to chemoprevention relates to the requirement for essentially no systemic toxicity, and the fact that when large numbers of people are treated, the emergence of systemic toxicity is almost universal. A rational means to address this in fact relates to a second basic tenet of the chemopreventive strategy: the focus of therapeutic intervention is to disrupt a process that is in essence localized to a single organ. Based upon this consideration, a strategy which is based upon local delivery of therapeutics to an at-risk organ will achieve therapeutic efficacy while avoiding systemic delivery and its associated toxicity. This article will review the rationale for undertaking such an approach, describe successful clinical achievements based on this strategy, describe ongoing efforts to expand the impact of this approach, and together will highlight the high impact that this approach has already had on the field as well as its extremely high potential for future impact. Cancer Prev Res; 10(1); 14-35. ©2016 AACR.

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“…It may be possible to avoid majority of the side effects of endocrine agents by local delivery to breast and avoiding systemic distribution. Research to develop novel delivery methods like topical gels [63, 64] or intraductal delivery (ClinicalTrials.gov Identifier: NCT02540330) is also an important area.…”

Section: Research Prioritiesmentioning

confidence: 99%

Preventing invasive breast cancer using endocrine therapy

Thorat

Cuzick

2017

The Breast

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Developments in breast cancer treatment have resulted in reduction in breast cancer mortality in the developed world. However incidence continues to rise and greater use of preventive interventions including the use of therapeutic agents is needed to control this burden. High quality evidence from 9 major trials involving more than 83000 participants shows that selective oestrogen receptor modulators (SERMs) reduce breast cancer incidence by 38%. Combined results from 2 large trials with 8424 participants show that aromatase inhibitors (AIs) reduce breast cancer incidence by 53%. These benefits are restricted to prevention of ER positive breast cancers. Restricting preventive therapy to high-risk women improves the benefit-harm balance and many guidelines now encourage healthcare professionals to discuss preventive therapy in these women. Further research is needed to improve our risk-prediction models for the identification of high risk women for preventive therapy with greater accuracy and to develop surrogate biomarkers of response. Long-term follow-up of the IBIS-I trial has provided valuable insights into the durability of benefits from preventive therapy, and underscores the need for such follow up to fully evaluate other agents. Full utilisation of preventive therapy also requires greater knowledge and awareness among both doctors and patients about benefits, harms and risk factors. Healthcare professionals should routinely discuss preventive therapy with women at high-risk of breast cancer.

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

Abstract: 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.

Cited by 37 publications

References 26 publications

Local Transdermal Delivery of Telapristone Acetate Through Breast Skin, Compared With Oral Treatment: A Randomized Double‐Blind, Placebo‐Controlled Phase II Trial

Local Transdermal Delivery of Telapristone Acetate Through Breast Skin, Compared With Oral Treatment: A Randomized Double‐Blind, Placebo‐Controlled Phase II Trial

A Way Forward for Cancer Chemoprevention: Think Local

Preventing invasive breast cancer using endocrine therapy

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