Seminars in Oncology 43 (2016) 107–115
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Novel routes for administering chemoprevention: local transdermal therapy to the breasts Oukseub Lee, Seema A. Khann Department of Surgery, Northwestern University Feinberg School of Medicine Chicago, IL, USA
a r t i c l e in fo
a b s t r a c t
Keywords: Local transdermal therapy DCIS Breast
Breast cancer prevention with pharmacologic agents requires that the breast be exposed to an effective drug; systemic exposure is unnecessary, and its harms lead many eligible women to decline preventive therapy. Local transdermal therapy (LTT) to the breast involves the application of active drugs to the breast skin, resulting in high concentrations in the breast but low systemic exposure. It is non-invasive, self-delivered, and not dependent on hepatic metabolism. Existing data on LTT include investigations demonstrating relief of mastalgia with topical 4-hydroxytamoxifen (4-OHT, an active tamoxifen metabolite). Two presurgical window trials in women with invasive breast cancer, and ductal carcinoma in situ (DCIS) demonstrate that LTT decreases proliferation of invasive and non-invasive cancer cells to a similar degree as oral tamoxifen, with low systemic levels, and no effect on coagulation proteins. These data are promising regarding the use of LTT for the primary prevention of breast cancer, and for therapy of DCIS, since systemic exposure is not required for either of these purposes. They also suggest that an LTT approach could be developed for any small, lipophilic molecule with good dermal permeation, thus greatly expanding the menu of drugs that could be tested for breast cancer prevention. & 2016 Elsevier Inc. All rights reserved.
1. Introduction Despite successful breast cancer prevention trials that established the efficacy of selective estrogen receptor modulators [1], and aromatase inhibitors [2,3], the acceptance of these drugs by women at high risk for breast cancer has been low. Reasons include quality of life impairments, the possibility of more serious side effects, and reluctance by healthy women to take oral medication for prevention. However, breast cancer prevention requires only that the breast be exposed to the drug; systemic exposure is both unnecessary and harmful. Oral tamoxifen is a good example; 5 years of systemic exposure leads to benefits to the breast and bone, but with costs to quality of life, and health [4–6]. The avoidance of systemic exposure through prevention strategies that target the breast locally, and have minimal systemic toxicity, may overcome these barriers. One proposed method of local therapy to the breast involves drug delivery to the ductal epithelium by cannulating the ductal orifice with a catheter [7,8]. However, this requires an office procedure by a specialist, the value of a single injection is not known, the feasibility of multiple injections is untested, and dissemination across multiple practice n Corresponding author. Department of Surgery, Northwestern University Feinberg School of Medicine, 303 E Superior St, Lurie 4-111, Chicago, IL 60611. E-mail address:
[email protected] (S.A. Khan).
settings and varied clinical environments seems dubious. A far simpler alternative is transdermal delivery of drugs through the breast skin; its advantages include the avoidance of fast hepatic metabolism, non-invasiveness, and self-administration across the globe without costly devices. Therefore, local transdermal therapy (LTT) to the breast is likely to improve the tolerability and the acceptance of pharmacological cancer prevention regimens by women. Transdermal delivery has long been recognized as an effective alternative form of therapy that avoids some of the pitfalls of conventional systemic therapy, including oral administration. Transdermal delivery is characterized by distinct pharmacokinetics. This includes longer retention in the local tissue and delayed excretion; in contrast, hepatic metabolism following oral delivery results in excretion of a large fraction ingested agents. The percutaneous route has provided an effective method for delivery of reproductive hormones. Several transdermal therapeutic systems releasing estrogens, progestogens, and androgens from patches applied to the skin are currently in clinical use. For women, transdermal systems have been developed for hormone replacement therapy (HRT) and contraception. However, due to the effective barrier function of the stratum corneum, only a relatively small number of lipophilic drugs with low molecular weights (o500 Da) have been successfully formulated for these purposes.
http://dx.doi.org/10.1053/j.seminoncol.2015.09.003 0093-7754/& 2016 Elsevier Inc. All rights reserved.
