Rivaroxaban compared to no treatment in ER-negative stage I-III early breast cancer patients (the TIP Trial): study protocol for a phase II preoperative window-of-opportunity study design randomised controlled trial

Abstract

Background: 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.

Methods: 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.

Discussion: 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.

Trial registration: 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 .

Keywords: Breast cancer; Clinical trial; DOAC; FXa; Ki67; NOAC; Rivaroxaban; Thrombin; Tissue Factor.

Fig. 1

The extrinsic coagulation pathway. Tissue Factor (TF), the main initiator of the coagulation cascade, complexes with Factor VIIa to activate Factor X, and in turn converts prothrombin (PT) to thrombin (Th) and ultimately fibrinogen to fibrin, with subsequent clot formation. FXa is inhibited by the direct oral anticoagulant Rivaroxaban. Thrombin also binds to protease-activated receptor 1 (PAR-1), and the TF/FVIIa/Xa complex to PAR-2. In cancer cells, this is proposed to result in pro-angiogenic, pro-proliferative and pro-invasive gene expression resulting in increased metastases. Figure created with BioRender.com [6]. Abbreviations: TF, Tissue Factor; FVIIa, activated Factor VII; FX, Factor X; FXa, activated Factor X; PT, prothrombin; Th, thrombin; PAR, protease-activated receptor

Fig. 2

Thrombin Inhibition Preoperatively (TIP) in Early Breast Cancer Trial flow diagram. In this multi-centre study patients are randomised 1:1 20 mg Rivaroxaban once daily (OD): No Treatment. Randomisation is blinded to pathologists, research laboratory staff and data analysts, but not to patients and clinicians

Fig. 3

TIP Trial Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) Figure. Abbreviations: mg, milligram; OD, once daily