Thrombin inhibition preoperatively in early breast cancer

INTERVENTION: Current interventions as of 20/09/2018: Patients will be randomised into 2 groups in a 1:1 ratio as follows: Group 1: Preoperative Rivaroxaban 20mg od and excisional approx 14 days later Group 2: No Preoperative therapy with surgery/research core biopsy approx 14 days later Patients should have their surgery/neoadjuvant chemotherapy booked prior to randomisation and scheduled for around two weeks ahead. All surgery will be completed to standard care. Patients will return 2 weeks following the date of surgery for post‐op complications and adverse events review. All further follow‐up will be as per standard NHS practice with annual clinical and mammographic examination. Previous interventions: Patients will be randomised into 3 groups in a 1:1:1 ratio as follows (with the Rivaroxaban treatment groups being combined for primary endpoint analysis creating a 2:1 randomisation for Rivaroxaban vs. no treatment): Group 1: Preoperative Rivaroxaban 20mg od and excisional approx 14 days later Group 2: Preoperative Rivaroxaban 10mg od and excisional approx 14 days later Group 3: No Preoperative therapy with surgery approx 14 days later Patients should have their surgery booked prior to randomisation and scheduled for around two weeks ahead, as long it is within 31 days from diagnosis. All surgery will be completed to standard care. Patients will return 2 weeks following the date of surgery for post‐op complications and adverse events review. All further follow‐up will be as per standard NHS practice with annual clinical and mammographic examination. CONDITION: Topic: Cancer; Subtopic: Breast Cancer; Disease: Breast ; Cancer ; Breast Cancer PRIMARY OUTCOME: Current primary outcome measure as of 20/09/2018:; Percentage reduction in tumour Ki67 expression is measured using tumour core biopsies at baseline (pre‐rivaroxaban), surgery/research core biopsy (post‐rivaroxaban).; ; Previous primary outcome measure:; Percentage reduction in tumour Ki67 expression is measured using tumour core biopsies at baseline (pre‐rivaroxaban), surgery (post‐rivaroxaban). SECONDARY OUTCOME: Current secondary outcome measure as of 20/09/2018:; In post Rivaroxaban compared to pre‐ Rivaroxaban patient samples:; 1. Reduction in tumour tissue expression of TF, TAT and PAR 1 is measured using patient samples at at baseline (pre‐rivaroxaban) and the time of surgery/research core biopsy (post‐rivaroxaban); 2. Reduction in tumour tissue expression of CD31 is measured using patient samples at baseline (pre‐rivaroxaban) and the time of surgery/research core biopsy (post‐rivaroxaban); 3. Increase in tumour tissue expression of p27, cleaved Caspase 3 and TUNEL is measured using patient samples at baseline (pre‐rivaroxaban) and the time of surgery/research core biopsy (post‐rivaroxaban); 4. Reduction in CTCs is measured using patient samples at at baseline (pre‐rivaroxaban) and the time of surgery/research core biopsy (post‐rivaroxaban); 5. Increase in circulating free DNA (cfDNA) and decrease in cfDNA Integrity (cfDI) is measured using patient samples at at baseline (pre‐rivaroxaban) and the time of surgery/research core biopsy (post‐rivaroxaban); 6. Reduction in plasma d‐dimer, TF and TAT is measured using patient samples at at baseline (pre‐rivaroxaban) and the time of surgery/research core biopsy (post‐rivaroxaban); 7. Alterations in proteomics, correlating to tumour response is measured using patient samples at at baseline (pre‐rivaroxaban) and the time of surgery/research core biopsy (post‐rivaroxaban); ; In post Rivaroxaban compared to post placebo patient samples:; 1. Reduction in MFE is measured using patient samples at baseline (pre‐rivaroxaban) and the time of surgery/research core biopsy (post‐rivaroxaban); 2. Reduction in tumour tissue expression of TF, TAT and PAR 1 is measured using patient samples at baseline (pre‐rivaroxaban) and the time of surgery/research core biopsy (post‐rivaroxaban); 3. Reduction in tumour tissue expression of CD31 is measured using patient samples at baseline (pre‐rivaroxaban) and the time of surgery/research core biopsy (post‐rivaroxaban); 4. Increase in tumour tissue expression of p27, cleaved Caspase 3 and TUNEL is measured using patient samples at baseline (pre‐rivaroxaban) and the time of surgery/research core biopsy (post‐rivaroxaban); 5. Reduction in CTCs is measured using patient samples at baseline (pre‐rivaroxaban) and the time of surgery/research core biopsy (post‐rivaroxaban); 6. Increase in circulating free DNA (cfDNA) and decrease in cfDNA Integrity (cfDI) is measured using patient samples at at baseline (pre‐rivaroxaban) and the time of surgery/research core biopsy (post‐rivaroxaban); 7. Reduction in plasma d‐dimer, TF and TAT is measured using patient samples at at baseline (pre‐rivaroxaban) and the time of surgery/research core biopsy (post‐rivaroxaban); 8. Alterations in proteomics, correlating to tumour response is measured using patient samples at at baseline (pre‐rivaroxaban) and the time