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2. Oral tamoxifen is the prototypic breast cancer prevention agent The National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 Breast Cancer Prevention Trial (BCPT) trial demonstrated that oral tamoxifen decreased the risk of breast cancer by 50%, and of estrogen receptor (ER)-positive breast cancer by about 66% [4]; an overview of the four tamoxifen prevention trials showed a 38% reduction in ER-positive breast cancers [9]. However, tamoxifen is a prodrug which, following oral delivery, requires conversion by the phase I drug metabolizing cytochrome P450 enzymes, such as CYP2D6 and CYP3A4/5, to its major antiestrogenic metabolites [10]. Chief among these are N-desmethyltamoxifen (N-desT), present in high concentrations in the serum (and tissues?) and 4-hydroxytamoxifen (4-OHT), both of which have high affinity for ERα, and a robust anti-estrogenic effect. Both of these molecules are converted to N-desmethyl-4-hydroxytamoxifen (endoxifen, ENX), which resembles N-desT in being present in high concentration (10-fold higher than that of 4-OHT in serum) and has an affinity for ERα that is equivalent to that of 4-OHT (100-fold greater than the affinity of tamoxifen) [11–13]. Recent reports suggest that ENX is the dominant metabolite responsible for the therapeutic effect of tamoxifen because of its high abundance combined with its high affinity for ERα as well as its ability to cause proteosomic degradation of ERα [14–16]. An important corollary of this metabolic requirement is that the effectiveness of tamoxifen may be compromised in about one third of women because of enzyme polymorphisms which result in decreased production of ENX [10]. This constitutional variability in genes encoding tamoxifen-metabolizing enzymes may contribute to the resistance of some ER-positive breast cancers to tamoxifen, although the clinical data are mixed [10]. Importantly, constitutional genetic variability is expected to influence tamoxifen metabolism regardless of the route of administration. This is true not only because the genetic variants are present in all cells in the body but also because drug activation via the phase I enzyme system occurs in organs other than the liver, including the breast. In addition, certain challenges to the preventive efficacy of tamoxifen are specifically related to its oral use. Hepatic metabolism allows for excretion of a considerable fraction of orally ingested drug before it reaches the target organ, contributing to reduced efficacy. Problems with toxicity can also result from systemic administration, due to the activity of tamoxifen in nonbreast tissues. This off-target action, often seen with long-term systemic exposure to tamoxifen, is associated with hot flashes, night sweats, and menstrual irregularity, as well as the more serious risks of thromboembolism and endometrial cancer [4]. Thus, the systemic delivery of tamoxifen is problematic both from the perspective of efficacy (through inefficient metabolism), and of toxicity (through high systemic exposure). In women with ductal carcinoma in situ (DCIS) and those at high risk of breast cancer, effective concentrations are required only in breast tissue; systemic exposure is redundant, and minimization of side effects is essential, since agents offered to healthy high-risk women need to be both safe and well tolerated.
that transdermally delivered drugs are disseminated throughout the breast.
4. Transdermal treatment of benign diseases The idea of transdermal administration of a drug locally to the breast was first tested with progesterone for local treatment of benign (nonmalignant) breast diseases, following the observation that it concentrated in the breast before its diffusion to systemic circulation [19,20]. Transdermal daily application of progesterone, 50 mg in hydroalcoholic gel for three months was efficacious in treating benign breast diseases such as mastodynia, fibroadenomas, etc [21,22]; this benefit was attributed to the local antiestrogenic activity of progesterone in the breast [23,24]. Mauvais-Jarvis et al. expanded the transdermal treatment of hormone-dependent benign breast diseases to include 4-OHT hydroalcoholic gel, with the rationale that 4-OHT is an active metabolite suitable for local delivery and in addition, shows greater antiestrogenic activity than tamoxifen in vitro. Furthermore, transdermal administration would avoid the metabolic sequelae of 4-OHT production in the liver following ingestion of oral tamoxifen, where it is then conjugated and inactivated by hepatic enzymes [25].
5. Transdermal 4-OHT gel to treat mastalgia A number of studies addressing relief of breast pain or tenderness have been performed in Europe using a hydro-alcoholic gel of 4-OHT (Besins, France), applied to the breast skin in daily doses ranging from 0.25 mg to 4 mg, divided equally between the two breasts [26]. The most recent report [27] described a randomized phase II study of a 4-month intervention, comparing a placebo control group to two treated groups (4 mg/d and 2 mg/d). The primary efficacy endpoint, change in mean pain intensity as measured by the Visual Analog Scale (VAS) showed a statistically significant improvement with the 4-OHT gel at a concentration of 4 mg/d for four menstrual cycles, despite the fact that average plasma levels of 4-OHT gel were 50764 pg/mL (mean7SD) [27], much lower than those seen with oral tamoxifen (1,1007700 pg/ mL, 6–10 weeks treatments) [28]. The benefit was greatest in the fourth cycle, with a 32-mm reduction in the VAS in the 4-mg/d group, compared to a 26 mm reduction in the 2- mg/d group, and a 19-mm reduction in the control group (P ¼ .0034). The frequency of hot flushes was low in these premenopausal women with a mean age of 36 years; in the last month of the study, 1/38 participants reported 6–10 flushes in the placebo group, none was reported by the 41 women in the 2-mg/d group, and 2/45 women reported flushes in the 4-mg/d group (1–5 flushes in one individual, and 16þ in the other). In contrast, 58% of the 35- to 49-year-old women in the NSABP P-1 trial reported hot flushes after 3 months on tamoxifen, with a relative risk of 1.6 compared to placebo [6]. Other adverse events in the 4-OHT gel trial included headaches (in 10% of the placebo group, 15% of the 2-mg/d group, and 20% of the 4-mg/d group) and application-site skin irritation (in 7% of the lower dose and 4% of the higher dose group).
