Tamoxifen (TAM) has been proven to reduce risk of both local recurrence and new primary breast cancer in women with DCIS, providing both preventive and therapeutic benefit. Oral TAM also has proven risk reduction value for women at increased risk for breast cancer, numbering over a million women in the United States alone. However, tamoxifen acceptance by DCIS and high-risk patients has been lower than expected, mainly because of toxicity concerns. A potential solution is the development of delivery methods that preserve efficacy through targeted local delivery to the breast, but minimize toxicity because of low systemic exposure. A potential alternative to oral tamoxifen is suggested by studies going back to the 1980s, which showed that 4-OHT, the monohydroxy metabolite of oral tamoxifen, has a far greater affinity for the estrogen receptor ? (ER) and is more effective than TAM in suppressing breast cancer cell growth. Pre-surgical studies indicate that the anti-proliferative activity of 4-OHT gel at 1, 2, and 4 mg/day in invasive breast tumors and DCIS is similar to that of oral TAM at 20 mg/day. 4-OHT is a potent antiestrogenic metabolite of oral TAM, an agent with an unparalleled record of therapeutic and preventive breast cancer efficacy. This randomized, double-blind, placebo-controlled neoadjuvant trial of 0.228% 4-hydroxy-tamoxifen (4-OHT) gel vs. oral tamoxifen (TAM) 20 mg daily will enroll 100 women with a core needle biopsy diagnosis of ER positive DCIS, regardless of grade, with 1:1 randomization to oral TAM and 4-OHT gel. The 4-OHT group will apply active gel 2 mg daily to each breast for a minimum of 24 and a maximum of 28 weeks and take oral placebo. The TAM group will take 20 mg TAM orally daily and apply gel placebo. The primary endpoint is Ki67 labeling index in the DCIS core compared to the surgical sample, with the expectation that the reduction in this parameter will be equivalent in the two groups. Therefore, this statement of work outlines the requirements for the study, including (but not limited to) participant accrual, agent administration and patient follow-up as well as associated biomarker analyses. This statement of work includes protocol activities to screen 150 participants and enroll 100 on trial stratified by menopausal status and site of enrollment.
