A randomized, double-blind, placebo-controlled study of 4-hydroxtamoxifen topical gel in women with mammographically dense breasts

Mammographic Density as Surrogate Biomarker Tamoxifen oral tablet at 20 mg/day for 5 years is currently FDA approved for the use of breast cancer risk reduction. However, despite the known fact that it can reduce breast cancer risk by 50%, less than 20 % of high risk women choose to take Tamoxifen for risk reduction; mostly because of the low, but still slight increased risk of endometrial cancer, thromboembolic events (TEE), arthralgia and menopausal side effects (hot flushes, weight gain, hair thinning). These systemic side effects unfortunately cause underutilization of this otherwise active risk reductive agent. One approach to improve the benefit/ risk ratio might be to consider an innovative way to administer the agent where the preventive effects remains, but systemic side effects are not present (or minimal). 4- hydroxytamoxifen topical gel ( 4-OHT gel) is a local (breast) transdermal administered agent. In previous studies (Lee O et al. Clin Canc Res Jul 2014); 6-10 weeks of 4-OHT gel at 4mg/day has been compared to 20 mg/day oral tamoxifen in patients with ductal carcinoma insitu. Results have shown that 4-OHT gel was able to achieve same breast adipose tissue concentration as oral tamoxifen. Furthermore, risk factors for TEE was increased in the oral Tamoxifen group, but not in the 4-OHT gel group (factor VIII, von Willebrand factor). While the toxicity profile is safer, it will be also important to show that the gel form achieves the ultimate desired endpoint; reduction in breast cancer incidence. Currently, there are no prospective studies evaluating the preventive effect of 4-OHT gel in high risk women. However, there is data showing that it can modulate breast cancer risk makers favorably, by decreasing KI-67 in breast tissue very similar to oral Tamoxifen (Ref).