3. Anatomy of breast 6. Local or systemic therapy? The unique features of the breast predict the success of LTT; these include the embryological origin of the breast as a skin appendage [17] with a well-developed internal lymphatic circulation [18], and the presence of a subcutaneous and retromammary fatty envelope. We hypothesize that the fatty envelope of the breast may serve as a drug reservoir for prolonged distribution to the breast, aided by the intramammary lymphatic circulation, so
Mauvais-Jarvis et al determined whether 4-OHT could be concentrated directly in the breast like progesterone. A presurgical study of 12 women with ER-positive breast cancer was undertaken to compare the concentration and metabolism of 3H-labeled trans4-OHT with that of tamoxifen following transdermal administration to the affected breast for up to 7 days. Surgically resected
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breast tissue obtained 12–24 hours after one transdermal dose (80 mCi in 60% alcoholic solution for each drug) showed that both 4-OHT and tamoxifen were detectable in the breast tumor tissue and surrounding normal mammary tissue. Neither drug underwent further metabolism, except that 20% of the administered trans-4OHT had been isomerized to cis-4-OHT when the tissue was obtained after 7 days [24]. Although the maximal concentration of both 4-OHT and tamoxifen in the breast tissue was reached 24 hours after a transdermal application, 4-OHT was retained for a much longer period in the breast than was tamoxifen. Plasma kinetics for 4-OHT and tamoxifen revealed that tamoxifen appeared in plasma more rapidly and decreased faster than did 4-OHT, possibly related to the lower affinity of tamoxifen for the ER present in breast tumors and breast epithelium. Next, 4-OHT was applied transdermally to two different anatomical sites (breast versus abdomen) to compare whether the breast tissue retention of 4-OHT is dependent on the site of application. The plasma and urine concentrations of 4-OHT during the first three days were much lower when 4-OHT was applied to the breast than the abdomen. Based on these observations, the authors postulated that 4-OHT was retained longer in sites containing ERs than in sites lacking ERs. Subsequently, Pujol et al showed that 4-OHT applied through the skin of the breast concentrates in the breast at 10-fold higher levels than when it is applied to the arm or shoulder [26]. The investigators attributed this differential accumulation to the binding of 4-OHT to ERs present in breast tumors and breast epithelium. In actuality, ERα expression in non-malignant breast tissue is very low but ERβ is high and may account for at least some of the localization in the normal breast. However, receptor binding alone is insufficient to explain 4-OHT retention in the breast [29,30]. A more plausible explanation relates to the embryological origin of the breast as a skin appendage (ie, a modified sweat or apocrine gland). Studies of the embryological development of the breast suggest that the breast gland (parenchyma) and its skin envelope are a single unit with a well-developed internal lymphatic circulation [17,18]. The conclusions of these embryological studies are supported by the fact that the skin and parenchyma of the breast drain to the same sentinel lymph nodes [31,32]. These common drainage patterns predict that other drugs applied to the skin of the breast should also concentrate in the parenchyma to a greater degree than can be expected based on systemic absorption and delivery through the circulation. Therefore, this model of transdermal local pharmacotherapy for the breast should be applicable to cancer prevention and to DCIS therapy with a variety of agents as long as they show sufficient dermal permeation. It is important to emphasize, however, that the issue of whether transdermal delivery to the breast is a local or a systemic treatment deserves further investigation. Several advantages can be anticipated by the delivery of active metabolites directly to the breast through its skin envelope. These include the bypass of first-pass metabolism in the liver, potentially avoiding changes in the clotting cascade, and therefore the prothrombotic effects of tamoxifen and raloxifene [9,33,34]. Since the risk of thromboembolism is a major concern not only with tamoxifen use, but with all selective ER modulators (SERMs) tested clinically to date, the avoidance of this toxicity would offer a considerable advantage for women considering SERM therapy for breast cancer prevention, and for treatment of DCIS. Additionally, the very low plasma concentrations observed following transdermal application of 4-OHT in the studies conducted so far suggest that uterine toxicity and hot flashes are likely to be reduced by the transdermal delivery of active tamoxifen metabolites to the breast [24,26,27]. Furthermore, by circumventing the need for prodrug activation, the limitations due to low bioavailability of active metabolites caused by polymorphisms in tamoxifen metabolizing genes should be overcome [14,15].
