Oral low dose and topical tamoxifen for breast cancer prevention: modern approaches for an old drug

Matteo Lazzeroni, Davide Serrano, Barbara K Dunn, Brandy M Heckman-Stoddard, Oukseub Lee, Seema Khan, Andrea Decensi, Matteo Lazzeroni, Davide Serrano, Barbara K Dunn, Brandy M Heckman-Stoddard, Oukseub Lee, Seema Khan, Andrea Decensi

Abstract

Tamoxifen is a drug that has been in worldwide use for the treatment of estrogen receptor (ER)-positive breast cancer for over 30 years; it has been used in both the metastatic and adjuvant settings. Tamoxifen's approval for breast cancer risk reduction dates back to 1998, after results from the Breast Cancer Prevention Trial, co-sponsored by the National Cancer Institute and the National Surgical Adjuvant Breast and Bowel Project, showed a 49% reduction in the incidence of invasive, ER-positive breast cancer in high-risk women. Despite these positive findings, however, the public's attitude toward breast cancer chemoprevention remains ambivalent, and the toxicities associated with tamoxifen, particularly endometrial cancer and thromboembolic events, have hampered the drug's uptake by high-risk women who should benefit from its preventive effects. Among the strategies to overcome such obstacles to preventive tamoxifen, two novel and potentially safer modes of delivery of this agent are discussed in this paper. Low-dose tamoxifen, expected to confer fewer adverse events, is being investigated in both clinical biomarker-based trials and observational studies. A series of systemic biomarkers (including lipid and insulin-like growth factor levels) and tissue biomarkers (including Ki-67) are known to be favorably affected by conventional tamoxifen dosing and have been shown to be modulated in a direction consistent with a putative anti-cancer effect. These findings suggest possible beneficial clinical preventive effects by low-dose tamoxifen regimens and they are supported by observational studies. An alternative approach is topical administration of active tamoxifen metabolites directly onto the breast, the site where the cancer is to be prevented. Avoidance of systemic administration is expected to reduce the distribution of drug to tissues susceptible to tamoxifen-induced toxicity. Clinical trials of topical tamoxifen with biological endpoints are still ongoing whereas pharmacokinetic studies have already shown that appropriate formulations of drug successfully penetrate the skin to reach breast tissue, where a preventive effect is sought.

Figures

Figure 1
Figure 1
The effects of tamoxifen on human tissues. (a, b) Systemic administration of low tamoxifen (a) and topical administration of tamoxifen metabolites (b). Topical tamoxifen avoids high systemic exposure to 4-hydroxytamoxifen compared with standard oral tamoxifen, a 16- to 18-fold difference, thus reducing the risk of systemic side effects. Breast tissue concentrations seem to be sufficient to achieve inhibition of tumor cell proliferation to the same degree as that seen with the standard dose of oral tamoxifen (20 mg/day) but with much lower plasma levels. Tamoxifen has both good and bad effects on specific human tissues. Development of new approaches should maximize the good effects and minimize the bad effects.

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