of surgery/research core biopsy (post‐rivaroxaban); ; Previous secondary outcome measure:; In post Rivaroxaban compared to pre‐ Rivaroxaban patient samples:; 1. Reduction in tumour tissue expression of TF, TAT and PAR 1 is measured using patient samples at at baseline (pre‐rivaroxaban) and the time of surgery (post‐rivaroxaban); 2. Reduction in tumour tissue expression of CD31 is measured using patient samples at at baseline (pre‐rivaroxaban) and the time of surgery (post‐rivaroxaban); 3. Increase in tumour tissue expression of p27, cleaved Caspase 3 and TUNEL is measured using patient samples at at baseline (pre‐rivaroxaban) and the time of surgery (post‐rivaroxaban); 4. Reduction in CTCs is measured using patient samples at at baseline (pre‐rivaroxaban) and the time of surgery (post‐rivaroxaban); 5. Increase in circulating free DNA (cfDNA) and decrease in cfDNA Integrity (cfDI) is measured using patient samples at at baseline (pre‐rivaroxaban) and the time of surgery (post‐rivaroxaban); 6. Reduction in plasma d‐dimer, TF and TAT is measured using patient samples at at baseline (pre‐rivaroxaban) and the time of surgery (post‐rivaroxaban); 7. Alterations in proteomics, correlating to tumour response is measured using patient samples at at baseline (pre‐rivaroxaban) and the time of surgery (post‐rivaroxaban); ; In post Rivaroxaban compared to post placebo patient samples:; 1. Reduction in MFE is measured using patient samples at at baseline (pre‐rivaroxaban) and the time of surgery (post‐rivaroxaban); 2. Reduction in tumour tissue expression of TF, TAT and PAR 1 is measured using patient samples at at baseline (pre‐rivaroxaban) and the time of surgery (post‐rivaroxaban); 3. Reduction in tumour tissue expression of CD31 is measured using patient samples at at baseline (pre‐rivaroxaban) and the time of surgery (post‐rivaroxaban); 4. Increase in tumour tissue expression of p27, cleaved Caspase 3 and TUNEL is measured using patient samples at at baseline (pre‐rivaroxaban) and the time of surgery (post‐rivaroxaban); 5. Reduction in CTCs is measured using patient samples at at baseline (pre‐rivaroxaban) and the time of surgery (post‐rivaroxaban); 6. Increase in circulating free DNA (cfDNA) and decrease in cfDNA Integrity (cfDI) is measured using patient samples at at baseline (pre‐rivaroxaban) and the time of surgery (post‐rivaroxaban); 7. Reduction in plasma d‐dimer, TF and TAT is measured using patient samples at at baseline (pre‐rivaroxaban) and the time of surgery (post‐rivaroxaban); 8. Alterations in proteomics, correlating to tumour response is measured using patient samples at at baseline (pre‐rivaroxaban) and the time of surgery (post‐rivaroxaban); ; In post 20mg od Rivaroxaban compared to post 10mg Rivaroxaban patient samples (subgroup analysis):; 1. Reduction in MFE is measured using patient samples at at baseline (pre‐rivaroxaban) and the time of surgery (post‐rivaroxaban); 2. Reduction in tumour tissue expression of TF, TAT and PAR 1 is measured using patient samples at at baseline (pre‐rivaroxaban) and the time of surgery (post‐rivaroxaban); 3. Reduction in tumour tissue expression of CD31 is measured using patient samples at at baseline (pre‐rivaroxaban) and the time of surgery (post‐rivaroxaban); 4. Increase in tumour tissue expression of p27, cleaved Caspase 3 and TUNEL is measured using patient samples at at baseline (pre‐rivaroxaban) and the time of surgery (post‐rivaroxaban); 5. Reduction in CTCs is measured using patient samples at at baseline (pre‐rivaroxaban) and the time of surgery (post‐rivaroxaban); 6. Increase in circulating free DNA (cfDNA) and decrease in cfDNA Integrity (cfDI) is measured using patient samples at at baseline (pre‐rivaroxaban) and the time of surgery (post‐rivaroxaban); 7. Reduction in plasma d‐dimer, TF and TAT is measured using patient samples at at baseline (pre‐rivaroxaban) and the time of surgery (post‐rivaroxaban); 8. Alterations in proteomics, correlating to tumour response is measured using patient samples at at baseline (pre‐rivaroxaban) and the time of surgery (post‐rivaroxaban); INCLUSION CRITERIA: Current inclusion criteria as of 20/09/2018: 1. Provision of written informed consent. 2. World Health Organisation (WHO) performance status 0‐1 with no deterioration over the previous 2 weeks 3. Patients must be able to swallow and retain oral medication 4. Female patients, age over 18, with histological confirmation of ER negative (ER Quick Score / Allred =5) invasive breast carcinoma 5. Any Her2 status 6. AJCC Stage 1‐ 3 with primary tumour in the breast amenable to biopsies 7. Scheduled to have definitive breast surgery 11 or more days after commencement of treatment or are able to take 11 or more days of rivaroxaban and have an additional core biopsy prior to starting neoadjuvant therapy. 8. Tumour size =10mm (large enough to provide sufficient tissue to be taken by core‐cut or tru‐cut biopsy (free‐hand or under ultrasound guidance as per local protocols)). 9. As judged by the Investigator, no evidence of severe or uncontrolle