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7. Clinical efficacy of transdermal 4-OHT gel in chemoprevention Transdermal application of 4-OHT has also been tested as a potential chemoprevention approach. Rouanet et al have reported promising results from a presurgical study of 55 postmenopausal women with T1 or T2 invasive ER-positive breast cancer [35]. Patients were randomized into five groups and treated for 2–3 weeks; three groups were treated with transdermal 4-OHT gels (0.5, 1, or 2 mg/ breast/d), one group received oral tamoxifen (20 mg/d), and the fifth group received no treatment. The primary endpoints of the study were reductions in the tumor tissue proliferation indices, Ki-67 and PCNA (proliferating cell nuclear antigen). For the 45 patients assessable for efficacy, the differences in tumor tissue Ki-67 levels between baseline and following 2–3 weeks of treatment were compared among treatment groups [35]. Drug-treated groups (transdermal 4OHT gels and oral tamoxifen) demonstrated a significant decrease in median Ki-67 levels as compared with the no-treatment group (P ¼ .0055). No significant dose-dependent difference in reduction of Ki67 levels was observed among the three transdermal 4-OHT groups (P ¼ .07; median values of reduction in Ki-67 level were -3.8 for oral tamoxifen (20 mg/d) and -0.8, -4.5, -3.9 for 4-OHT gels 0.5 mg/d, 1 mg/d, and 2 mg/d, respectively, with 8–10 subjects per group. Thus, the daily transdermal application of 1 or 2 mg 4-OHT hydroalcoholic gel to the breast skin resulted in sufficient breast tissue concentrations to achieve inhibition of tumor cell proliferation to the same degree as that seen with the standard dose of oral tamoxifen (20 mg/ d) but with plasma levels that were 2%–11% of those seen with oral tamoxifen. The no-treatment group and the 0.5-mg/d group experienced no adverse effects. Although hot flushes were reported in the oral tamoxifen group and the 1- and 2-mg/d gel treatment groups, all patients were postmenopausal women with some level of baseline hot flushing. Despite this, an exacerbation related to systemic exposure to 4-OHT cannot be ruled out in this very short-term study. Of note, the lowest plasma level of tamoxifen metabolite exposure that is associated with hot flushes has not been defined, and the possibility remains that the low-level exposure (2%–11% of the levels seen with oral tamoxifen) observed in this study may be sufficient for vasomotor symptoms in some women. Besins and its affiliated company Ascend Therapeutics (Herndon, VA) have multiple US patents for 4-OHT gel including indications for benign breast disease and reduction in breast density [36,37]. A phase I trial was conducted to examine tolerance and pharmacokinetics in healthy premenopausal women age 18-45 with application of the gel daily for two menstrual cycles. Multiple doses of 4-OHT gel were examined (0.5, 1, and 2 mg/d). Transdermal 4-OHT was well tolerated in all 36 patients with no systemic effect on folliclestimulating hormone (FSH), luteinizing hormone (LH), estradiol, or progesterone hormone levels. Additionally, a phase II randomized, placebo-controlled study examined the efficacy of transdermal 4-OHT to reduce mammographic density in women on continuous HRT. After a period of 4 months mammographic density was significantly reduced in the 1.5- and 2-mg/d treatment groups. A phase II randomized, double blind, placebo-controlled trial has been completed in 100 premenopausal women ages 30–50 examining the effect of transdermal 4-OHT on breast density [36]. These trials provided preliminary data regarding the safety and tolerability of 4OHT gel, allowing the examination of its efficacy in women with DCIS.
8. 4-OHT gel in women with DCIS Using the same formulation of 4-OHT as in prior studies [35,36] (Besins, France), we have completed a multi-center presurgical window study in women with DCIS (NCT00952731) in the United States. We conducted a randomized, double-blind, placebo-
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controlled phase II trial comparing transdermal 4-OHT gel to oral tamoxifen (oral-T) in women with DCIS. Twenty-seven pre- and postmenopausal women were randomized to 4-OHT gel (4 mg/d) or oral tamoxifen (oral-T) (20 mg/d) for 6–10 weeks before surgery. The primary endpoint was reduction of cell proliferation in the DCIS lesion (as reflected in the Ki-67 labeling index), measured by immunohistochemistry, but additional parameters of interest include plasma, nipple aspirate fluid, and breast adipose tissue concentrations of tamoxifen and its major metabolites; plasma insulin-like growth factor-1 (IGFI), sex hormone-binding globulin (SHBG), and coagulation protein concentrations; and the presence of hot flushes. We found that post-therapy Ki67 decreased by 3.4% in the 4-OHT and 5.1% in the oral-T group (Pr.03 in both); the decline in Ki67 was statistically similar in the two groups (betweengroup P¼.99). The mean plasma 4-OHT concentration was 5.5-fold higher in the oral-T group than in the 4-OHT gel group (0.2 and 1.1 ng/mL in 4-OHT and oral groups respectively, P¼ .0003), whereas mean breast adipose tissue concentrations of 4-OHT were equivalent, at 5.8 ng/g in the 4-OHT group and 5.4 ng/g in the oral group (P ¼ 0.88). We also measured systemic effects of therapy, in the form of changes in plasma IGF-1, SHBG, factor VIII, and von Willebrand factor. Women treated with oral-T displayed the expected increases in these proteins, and a decrease in plasma IGFI, but those treated with 4-OHT gel did not. The incidence of hot flashes was similar in both groups. These pilot data support the notion that local transdermal drug delivery to the breast will achieve sufficient drug concentrations to be effective, with low systemic exposure. This concept deserves further testing with 4-OHT, and is likely to be applicable to other lipophilic drugs with low molecular weight.
