Manchester Cancer Research Centre, The University of Manchester, Wilmslow Road, Manchester, M20 4GJ, UK.
The Nightingale Centre, Wythenshawe Hospital, Manchester, M23 9LT, UK.
Trials. 2020 Aug 27;21(1):749. doi: 10.1186/s13063-020-04675-7.
Breast cancer patients are at a four-fold increased risk of developing a venous thromboembolism (VTE), a major cause of death in this group. Conversely, coagulation factors promote tumour growth and metastasis. This has been evidenced in preclinical models, with an inhibitory effect of anticoagulants on cancer growth through proliferative, angiogenic, apoptotic, cancer stem cell and metastatic processes. The extrinsic clotting pathway is also more upregulated in patients in the relatively poorer prognosis oestrogen receptor (ER)-negative breast cancer subgroup, with increased tumour stromal expression of the coagulation factors Tissue Factor and thrombin. Rivaroxaban (Xarelto®, Bayer AG, Leverkusen, Germany) is a direct oral anticoagulant (DOAC). It is a Factor Xa inhibitor that is routinely prescribed for the prevention of stroke in non-valvular atrial fibrillation and for both VTE prophylaxis and treatment. This trial will assess the anti-proliferative and other anti-cancer progression mechanisms of Rivaroxaban in ER-negative early breast cancer patients.
This UK-based preoperative window-of-opportunity phase II randomised control trial will randomise 88 treatment-naïve early breast cancer patients to receive 20 mg OD Rivaroxaban treatment for 11 to 17 days or no treatment. Treatment will be stopped 24 h (range 18-36 h) prior to surgery or repeat core biopsy. All patients will be followed up for 2 weeks following surgery or repeat core biopsy. The primary endpoint is change in tumour Ki67. Secondary outcome measures include tumour markers of apoptosis and angiogenesis, extrinsic clotting pathway activation and systemic markers of metastasis, tumour load and coagulation.
Laboratory evidence supports an anti-cancer role for anticoagulants; however, this has failed to translate into survival benefit when trialled in patients with metastatic disease or poor prognosis cancers, such as lung cancer. Subgroup analysis supported a potential survival benefit in better prognosis advanced disease patients. This is the first study to investigate the anti-cancer effects of anticoagulants in early breast cancer.
UK National Research Ethics Service (NRES) approval 15/NW/0406, MHRA Clinical Trials Authorisation 48380/0003/001-0001. The sponsor is Manchester University NHS Foundation Trust, and the trial is co-ordinated by Cancer Research UK Liverpool Cancer Trials Unit (LCTU). EudraCT 2014-004909-33 , registered 27 July 2015. ISRCTN14785273 .
乳腺癌患者发生静脉血栓栓塞症（VTE）的风险增加了四倍，这是该人群死亡的主要原因。相反，凝血因子促进肿瘤生长和转移。临床前模型已经证明了这一点，抗凝剂通过增殖、血管生成、凋亡、癌症干细胞和转移过程对肿瘤生长具有抑制作用。外源性凝血途径在预后较差的雌激素受体（ER）阴性乳腺癌亚组患者中也更为上调，凝血因子组织因子和凝血酶在肿瘤基质中的表达增加。利伐沙班（Xarelto®，拜耳公司，德国勒沃库森）是一种直接口服抗凝剂（DOAC）。它是一种 Xa 因子抑制剂，常规用于预防非瓣膜性心房颤动的中风，以及预防和治疗静脉血栓栓塞症。这项试验将评估利伐沙班在 ER 阴性早期乳腺癌患者中的抗增殖和其他抗癌进展机制。
这项基于英国的术前机会窗 II 期随机对照试验将随机招募 88 名未经治疗的早期乳腺癌患者，接受 20mg OD 利伐沙班治疗 11-17 天或不治疗。治疗将在手术或重复核心活检前 24 小时（18-36 小时范围内）停止。所有患者将在手术或重复核心活检后随访 2 周。主要终点是肿瘤 Ki67 的变化。次要终点包括细胞凋亡和血管生成、外源性凝血途径激活和系统转移标志物、肿瘤负荷和凝血的肿瘤标志物。
实验室证据支持抗凝剂具有抗癌作用；然而，当在转移性疾病或预后不良的癌症（如肺癌）患者中进行试验时，这并没有转化为生存获益。亚组分析支持预后较好的晚期疾病患者有潜在的生存获益。这是第一项研究抗凝剂在早期乳腺癌中的抗癌作用。
英国国家伦理服务局（NRES）批准 15/NW/0406，药品和保健品管理局（MHRA）临床试验授权 48380/0003/001-0001。赞助商是曼彻斯特大学 NHS 基金会信托基金，试验由癌症研究英国利物浦癌症试验单位（LCTU）协调。EudraCT 2014-004909-33，注册于 2015 年 7 月 27 日。ISRCTN80544305。
