Division of Cancer Prevention and Genetics, European Institute of Oncology, Milan, Italy.
BMC Cancer. 2012 Dec 5;12:575. doi: 10.1186/1471-2407-12-575.
Despite positive results from large phase III clinical trials proved that it is possible to prevent estrogen-responsive breast cancers with selective estrogen receptor modulators and aromatase inhibitors, no significant results have been reached so far to prevent hormone non-responsive tumors. The Ductal Lavage (DL) procedure offers a minimally invasive method to obtain breast epithelial cells from the ductal system for cytopathologic analysis. Several studies with long-term follow-up have shown that women with atypical hyperplasia have an elevated risk of developing breast cancer. The objective of the proposed trial is to assess the efficacy and safety of a daily administration of nimesulide or simvastatin in women at higher risk for breast cancer, focused particularly on hormone non-responsive tumor risk. The primary endpoint is the change in prevalence of atypical cells and cell proliferation (measured by Ki67) in DL or fine needle aspirate samples, after 12 months of treatment and 12 months after treatment cessation. METHODS-DESIGN: From 2005 to 2011, 150 women with a history of estrogen receptor negative ductal intraepithelial neoplasia or lobular intraepithelial neoplasia or atypical hyperplasia, or unaffected subjects carrying a mutation of BRCA1 or with a probability of mutation >10% (according to BRCAPRO) were randomized to receive nimesulide 100mg/day versus simvastatin 20mg/day versus placebo for one year followed by a second year of follow-up.
This is the first randomized placebo controlled trial to evaluate the role of DL to study surrogate endpoints biomarkers and the effects of these drugs on breast carcinogenesis. In 2007 the European Medicines Agency limited the use of systemic formulations of nimesulide to 15 days. According to the European Institute of Oncology Ethics Committee communication, we are now performing an even more careful monitoring of the study participants. Preliminary results showed that DL is a feasible procedure, the treatment is well tolerated and the safety blood tests do not show any significant liver toxicity. There is an urgent need to confirm in the clinical setting the potential efficacy of other compounds in contrasting hormone non-responsive breast cancer. This paper is focused on the methodology and operational aspects of the clinical trial.
(ClinicalTrials.gov Identifier: NCT01500577).
尽管大型 III 期临床试验的阳性结果表明，使用选择性雌激素受体调节剂和芳香酶抑制剂预防雌激素反应性乳腺癌是可能的，但迄今为止，还没有取得预防激素非反应性肿瘤的显著效果。乳腺导管冲洗术（DL）为获取乳腺导管系统中的乳腺上皮细胞进行细胞病理学分析提供了一种微创方法。几项长期随访的研究表明，不典型增生的女性发生乳腺癌的风险增加。该试验的目的是评估尼美舒利或辛伐他汀每日给药在乳腺癌高危女性中的疗效和安全性，特别关注激素非反应性肿瘤的风险。主要终点是治疗 12 个月和治疗停止 12 个月后，DL 或细针抽吸样本中不典型细胞和细胞增殖（通过 Ki67 测量）的变化。方法-设计：2005 年至 2011 年，150 名患有雌激素受体阴性导管上皮内瘤变或小叶上皮内瘤变或不典型增生史的女性，或携带 BRCA1 突变或突变概率>10%（根据 BRCAPRO）的未受影响的受试者，被随机分为尼美舒利 100mg/天组、辛伐他汀 20mg/天组和安慰剂组，进行为期一年的治疗，然后进行第二年的随访。
这是第一项评估 DL 以研究替代终点生物标志物的作用以及这些药物对乳腺癌发生的影响的随机安慰剂对照试验。2007 年，欧洲药品管理局限制了尼美舒利的全身制剂的使用时间为 15 天。根据欧洲肿瘤研究所伦理委员会的沟通，我们现在正在对研究参与者进行更仔细的监测。初步结果表明，DL 是一种可行的方法，治疗耐受性良好，血液安全性检查未显示出任何明显的肝毒性。迫切需要在临床环境中确认其他化合物在对抗激素非反应性乳腺癌方面的潜在疗效。本文侧重于临床试验的方法学和操作方面。
（ClinicalTrials.gov 标识符：NCT01500577）。