9. Other tamoxifen metabolites: In vitro skin permeation of endoxifen Given the encouraging early results with transdermal 4-OHT, the other important tamoxifen metabolite, ENX, is particularly well suited for development as a breast LTT agent. ENX is expected to be more efficacious than 4-OHT related to its proteosomic degradation of ERα, and the possibility of more selective antiestrogenic effects [14–16]. Its specific toxicity profile is under study, but results from Goetz and colleagues suggest that, in terms of uterine weight, luminal epithelial cell height, and cell proliferation in the stroma and luminal epithelium of the uterus, ENX has similar uterotrophic effects to TAM when administered orally to rats [38]. If it shares the toxicity of the parent drug and its dermal permeation is equivalent to that of 4-OHT (or better), LTT would be an excellent route for the delivery of ENX as a breast cancer prevention agent. Additionally, the chemical structure of ENX would render it more promising for transdermal application because it is more amenable to conjugation to nanoparticles for controlled release. For these reasons and because the binding affinities of 4-OHT and ENX are both 25-fold greater for ERα and 56-fold greater for ERβ than that of tamoxifen [39,40], we investigated the relative permeation of 4-OHT and ENX using human split-thickness skin (STS) [41]. We used estradiol as a reference molecule, since it is widely used as a transdermal agent. An ethanol-based vehicle was necessary to solubilize the agents, but ethanol is also a widely used skin permeation enhancer for transdermal formulations of estradiol, progesterone, fentanyl, and other drugs. To further improve permeation, we tested the addition of oleic acid, a well-known permeation enhancer [42], in a 60% (vol/vol) ethanol-PB vehicle. Several researchers have observed a permeation enhancing effect with oleic acid in ethanol-water systems across hairless rodent skin [43–45]. We found that the permeation of ENX into human skin was not as
efficient as that of 4-OHT in a vehicle of 60 % (vol/vol) ethanolphosphate buffer (PB), but the addition of 1% (vol/vol) oleic acid greatly improved permeation of ENX over 24 hours. Although significant increases in permeation parameters were also seen for 4-OHT with the addition of oleic acid, the increase in ENX permeation was larger, bringing ENX permeation into a range which is very compatible with transdermal therapy [41]. The greater permeation enhancement that oleic acid caused when added to ENX compared to 4-OHT may be related to a difference in their structure. ENX is smaller and more polar than 4-OHT because one methyl group at a tertiary amine is replaced with a hydrogen, resulting in a secondary amine, which is more hydrophilic than the tertiary amine of 4-OHT. Because oleic acid appears to make the stratum corneum fluidic [46,47] and ethanol gives a continuous driving force [42,48], together oleic acid and ethanolic solution show improved permeation compared to ethanol alone. This is true for both 5-OHT and endoxifen, but more so for endoxifen. The amine group of ENX may provide a favorable balance of hydrophilic and hydrophobic properties, allowing ENX to traverse the stratum corneum more easily. In support of this, the results reported in the hairless rat skin model showed that the cosolvent system of oleic acid-ethanol-water efficiently increased skin permeation of both lipophilic and hydrophilic drugs [44]. The permeation enhancing effect of oleic acid for ENX appears to be optimal at concentrations of 0.25%–0.5% in 60% ethanolic solution, with estradiol (E2) as a reference transdermal compound to determine whether the permeation of ENX with oleic acid can be improved to a level consistent with effective transdermal delivery. Furthermore, although ENX alone permeates human skin more slowly than E2, the addition of oleic acid improves the permeation of ENX to a level similar to that of E2 (Fig. 1) [41]. We have extended our studies of ENX LTT to the in vivo realm, in an experiment utilizing nude rats randomized to oral tamoxifen, 4-OHT gel, and ENX gel in the same formulations described above for the in vitro studies (manuscript under review). We find excellent permeation of ENX in this model, and evidence for local delivery in that the mammary drug concentrations were significantly (fivefold) higher in the mammary gland to which the ENX gel was applied, compared to untreated mammary glands. Together, these results suggest that ENX is an excellent candidate for transdermal delivery, providing strong justification for the development of ENX for local transdermal delivery to the breast.
10. Potential for existing transdermal formulations of other drugs for local transdermal therapy Several agents have compelling biologic rationale for testing as breast cancer prevention drugs, but concerns about toxicity have either halted this testing, or it has not been initiated. Some of these also exist as transdermal formulations, for example, diclofenac, a nonsteroidal anti-inflammatory drug (NSAID), and bexarotene, a retinoic acid analogue. Others are under development, such as the second-generation anti-progesterone drug, telapristone acetate (TPA). 10.1. Coxibs The testing of NSAIDS for cancer prevention was abandoned after data emerged regarding the cardiovascular risk of celecoxib and other NSAIDs, but data regarding the importance of COX-2 activity in breast cancer biology have continued to accumulate [49]. Several conditions associated with increased breast cancer risk appear to operate through activation of COX-2–mediated inflammation; these include post-pregnancy involution of the mammary gland and its connection with pregnancy-associated breast cancer [50] and the inflammation associated with obesity [51].
