Anthracycline-free Taxane Based Chemotherapy in Patients With HER2/Neu Negative Early Breast Cancer

Randomised Comparison of Adjuvant Docetaxel / Cyclophosphamide With Sequential Adjuvant EC / Docetaxel Chemotherapy in Patients With HER2/Neu Negative Early Breast Cancer

The planned trial compares an anthracycline-free taxane based regimen versus a modern third generation (anthracycline/taxane-based) regimen in HER2/neu non-over expressing tumors. The aim is to define a further anthracycline-free standard and to spare anthracycline toxicity to a patient, who will only have a modest benefit from this compound. Prior to randomization for chemotherapy for all patients with HR positive disease OncotypeDX® will be performed to identify patients who should not receive chemotherapy.

Secondary objectives of this trial will be to compare overall survival and toxicity between the two chemotherapy arms, to evaluate survival in the observation arm and to perform translational research regarding prognostic and predictive factors.

Inclusion Criteria(Screening):

• Female patients, age at diagnosis 18 - 75 years
• Histological confirmed unilateral primary invasive carcinoma of the breast
• Adequate surgical treatment with complete resection of the tumor (R0) and resection of > or = 10 axillary nodes or SLN in clinically N0 patients
• T1 - T4 (if operable, inflammatory breast cancer is excluded)
• Her-2 non-over expressing tumor confirmed by IHC/FISH
• Estrogen and/or progesterone receptor analysis performed on the primary tumor prior to randomization. Results must be known at the time of randomization
• Node positive disease or node negative disease with at least one other risk factor (tumor size > or = 2 cm, grade > or = 2, ER and PR negative, high uPA//PAI-1 levels)
• No evidence for distant metastasis (M0) after conventional staging
• Performance Status ECOG < or = 1 or KI > or = 80 %
• The patient must be accessible for treatment and follow-up
• Written informed consent for central pathology review and evaluation of Recurrence Score (HR positive) and participation in the planB trial prior to beginning specific protocol procedures

HR positive patients:

• Patient willingness to participate in adjuvant chemotherapy planB trial if RS > 11
• Indication for chemotherapy given provided either > 4 involved lymph nodes or RS > 11 in 1-3 lymph nodes or N0 disease

Additional Inclusion Criteria (Randomisation to chemotherapy):

• Laboratory requirements (within 21 days prior to randomization):

  • Leucocytes > or = 3.5 109/L
  • platelets > or = 100 109/L
  • haemoglobin > or = 10 g/dL
  • total bilirubin < or = 1 ULN
  • ASAT (SGOT) and ALAT (SGPT) < or = 2.5 UNL
  • creatinine < 175 ymol/L (2 mg/dL)

• Negative pregnancy test (urine or serum) within 7 days prior to randomization in premenopausal patients

• LVEF within normal limits of each institution measured by echocardiography or MUGA scan and

Exclusion Criteria(Screening):

• HER2 over expression confirmed by IHC/FISH/CISH
• Known hypersensitivity reaction to the compounds or incorporated substances
• Known polyneuropathy > or = grade 2
• Severe and relevant comorbidity that would interact with the application of cytotoxic agents or the participation in the study including acute cystitis and ischuria and chronic kidney disease.
• Prior malignancy with a disease-free survival of < 10 years, except curatively treated basalioma of the skin, pTis of the cervix uteri or ipsilateral ductal carcinoma in-situ (DCISpTis of the breast)
• Non-operable breast cancer including inflammatory breast cancer
• Previous or concurrent treatment with cytotoxic agents for any reason after consultation with the sponsor
• Concurrent treatment with other experimental drugs. Participation in another clinical trial with any investigational not marketed drug within 30 days prior to study entry
• Male breast cancer
• Concurrent pregnancy; patients of childbearing potential must implement a highly effective (less then 1% failure rate) non-hormonal contraceptive measures during the study treatment
• Breast feeding woman
• Sequential breast cancer
• Lack of patient compliance

Additional Exclusion Criteria (Randomisation):

• Inadequate organ function including:

  • Leucocytes < 3,5 G/l
  • platelets < 100 G/l
  • creatinine or bilirubin above normal limits
  • alkaline phosphatise > 5 UNL
  • ASAT and/or ALAT associated with AP > 2.5 UNL
  • uncompensated cardiac function

• Time since axillary dissection > 42 days