Chemotherapy or Letrozole Before Surgery in Treating Postmenopausal Women With Breast Cancer That Can Be Removed By Surgery

OBJECTIVES:

• To compare the efficacy and tolerability of cytotoxic chemotherapy versus aromatase inhibition for the down-staging of strongly ER+ primary breast cancer in postmenopausal women.
• To identify biological predictors of response to these two treatment modalities.

OUTLINE: This is a multicenter pilot, feasibility study followed by a randomized study. In the pilot study, a record of all patients screened and invited to participate in the study is compiled. Reasons for failure to recruit will be recorded. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive fluorouracil IV, epirubicin IV, and cyclophosphamide IV on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients who do not achieve at least partial response after 3 courses receive docetaxel IV on day 1 of 3-week courses for an additional 3 courses.
• Arm II: Patients receive oral letrozole daily for 18-23 weeks until day of surgery.

Patients in both arms undergo surgery at week 18-23. Most patients then receive adjuvant therapy.

Quality of life is assessed at baseline, periodically during study treatment, and then during follow up.

Blood is collected pre-treatment, at mid-treatment, and before surgery. Blood is then collected every 6 months for 2 years. Blood samples and preserved tumor samples are used for correlative studies.

After completion of surgery, patients are followed up at least annually for 10 years.

PROJECTED ACCRUAL: A total of 40 patients for the pilot study and 716 patients for the phase III study will be accrued.

DISEASE CHARACTERISTICS:

• Histologically proven primary invasive breast cancer that is thought to be suitable for neoadjuvant treatment

• No cytological proof of malignancy only
• T2 tumor or greater (≥ 20 mm by ultrasound) or any T stage with nodal disease ≥ 20 mm diameter on ultrasound assessment
• No evidence of distant metastatic disease as disclosed by bone scan, liver, and chest imaging
• Definite indication for neoadjuvant and adjuvant chemotherapy
• Primary tumor amenable to biopsy
• No inoperable disease that is judged very unlikely to be rendered operable by neoadjuvant treatment
• No inflammatory breast cancer
• No bilateral invasive breast cancer
• HER-2 positivity is NOT an exclusion criterion in the feasibility (pilot) study
• Estrogen receptor (ER) positive tumor

• No ER-poor disease as defined locally (e.g., H-score < 100, Allred 3/4/5)
• Allred 6/7/8, H-score H ≥100 allowed

PATIENT CHARACTERISTICS:

• Postmenopausal, meeting 1 of the following criteria:

• Over 12 months since last menstrual period
• Postmenopausal gonadotrophin levels (luteinizing hormone or follicle-stimulating hormone levels above local criteria)
• Postmenopausal estradiol levels below local criteria
• Prior bilateral oophorectomy
• Menopause induced by gonadotrophin-releasing hormone not allowed
• WHO performance status 0 or 1
• WBC ≥ 3.0 × 10^9/L
• ANC ≥ 1.5 × 10^9/L
• Platelets ≥ 100 × 10^9/L
• Hemoglobin > 9 g/dL
• AST/ALT ≤ 1.5 times upper limit of normal (ULN)
• Serum bilirubin ≤ 1.5 times ULN
• Alkaline phosphatase ≤ 1.5 times ULN
• Serum creatinine ≤ 1.5 times ULN
• No active, uncontrolled infection
• No malignancy within the past 10 years except for basal cell carcinoma or cervical carcinoma in situ

• Treatment for previous malignancy confined to resection alone
• No concomitant medical, psychiatric, or geographic problems that might prevent completion of treatment or follow-up
• No known severe hypersensitivity to aromatase inhibitors
• No contraindication to receiving aromatase inhibitors (clinical evidence or recorded history of osteoporosis)
• No other serious illness or medical condition including any of the following:

• Congestive heart failure or unstable angina pectoris
• Myocardial infarction within the past year
• Uncontrolled hypertension or high-risk uncontrolled arrhythmias
• History of significant neurologic or psychiatric disorders, including psychotic disorders, dementia, or seizures, that would prohibit the understanding and giving of informed consent
• Active peptic ulcer
• Unstable diabetes mellitus
• No definite contraindications for the use of corticosteroids
• No contraindication to receiving combination anthracycline/taxane chemotherapy
• Willing to undergo repeat biopsies

PRIOR CONCURRENT THERAPY:

• No hormone replacement therapy within 4 weeks of starting treatment
• No chronic oral treatment with corticosteroids unless initiated > 6 months prior to study entry and at low dose (≤ 20 mg methylprednisolone or equivalent)
• No concurrent warfarin or heparin therapy