ARTemis

• Patient with histological diagnosis of HER2 negative invasive breast cancer.

• Unifocal tumour:

  • T2 or T3 tumours (>20mm diameter on ultrasound*; see Appendix 3).

  • T4 tumour of any size with direct extension to (a) chest wall or (b) skin.

OR

• Inflammatory carcinoma with tumour of any size.

OR

• Other Locally Advanced disease:

  • Involvement of ipsilateral large or fixed axillary lymph nodes, or infra or supraclavicular nodes (>20mm diameter on ultrasound*,or clinical N2 or N3, see appendix 3) and primary breast tumour of any diameter.

  • Involvement of ipsilateral large or fixed axillary lymph nodes, or infra or supraclavicular nodes (>20mm diameter on ultrasound*, or clinical N2 or N3, see appendix 3), without a primary breast tumour, identified the presence of breast cancer in a Lymph Node (LN) must be histopathologically confirmed by LN biopsy (trucut or whole LN).

OR

• Multifocal tumour:

  • The sum of each tumours’ maximum diameter must be >20mm on ultrasound* (total radiological tumour size >20mm in the breast only, i.e. excluding axilla).

• Patients with bilateral disease are eligible to enter the trial provided that one of the breast diseases meets the above criteria.

• Any hormone receptor status.

• Patient fit to receive the trial chemotherapy regimen in the opinion of the responsible clinician:

  • Patient must have adequate bone marrow, hepatic, and renal function^.

• Patient must not have clinically significant cardiac abnormalities and must not have had a previous myocardial infarction during the 6 months prior to recruitment. Cardiac function should be assessed by physical examination and baseline measurement MUST be made of LVEF by MUGA scan or ECHOcardiogram. LVEF must be within the normal range as defined locally by the treating centre (usually at least 50%).

• ECOG performance status of 0, 1, or 2 (see Appendix 2).

• No previous or concomitant chemotherapy or biological agents.

• No previous diagnosis of other malignancy unless:

  • managed by surgical treatment with or without radiotherapy or endocrine therapy, and disease-free for 5 years

  • OR

  • previous basal cell carcinoma

  • previous cervical carcinoma in situ, or other in situ malignancy without invasion

  • contralateral ductal carcinoma in situ of the breast treated by surgery with or without radiotherapy

  • ipsilateral ductal carcinoma in situ of the breast treated by surgery only

• Non-pregnant and non-lactating, with no intention of pregnancy during chemotherapy, and prepared to adopt adequate barrier contraceptive measures if there is any possibility of pregnancy (males and females).

• No concomitant medical or psychiatric problems that might prevent completion of treatment or follow-up.
  18 years or older

• Male or female

• Written informed consent for the trial.

• Randomisation is recommended within 4 weeks of diagnostic biopsy and chemotherapy should start within 1 week after randomisation. Authorisation must be sought from the Trial Coordinators before randomisation if there is any delay outside of these time frames.

• Availability of slides and paraffin-embedded tumour blocks from pre-chemotherapy biopsy and from surgical specimen is required.

^Recommendations:

• Hepatic function:

  • AST/ALT 1.5 x ULN (If <2 x ULN, contact TMG for randomisation authorisation)

  • Alkaline phosphatase 2 x ULN

  • Bilirubin within normal range. If AST/ALT and Alkaline phosphatase are within normal limits then isolated elevation of bilirubin to 3 ULN and a presumptive diagnosis of Gilbert’s syndrome is permitted.

• Renal function: Creatinine ≤1.5 x ULN (see Appendix 4 for Cockroft and Gault formula)

• Bone marrow function: Hb >10g/dL; WBC >3 10₉/L; platelets >100 x 10₉/L

• Prothrombin time (PT) and Partial thromboplastin time (PTT/ aPTT): 1.5 x ULN.

*Ultrasound measurements are mandatory for completion of trial CRFs however, if a more accurate radiological test (MRI, spiral CT) is performed at baseline and shows >20mm measurement where the US is ≤20mm, please contact the ARTemis trial office for confirmation of eligibility.

1. HER2 positive invasive breast cancer (IHC 3+ or FISH positive).

2. T0 and T1 tumours in absence of large (total tumour size >20mm) or fixed axillary nodes (see Appendix 3).

3. Evidence of metastatic disease.

4. Prior diagnosis of ischaemic heart disease, cerebrovascular disease, peripheral vascular disease, arterial or

5. venous thromboembolic disease, cardiac failure.

6. Prior diagnosis of gastroduodenal ulcer, symptomatic diverticulitis, inflammatory bowel disease.

7. Bleeding diathesis.

8. On full therapeutic dose of anti-coagulants, or aspirin >325mg/day, clopidogrel >75mg/day or corticosteroids

9. Uncontrolled hypertension defined by a systolic pressure >150mmHg or diastolic pressure >90mmHg, with or

10. without anti-hypertensive medication. Patients with initial blood pressure elevations are eligible if initiation or

11. adjustment of antihypertensive medication lowers pressure to meet entry criteria.

12. Presence of active uncontrolled infection.

13. History of nephritic or nephrotic syndrome.

14. Major surgical procedure or traumatic injury within 28 days prior to randomisation.

15. Any evidence of other disease which in the opinion of the investigator places the patient at high risk of

16. treatment related complication.

17. Any concomitant medical or psychiatric problems which in the opinion of the investigator would prevent

18. completion of treatment or follow-up.

19. Non-healing wound, or peptic ulcer, or bone fracture.

20. On LHRH-agonists for ER strongly positive disease