Image-Guided Intraductal Ablative Procedure for Primary Prevention of Breast Cancer

项目摘要 乳腺癌（BC）是最常见的癌症，也是癌症相关死亡的第二大原因， 美国的女人。对于中度风险，特别是低风险女性，其一生中有八分之一的机会发展为 BC，有很少的选择，以减少他们的风险。对于高危女性，预防性乳房切除术是 这是目前预防BC最有效的方法。这种侵略性的外科手术会影响女性 身体上，情感上，心理上，审美上，社交上。因此，需要开发新的 初级预防战略，重点是高风险妇女，但也可适用于中度和 低风险女性我们的总体假设是，局部杀死乳腺上皮细胞将与 预防性乳房切除术预防乳腺癌，但副作用最小。我们的初步和公布的数据 证明导管内（ID）注射70%乙醇（EtOH）溶液可有效局部消融 在啮齿动物模型中的乳腺上皮细胞，以及在侵袭性小鼠模型中预防肿瘤形成， 公元前先前临床前和临床研究的科学严谨性以及ID程序的临床使用 强烈支持我们方法的翻译可行性。我们开发了一种精制的乙醇基解决方案 包含：氧化钽（TaOx）纳米颗粒作为高分辨率造影剂，用于监测体内充盈 通过CT/X射线成像的导管树;乙基纤维素作为胶凝剂，以进一步减少侧支组织 损害本研究的研究目标是：a）优化实现和体内可视化的方法 B）确定不完全上皮消融的保护益处和安全性问题; 消融; c）了解消融溶液的组分与组织的相互作用（例如，纤维化） 以及它们对成像发现的潜在干扰（例如，造影剂清除率）;以及d）应用这些知识 建立一种临床上兼容的图像引导消融治疗程序。为了实现这些目标，我们 提出以下两个具体目的：目的1）评价ID的疗效和安全性 乳腺癌大鼠模型中的消融程序;目的2）评估这种图像引导ID消融的可扩展性 程序中的多导管树系统的兔子模型。鉴于EtOH的临床用途，诊断ID 程序和临床兼容的成像协议，这项研究的积极结果可能会迅速导致 在针对高危女性的首次人体临床试验中评价基于图像引导EtOH的消融术。 如果在高风险环境中取得成功，这种ID程序可以提供给中度和低风险的妇女， 降低他们患乳腺癌的机会，以及影响他们生活质量的癌症相关焦虑。

PROJECT ABSTRACT Breast cancer (BC) is the most prevalent cancer and the second-leading cause of cancer-related death for women in the USA. For moderate-risk and, especially, low-risk women with a 1-in-8 lifelong chance of developing BC, there are very few options available to reduce their risk. For high-risk women, prophylactic mastectomy is currently the most effective procedure for preventing BC. This aggressive surgical procedure affects women physically, emotionally, psychologically, aesthetically, and socially. Therefore, there is a need to develop new strategies for primary prevention that focus on high-risk women, but that could also be applied to moderate- and low-risk women. Our overall hypothesis is that the local killing of mammary epithelial cells will be as effective as prophylactic mastectomy in preventing BC, but with minimal side effects. Our preliminary and published data demonstrate that intraductal (ID) injection of a 70% ethanol (EtOH) solution is effective at locally ablating mammary epithelial cells in rodent models and at preventing tumor formation in an aggressive mouse model of BC. The scientific rigor of prior preclinical and clinical research studies as well as clinical use of ID procedures strongly support the translational feasibility of our approach. We have developed a refined EtOH-based solution that contains: tantalum oxide (TaOx) nanoparticles as a high-resolution contrast agent to monitor in vivo filling of ductal trees by CT/X-ray imaging; and ethyl cellulose as gelling agent to further minimize collateral tissue damage. The research objectives of this study are: a) to optimize methods for achieving and in vivo visualizing maximal epithelial ablation; b) to determine the protective benefit and safety concerns of incomplete epithelial ablation; c) to understand the interactions of the components of the ablative solution with the tissue (e.g., fibrosis) and their potential interference with imaging findings (e.g., contrast clearance); and d) To apply this knowledge to establish a clinically compatible procedure for image-guided ablative therapy. To accomplish these, we propose the following two specific aims: Aim 1) To evaluate therapeutic efficacy and safety profile of the ID ablative procedure in rat models of breast cancer; Aim 2) To assess scalability of this image-guided ID ablative procedure in the multi-ductal tree system of a rabbit model. Given the clinical uses of EtOH, diagnostic ID procedures, and clinically compatible imaging protocols, positive results of this study could rapidly lead to the evaluation of image-guided EtOH-based ablation procedure in first-in-human clinical trials for high-risk women. If successful in a high-risk setting, this ID procedure could be offered to moderate- and low-risk women who want to decrease their chance of developing BC and the cancer-associated anxiety that affects their quality of life.