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O. Lee, S.A. Khan / Seminars in Oncology 43 (2016) 107–115
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Fig. 1. Permeation parameters of ENX compared with E2. The applied dose of the compounds was 78.9 μg/cm2. The skin samples from three subjects were used and each treatment condition was tested in duplicate on the skin samples from a subject in each experiment. (A) Permeation profile, (B) flux (μg/cm2/h), (C) absorption at 24 h (μg/cm2), and (D) Skin content (μg/cm2) of the compounds was measured separately from epidermis and dermis and was combined as total skin content after 24 hours. All measurements were expressed as the mean 7 SEM, n ¼ 5–6. aP o.05; bP ¼ .045. P values were determined using the Wilcoxon rank sum test. ENX, endoxifen; E2, estradiol; OA, oleic acid; SEM, standard error of the mean. (Reprinted from Breast Cancer: Targets and Therapy 3(1), Lee O, Ivancic D, Chatterton RT, Rademaker A, Khan SA: In vitro human skin permeation of endoxifen: potential for local transdermal therapy for primary prevention and carcinoma in situ of the breast. Pages 61-70, 2011, with permission from Dove Medical Press Ltd.)
Furthermore, increased COX-2 expression has been observed in breast biopsy samples of atypical hyperplasia in women who subsequently develop breast cancer [52] and in DCIS lesions that recur [53]. For these reasons, coxibs remain attractive as candidate breast cancer prevention agents, since epidemiologic data also support the preventive efficacy of aspirin. Whether selective COX2 inhibition would be more effective than unselective agents is not known, but both types of coxibs have been formulated for transdermal delivery, with the non-selective agent diclofenac commercially available as both a patch and as a gel. We have tested the intramammary distribution of diclofenac when a patch is applied to the breast skin, compared to application of the same patch to the abdominal skin in women undergoing mastectomy (manuscript under review). We found that breast tissue concentrations of diclofenac are significantly higher with breast than with abdominal application of the patch, consistent with a local therapy approach, particularly since serum concentrations are very low. 10.2. Retinoids and rexinoids The potential value of retinoids for the prevention of both ERpositive and ER-negative breast cancer is based on the biology of
retinoid action in breast tissue (reviewed by Litzenburger and Brown [54]; see also Uray et al in this issue). Retinoids have been shown to have a multiplicity of effects that are consistent with potential for breast cancer prevention. These include the down-regulation of COX2 and cyclin D1 expression, the inhibition of AP1 transcription factor activity, and an increase in the expression of TGF-beta, and G1 cell cycle blockade [55–57]. A phase III clinical trial of fenretinide for prevention of second breast cancer did not demonstrate a reduction in second primaries in the overall trial population, but subset analysis of premenopausal women did show a significant reduction [58]. The synthetic rexinoids bexarotene and LG100268, activate RXR receptors selectively, and have been investigated for mammary cancer prevention by Brown and colleagues, with promising results in rodent models of ER-negative breast cancer. Specifically, the synthetic rexinoids bexarotene and LG100268 have been shown to prevent ER-negative breast cancer in various mouse models including transgenic lines of MMTV-ErbB2–overexpressing, p53-null, and C3(1)-SV40 T-antigen (Tag)-expressing mice and rats [59–62]. In addition, LGD100268 significantly prevents premalignant lesions including hyperplasia and ductal carcinoma in situ, suggesting that it affects mammary tumorigenesis at the early stages [63]. In a human biomarker modulation trial, women at high risk of breast
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cancer used bexarotene for a 4-week period; in postmenopausal (but not premenopausal) women, significant downregulation of cyclin D1 expression and a non-significant decrease in Ki67 staining was observed [64]. However, bexarotene use frequently causes hyperlipidemia which can result in pancreatitis; central hypothyroidism is another concerning side effect [65], as is leukopenia [66]. A variety of other adverse effects are observed less commonly (headache, diarrhea, pruritus, among others). This toxicity profile does not currently favor its further testing in healthy women at high risk for breast cancer. However, a topical formulation of bexarotene is approved for the therapy of cutaneous T-cell lymphoma; although irritant dermatitis and erythema may be observed at the site of application with more frequent dosing (up to four times daily), the gel is generally well tolerated and deserves investigation as a topical breast cancer prevention agent (personal communication with Dr Powell Brown). 10.3. Progesterone receptor modulators Extensive epidemiological and preclinical data support the notion that progesterone and progestin exposure increases breast cancer risk. Unlike ER modulators, however, newer-generation selective progesterone receptor modulators (SPRMs) have only recently become available. These new SPRMs are of interest because progesterone receptor blockade is more specific than with mifepristone, and the toxicity profile is sufficiently favorable that telapristone acetate (TPA) and ulipristal acetate are being tested in the United States and Europe for benign gynecologic conditions such as endometriosis and uterine fibroids [67–71]. Although no breastspecific endpoints have been reported, these trials do demonstrate that at low doses the toxicity profile is favorable and use in healthy women is feasible. However, SPRMs do inhibit ovulation and cause a variety of quality of life symptoms such as headache and joint pains, which present potential barriers against use by healthy women. We are presently conducting a presurgical window trial of TPA in stage I–II breast cancer patients, since preclinical data support the development of progesterone receptor antagonism for breast cancer prevention. These include two studies demonstrating a tumor-protective effect of TPA (Repros Therapeutics, The Woodlands, TX) in rat mammary carcinogenesis models [72,73]. In one study, N-methyl-N-nitrosourea (NMU)-induced mammary carcinogenesis [73] was suppressed by TPA at a dose of 30 mg/pellet (90-day release) as reflected by significantly increased tumor latency, decreased tumor incidence and tumor burden, and reduced multiplicity (P o.001). It also inhibited cell proliferation and induced apoptosis in MNU-induced mammary tumors, which correlated with a decreased proportion of progesterone receptor– positive tumor cells and with decreased serum progesterone, but no effect was seen on serum estradiol. Mechanistically, in T47D cells,
