IGF::OT::IGF PHASE IIB TRIAL OF NEOADJUVANT ORAL TAMOXIFEN VERSUS TRANSDERMAL 4-HYDROXYTAMOXIFEN IN WOMEN WITH DCIS OF THE BREAST

他莫昔芬（TAM）已被证明可以降低DCIS女性局部复发和新发原发性乳腺癌的风险，提供预防和治疗双重益处。口服TAM也被证明对乳腺癌风险增加的妇女具有降低风险的价值，仅在美国就有100多万妇女。然而，DCIS和高危患者对他莫昔芬的接受度低于预期，主要是因为对其毒性的担忧。一种潜在的解决方案是开发一种递送方法，通过靶向局部给药到乳房来保持疗效，但由于全身暴露低，毒性最小。早在20世纪80年代就有研究表明，口服他莫昔芬的单羟基代谢物4-OHT对雌激素受体α (ER)具有更强的亲和力，在抑制乳腺癌细胞生长方面比TAM更有效。术前研究表明，1、2、4 mg/天的4- oht凝胶对侵袭性乳腺肿瘤和DCIS的抗增殖活性与口服20 mg/天的TAM相似。4-OHT是口服TAM的一种有效的抗雌激素代谢物，在治疗和预防乳腺癌方面具有无与伦比的疗效。

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 α (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.