Thomas Scott, Roche Elysia, Desai Pujan, Pawlowska Nela, Bauer Diana, Gingrich David, Hsu Emily, Deitchman Amelia N, Aweeka Fran, Munster Pamela N
Division of Hematology and Oncology, University of California, 1450 3rd Street, San Francisco, CA, 94143, USA.
Laboratory Animal Resource Center, University of California, San Francisco, USA.
Sci Rep. 2025 Jan 24;15(1):3028. doi: 10.1038/s41598-024-77186-z.
For individuals at high risk of developing breast cancer, interventions to mitigate this risk include surgical removal of their breasts and ovaries or five years treatment with the anti-estrogen tamoxifen or aromatase inhibitors. We hypothesized that a silicone based anti-estrogen-eluting implant placed within the breast would provide the risk reduction benefit of hormonal therapy, but without the adverse effects that limit compliance. To this end, we demonstrate that when placed adjacent to mammary tissue in the 7,12-dimethylbenz[a]anthracene-induced rat breast cancer model a fulvestrant-eluting implant delays breast cancer with minimal systemic exposure. Using adult female sheep, surgical placement of fulvestrant-eluting implants was safe and did not elicit significant breast tissue pathology when placed at the base of the udder for directed elution into the mammary tissue. At 30 days of elution, fulvestrant was found to penetrate mammary tissue forming a concentration gradient beyond 15 mm from the implant. Consistent with the small animal rat study, minimal systemic fulvestrant biodistribution was found. Together, these studies provide the proof of principle that a breast indwelling fulvestrant-eluting implant can reduce the risk of breast cancer and limit systemic exposure, while penetrating and distributing through breast tissue.
对于有患乳腺癌高风险的个体，降低这种风险的干预措施包括手术切除乳房和卵巢，或使用抗雌激素他莫昔芬或芳香化酶抑制剂进行五年治疗。我们假设，置于乳房内的含硅抗雌激素洗脱植入物将提供激素治疗降低风险的益处，但不会产生限制依从性的不良反应。为此，我们证明，在7,12-二甲基苯并[a]蒽诱导的大鼠乳腺癌模型中，当将氟维司群洗脱植入物置于乳腺组织附近时，可延缓乳腺癌进展，且全身暴露最小。使用成年雌性绵羊，将氟维司群洗脱植入物手术放置在乳房基部以定向洗脱到乳腺组织中是安全的，且不会引发明显的乳腺组织病理学变化。在洗脱30天时，发现氟维司群穿透乳腺组织，形成距植入物超过15毫米的浓度梯度。与小动物大鼠研究一致，发现全身氟维司群的生物分布最小。总之，这些研究提供了原理证明，即乳房内植入氟维司群洗脱植入物可降低乳腺癌风险并限制全身暴露，同时穿透并分布于乳腺组织。
