BACKGROUND Prophylactic mastectomy is the most effective intervention to prevent breast cancer. However, this major surgery has life-changing consequences at the physical, emotional, psychological, and social levels. Therefore, only high-risk individuals consider this aggressive procedure, which completely removes the mammary epithelial cells from which breast cancer arises along with surrounding tissue. Here, we seek to develop a minimally invasive procedure as an alternative to prophylactic mastectomy by intraductal (ID) delivery of a cell-killing solution that locally ablates the mammary epithelial cells before they become malignant. METHODS After ID injection of a 70% ethanol-containing solution in FVB/NJ female animals, ex vivo dual stained whole-mount tissue analysis and in vivo X-ray microcomputed tomography imaging were used to visualize ductal tree filling, and histological and multiplex immunohistochemical assays were used to characterize ablative effects and quantitate the number of intact epithelial cells and stroma. After ID injection of 70% ethanol or other solutions in cancer-prone FVB-Tg-C3(1)-TAg female animals, mammary glands were palpated weekly to establish tumor latency and examined after necropsy to record tumor incidence. Statistical difference in median tumor latency and tumor incidence between experimental groups was analyzed by log-rank test and logistic mixed-effects model, respectively. RESULTS We report that ID injection of 70% ethanol effectively ablates the mammary epithelia with limited collateral damage to surrounding stroma and vasculature in the murine ductal tree. ID injection of 70% ethanol into the mammary glands of the C3(1)-TAg multifocal breast cancer model significantly delayed tumor formation (median latency of 150 days in the untreated control group [n = 25] vs. 217 days in the ethanol-treated group [n = 13], p value < 0.0001) and reduced tumor incidence (34% of glands with tumors [85 of 250] in the untreated control group vs. 7.3% of glands with tumor [7 of 95] in the ethanol-treated group, risk ratio = 4.76 [95% CI 1.89 to 11.97, p value < 0.0001]). CONCLUSIONS This preclinical study demonstrates the feasibility of local ductal tree ablation as a novel strategy for primary prevention of breast cancer. Given the existing clinical uses of ethanol, ethanol-based ablation protocols could be readily implemented in first-in-human clinical trials for high-risk individuals.

中文翻译：

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通过局部递送乙醇进行导管树消融可防止在侵略性乳腺癌小鼠模型中形成肿瘤。

背景技术预防性乳房切除术是预防乳腺癌的最有效干预措施。但是，这项重大手术在身体，情感，心理和社会层面都会改变生活。因此，只有高危个体才考虑采用这种侵略性程序，因为这种程序会完全清除乳腺癌和周围组织从中产生的乳腺上皮细胞。在这里，我们寻求开发一种微创手术方法，作为预防性乳房切除术的替代方法，方法是通过导管内（ID）递送细胞杀灭溶液，从而在它们变得恶性之前局部消融乳腺上皮细胞。方法在FVB / NJ雌性动物中ID注射含70％乙醇的溶液后，使用了体外双染色全片组织分析和体内X射线微计算机断层摄影成像来可视化导管树的充盈，并使用组织学和多重免疫组织化学分析来表征消融作用并定量完整的上皮细胞和基质的数量。在易患癌症的FVB-Tg-C3（1）-TAg雌性动物中ID注射70％乙醇或其他溶液后，每周触诊一次乳腺以建立肿瘤潜伏期，并在尸检后检查以记录肿瘤发生率。用log-rank检验和logistic混合效应模型分别分析实验组之间的中位肿瘤潜伏期和肿瘤发生率的统计学差异。结果我们报告70％乙醇的ID注射有效消融了乳腺上皮，对小鼠导管树周围的基质和脉管系统的附带损害有限。在C3（1）-TAg多灶性乳腺癌模型的乳腺中ID注射70％乙醇可显着延迟肿瘤形成（未经治疗的对照组中位潜伏期为150天[n = 25]，而乙醇组为217天。治疗组[n = 13]，p值<0.0001）并降低了肿瘤的发生率（未治疗的对照组中有肿瘤的腺体占34％[85/250]，而在乙醇中有7.3％的肿瘤体[95/7]）治疗组，风险比= 4.76 [95％CI 1.89至11.97，p值<0.0001]。结论这项临床前研究证明了局部导管树消融术作为乳腺癌的一级预防新策略的可行性。