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

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Estrogen can stimulate the growth of breast cancer cells. Hormone therapy using letrozole may fight breast cancer by reducing the production of estrogen. It is not yet known whether giving more than one drug (combination chemotherapy) or giving letrozole before surgery is more effective in treating women with breast cancer. PURPOSE: This randomized phase III trial is studying giving combination chemotherapy before surgery to see how well it works compared with letrozole given before surgery in treating postmenopausal women with breast cancer that can be removed by surgery.

Detailed Description
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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.

Official Title
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A Neoadjuvant Study of Chemotherapy Versus Endocrine Therapy in Postmenopausal Patients With Primary Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: cyclophosphamide
* Drug: docetaxel
* Drug: epirubicin hydrochloride
* Drug: fluorouracil
* Drug: letrozole


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>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. | Drug: cyclophosphamide<br>* Given IV<br>Drug: docetaxel<br>* Given IV<br>Drug: epirubicin hydrochloride<br>* Given IV<br>Drug: fluorouracil<br>* Given IV<br>|
| Experimental: Arm II<br>Patients receive oral letrozole daily for 18-23 weeks until day of surgery. | Drug: letrozole<br>* Given orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of patient recruitment (pilot) |  |  | 
| Feasibility of tissue collection (pilot) |  |  | 
| Ultrasound (or mammogram) response rate |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical response rate |  |  | 
| Radiologic response rate by ultrasound (pilot) |  |  | 
| Quality of life |  |  | 
| Pathological complete response rate (pCR) defined as no residual invasive or pre-invasive carcinoma in breast or axilla (pilot) |  |  | 
| Plasma DNA changes in relation to treatment response |  |  | 
| Rate of conservation surgery |  |  | 
| Degree of pathological response |  |  | 
| Ki-67 changes and its relationship to treatment response |  |  | 
| Length of time to maximum response within the treatment period |  |  | 
| Tolerability of the various treatments |  |  | 
| Disease-free survival |  |  | 
| Overall survival |  |  | 
| MRI response |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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estrogen receptor-positive breast cancer, recurrent breast cancer, stage II breast cancer, stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer