title: PO-36 - Thrombin Inhibition Preoperatively (TIP) in early breast cancer, the first clinical trial of NOACs as an anti-cancer agent: trial methodology.
abstract: BACKGROUND
  Breast cancer is associated with a 3-4 fold increased risk of VTE. These patients have a 4-fold lower survival than those remaining free of VTE, implying VTE is a surrogate marker for aggressive cancer. Tumour expression of thrombin pathway markers are increased in the oestrogen receptor negative (ER-), high Ki67, more aggressive breast cancer subtypes. In in vitro and in vivo studies, the thrombin pathway promotes cancer growth and metastases, highlighting the potential role of the thrombin pathway as a therapeutic target in cancer.
  
  
  OBJECTIVE
  To determine whether 14days of a preoperative oral Factor Xa inhibitor (Rivaroxaban) in oestrogen receptor negative early breast cancer patients results in inhibition of tumour proliferation as determined by a reduction in tumour Ki67 from baseline (pre-treatment) to 14days post treatment start (at time of surgical excision).
  
  
  METHODS
  
  
  
  BACKGROUND
  The TF-VIIa-FXa complex activates Protease Activated Receptor (PAR)2 to induce angiogensis, growth factors and tumour cell migration. Thrombin, in part via PAR1, induces angiogenesis, tumour cell proliferation as well as in vivo metastasis. In early breast cancer, TF and PAR2 expression is increased in the stroma, particularly in the more aggressive ER-, high Ki67 (proliferation) cancers. Rivaroxaban is an orally active direct Factor Xa inhibitor. Through inhibition of the TF-FVIIa-FXa complex, it can downregulate TF-FVIIa-FXa activation of PAR2, and inhibit conversion of prothrombin to thrombin. We hypothesise that 14days of Rivaroxaban will reduce breast cancer proliferation, as a surrogate marker for anti-cancer efficacy, in early breast cancer patients awaiting resectional surgery.
  
  
  RESULTS
  Trial methodology: A multi-centre phase II preoperative 'Window-of Opportunity' randomised controlled trial of Rivaroxaban compared to no treatment in ER-, stage I-III early breast cancer patients. Patients will be randomised 1:1:1 (Rivaroxaban 20mg od: Rivaroxaban 10mg od: no treatment) and receive 14 (+/-3) days of treatment in the window between diagnosis and surgery. Randomisation will be blinded to pathologists, but not to patients or clinicians. Primary analysis will be based on the two Rivaroxaban arms being combined to form a Rivaroxaban: no treatment, 2:1 trial design, with change in Ki67 from baseline (pre) to post Rivaroxaban/no treatment (post) being the primary endpoint, and the no treatment arm acting as a reference group. Subgroup analysis of the Rivaroxaban arm (20mg od:10mg od) will allow assessment of dose-response.
  Funder: National Institute for Health Research Eudract No: 2014-004909-33 REC Number: 15/NW/0406 UKCRN ID: 19731 Expected commencement: January 2016. For further information please contact Chief Investigator: cliona.kirwan@manchester.ac.uk.
authors.affiliation: Institute of Cancer Sciences, University of Manchester; The Nightingale and Genesis Breast Cancer Prevention Centre, University Hospital of South Manchester.
authors.forename: C C
authors.initials: CC
authors.lastname: Kirwan
authors.affiliation: Institute of Cancer Sciences, University of Manchester; The Nightingale and Genesis Breast Cancer Prevention Centre, University Hospital of South Manchester.
authors.forename: N J
authors.initials: NJ
authors.lastname: Bundred
authors.affiliation: Institute of Cancer Sciences, University of Manchester.
authors.forename: J
authors.initials: J
authors.lastname: Castle
authors.affiliation: Institute of Cancer Sciences, University of Manchester.
authors.forename: R
authors.initials: R
authors.lastname: Clarke
authors.affiliation: Institute of Cancer Sciences, University of Manchester.
authors.forename: C
authors.initials: C
authors.lastname: Dive
authors.affiliation: Department of Medical statistics, University Hospital of South Manchester.
authors.forename: J
authors.initials: J
authors.lastname: Morris
authors.affiliation: Royal Liverpool University Hospital, Liverpool; United Kingdom.
authors.forename: C
authors.initials: C
authors.lastname: Holcombe
authors.affiliation: The Nightingale and Genesis Breast Cancer Prevention Centre, University Hospital of South Manchester.
authors.forename: J R
authors.initials: JR
authors.lastname: Harvey