TPA suppressed G1/G0–S transition by inhibiting cdk2 and cdk4 expression, which correlated with decreased ER expression [73]. We have examined the dermal permeation of TPA in a similar fashion as with ENX: first in an in vitro human skin setting, with oleic acid as a permeation enhancer [74], and then in a nude rat model, compared to systemic TPA delivered as a subcutaneous pellet (manuscript under review). Briefly, we found that application of a TPA gel to the mammary skin produced significantly higher TPA concentrations in the treated mammary glands, compared to untreated mammary glands, or the systemic circulation. The intramammary concentrations in the treated glands were also significantly higher than in animals receiving TPA systemically, as a subcutaneous implant [74]. Thus it appears that TPA, which is a small lipophilic molecule, permeates human skin in vitro, and rat skin in vivo, sufficiently well that it is a candidate agent for local transdermal therapy for breast cancer prevention. We will soon open a randomized phase II presurgical window trial intended to demonstrate that high mammary gland concentrations can be achieved with LTT to the breast skin.
11. Nanoparticles to enhance transdermal permeation The optimal concentration of drugs required for preventive efficacy is uncertain, since the minimal required breast tissue concentrations of effective drugs such as tamoxifen have never been documented. The tissue concentrations achieved with transdermal delivery are, however, likely to be lower than those achieved with oral delivery. Therefore techniques that enhance permeation to improve drug delivery to the breast parenchyma, or provide a slow release mechanism to provide a constant exposure of the breast to the prevention agent would clearly be advantageous. A number of nanoparticle-based approaches have been tested for a variety of agents, with encouraging results. In a collaboration with Seungpyo Hong at the University of Illinois (Chicago) we have tested two nanoparticle-based approaches for transdermal delivery of ENX in vitro: dendrimers and dendron micelles (Fig. 2). Dendrimers are synthetic, spherical macromolecules with tree-like branched structures (Fig. 2) with a size of 3 10 nm, which are easily functionalized, with high water solubility and excellent biocompatibility [75–77]. Poly(amidoamine) (PAMAM) dendrimers have an advantage over linear polymers due to their multivalency, which can be precisely controlled by engineering their surface functional groups [75,78]. Positively charged PAMAM dendrimers induce nanoscale hole formation in cells at non-cytotoxic concentrations [79–81], thereby potentially breaching the stratum corneum for transdermal drug delivery. We found that the smaller generation 2
Hydrophilic block (PEG) Selfassembly
Hydrophobic drug
Hydrophobic block (PCL) Dendrimer
Amphiphilic Dendron
Drug-loaded dendron micelle
Fig. 2. Schematics of the dendrimer and PEGylated dendron-based copolymer (PDC). (Reprinted from Advanced Functional Materials 24 (17), Yang Y, Pearson RM, Lee O, Lee CW, Chatterton RT, Khan SA, Hong S: Dendron-Based Micelles for Topical Delivery of Endoxifen: A Potential Chemo- Preventive Medicine for Breast Cancer. Pages 2442-2449, 2014, with permission from the Wiley Online Library.)
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(G2) dendrimers penetrated the skin layers more efficiently than larger ones and that surface-modification by either acetylation or carboxylation resulted in increased skin permeation. Conjugation of oleic acid to G2 dendrimers increased their 1-octanol/PBS partition coefficient, further increasing skin absorption and retention [82]. Thus we proceeded to test positively charged dendrimers as permeation enhancers to improve skin penetration of ENX. However, ENX is limited by two factors: the requirement for chemical conjugation which could result in decreased drug efficacy [83], and the fact that ENX lacks a highly reactive functional group. To preserve the advantage of the dendritic structure while maintaining the efficacy of hydrophobic drugs, Hong’s team subsequently developed amphiphilic PEGylated dendron-based copolymers (PDCs) that are a hybrid of dendritic structure and linear-block copolymers [84]. In an aqueous environment, PDCs self-assemble into dendron micelles that can efficiently encapsulate hydrophobic molecules into the core (Fig. 2) and demonstrate remarkable thermodynamic stability for hydrophobic drug delivery. Additionally, the hyperbranched dendrons confer similar properties as dendrimers, such as high-density peripheral functional groups and ease of surface functionalization [83,84]. We encapsulated ENX into dendron micelles (DMs) with various surface groups (-NH 2,-COOH, or -Ac) and into cationic liposomes as a control. The DM-COOH micelles allowed the most efficient encapsulation. Furthermore, unlike the burst release from the liposomes, all DMs show sustained release of ENX over 6 days. Each formulation was evaluated for its potential to deliver ENX across the skin layers. DMs substantially enhance the in vitro permeation of ENX through both mouse skin (up to 20-fold) and human (up to fourfold) skin samples relative to ethanol, a widely used chemical penetration enhancer [85]. Franz diffusion cell experiments revealed that DM-COOH induced the highest flux of ENX among all formulations. The enhanced drug loading, controlled release profiles, and enhanced skin permeation all demonstrate that DMs are a useful platform for the topical delivery of ENX, offering a potential alternative administration route for chemoprevention. These findings will be further pursued in the next generation of studies, and demonstrate that nanoparticle-based platforms hold significant promise for improving transdermal delivery, and can be applied to other drugs with preventive potential, particularly of those with borderline dermal permeation. Cheng et al have used a similar approach for improving permeation of NSAIDs [86].
12. Discussion A major barrier to the development and implementation of preventive medications for breast cancer is the low toxicity threshold that is a necessary condition for their use. Additionally, the only proven prevention agents to date are endocrine agents, effective against luminal breast cancer, but declined by the majority of women who would benefit from them. The more aggressive subtypes of breast cancer (HER-2–positive and triplenegative) remain untouched in terms of preventive strategies. A number of candidate agents that may be useful for the prevention of these distinct subtypes of breast cancer cannot be implemented (or even tested in trials) because of safety and tolerability concerns. If local transdermal delivery of these (and other, yet to be identified) agents is possible, if they are delivered in sufficient quantities to be effective, and if they are widely accepted by women, breast cancer prevention will enter a new era where the barrier of systemic toxicity is minimized, and the prevention drug armamentarium correspondingly increased. Present results are encouraging; to summarize our data and that of others, it appears that dermal permeation of 4-OHT is excellent, as shown in clinical trials [28,35]; and that of two other steroid receptor
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modulators (ENX and TPA ) is at least as good when tested in vitro on human skin, and in vivo in rats [41,74]. Additionally, we have confirmed the observation of Pujol et al, that drugs applied to the breast skin of women provide local delivery to the breast. For example, we were able to show that a diclofenac patch applied to the breast provides high concentrations in the breast, compared to transdermal application on the abdominal skin (manuscript under review). Furthermore, the use of diclofenac allows us to conclude that selective retention in the breast also occurs with nonsteroidal drugs. Our rodent studies did demonstrate that excellent axillary mammary concentrations of (Z) 4-OHT, (Z) ENX, and TPA can be achieved by transdermal administration, and that this is not dependent on the presence of estrogen receptor-rich tumors, as suggested by previous authors [5,26]. The high drug concentrations observed in the axillary mammary gland replicate the human data; and provide evidence that both of the new drugs tested (ENX and TPA) show superior permeation and retention in the axillary gland, compared to 4-OHT, and are candidates for further development as transdermal agents for the breast. The effectiveness of ENX as a prevention agent is not in question given the long experience with tamoxifen and the emerging data on oral ENX [87]. Preclinical data on TPA are promising [72,73], but it is untested as a prevention agent in humans. We are presently conducting a presurgical window trial in stage I–II breast cancer patients, the results of which will guide further development (NCT01800422). We have previously discussed the importance of the embryological origin of the breast as a modified sweat or eccrine gland [17], with the parenchyma and its skin envelope comprising a single unit with a well-developed internal lymphatic and venous circulation [18,31,32]. This anatomy predicts that drugs applied to the breast skin should concentrate in the parenchyma to a greater degree than if applied to skin elsewhere, that LTT can be generalized to any drug that can penetrate the skin, and that receptor binding is not involved. Our data showing good retention of diclofenac in the breast with application of a patch to the breast skin validate this concept; binding of diclofenac within the breast to its target enzyme is expected to represent a minor component of its retention in adipose tissue of the breast. As with other transdermally delivered drugs, systemic toxicity (cardiovascular, gastrointestinal, and anti-platelet effect) is not an issue. Of note, there are no previous studies of drug distribution through the breast, even with oral delivery, and the degree of variation with oral delivery is unknown. Although breast drug concentrations achieved with transdermal delivery may be lower or more variable than those achieved with oral delivery, it is helpful to recall that for disease prevention drug dose should be defined as the lowest effective dose, rather than the maximal tolerated dose. Along these lines, data on low dose tamoxifen [88] are encouraging, and remind us that the more relevant endpoint in early trials of transdermal therapy is biologic effect rather than drug concentration. Our future plans include an assessment of intra-mammary distribution of TPA following transdermal versus oral delivery; and the development of a gel formulation of ENX in partnership with the National Cancer Institute, an important consideration since new supplies of 4-OHT gel are not available. Encouragingly, transdermal permeation of both these drugs is superior to that of 4-OHT in the present study, and we have previously reported on the suitability of ENX for LTT [41]. Since diclofenac is also available as a gel, this is another potentially fruitful avenue. We have recently completed a focus group study of high risk women to assess preferences between drug delivery routes.
Conflicts of interest None.
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