Biomarker (p53 Gene) Analysis and Combination Chemotherapy Followed by Radiation Therapy and Surgery in Treating Women With Large Operable or Locally Advanced or Inflammatory Breast Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. Currently patients with breast cancer are treated with one of several very similar combinations of drugs. Analysis of biomarkers in tumor tissue may help doctors predict how well patients with breast cancer will respond to treatment and help doctors choose the best drug regimen to treat each patient. PURPOSE: This randomized phase III trial is studying giving different regimens of chemotherapy and comparing how well they work in treating women with large operable or locally advanced or inflammatory breast cancer. This study is also looking at whether analyzing a specific biomarker (p53) in tumor tissue may help doctors predict how well patients will respond to treatment and help doctors choose the best drug to treat each patient.

Detailed Description
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OBJECTIVES: Primary Compare neoadjuvant fluorouracil, epirubicin, and cyclophosphamide vs docetaxel and epirubicin followed by radiotherapy and surgery in women with locally advanced, inflammatory, or large operable breast cancer. Assess overall differences between the two arms. Assess interaction between p53 status and outcomes in each arm. Compare the progression-free survival of patients treated with these regimens. Secondary Compare the distant metastasis-free survival and survival of patients treated with these regimens. Compare the clinical and pathological responses to these regimens in these patients. Compare the toxicity of these regimens in these patients. Translational Determine the p53 status in order to study the treatment effect in each of the p53 subgroups and test the interaction between treatment and p53 status. Assess the level of agreement between p53 assessment by IHC method and functional test in yeast. Evaluate the prognostic and predictive value of high risk p53 mutations. Perform a survival analysis according to gene clusters defined with the use of microarrays. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to stage of disease (large T2-3 vs locally advanced or inflammatory), p53 status (negative vs positive vs unknown), and participating center. Patients are randomized to 1 of 2 chemotherapy treatment arms. Arm I (non-taxane arm): Patients receive 1 of 3 chemotherapy regimens comprising fluorouracil, epirubicin, and cyclophosphamide (FEC) (according to participating institution). FEC 100: Patients receive fluorouracil IV over 15 minutes, epirubicin IV over 1 hour, and cyclophosphamide IV over 1 hour on day 1. Treatment repeats every 3 weeks for 6 courses in the absence of disease progression or unacceptable toxicity. Canadian FEC: Patients receive oral cyclophosphamide on days 1-14 and epirubicin IV and fluorouracil IV on days 1 and 8. If oral medications are not tolerated, patients may switch to cyclophosphamide IV on days 1 and 8. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity. Tailored FEC: Patients receive fluorouracil IV over 15 minutes, epirubicin IV over 1 hour, and cyclophosphamide IV over 1-2 hours on day 1. Patients also receive filgrastim (G-CSF) subcutaneously on days 2-15 or until blood counts recover. Treatment repeats every 3 weeks for 6 courses in the absence of disease progression or unacceptable toxicity. Arm II (taxane arm): Patients receive docetaxel IV over 1 hour on days 1, 22, and 43 followed by epirubicin IV over 15 minutes and docetaxel IV over 1 hour on days 64, 85, and 106 in the absence of disease progression or unacceptable toxicity. Following chemotherapy, patients may undergo loco-regional therapy comprising radiotherapy with or without breast conservation surgery or mastectomy. Patients with estrogen- and/or progesterone-receptor-positive disease also receive tamoxifen or an aromatase inhibitor for 5 years. Two tumor samples (incisional or tricut biopsies) are taken before chemotherapy. Samples are analyzed by IHC, a functional test in yeast, and microarray analysis. Patients are followed every 3 months for 1 year, every 4 months for 1.5 years, and then every 6 months thereafter. PROJECTED ACCRUAL: A total of 1,850 patients will be accrued for this study within 5.5 years.

Official Title
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First Prospective Intergroup Translational Research Trial Assessing the Potential Predictive Value of p53 Using a Functional Assay in Yeast in Patients With Locally Advanced/Inflammatory or Large Operable Breast Cancer Prospectively Randomised to a Taxane Versus a Non Taxane Regimen

Conditions
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Breast Cancer

Intervention / Treatment
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* Biological: filgrastim
* Drug: cyclophosphamide
* Drug: docetaxel
* Drug: epirubicin hydrochloride
* Drug: fluorouracil
* Genetic: microarray analysis
* Other: immunohistochemistry staining method
* Other: laboratory biomarker analysis
* Procedure: biopsy
* Procedure: conventional surgery
* Procedure: neoadjuvant therapy
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed breast cancer Locally advanced or inflammatory disease T4a-d, any N, M0 OR Any T, N2 or N3, M0 Large operable T2 or T3 tumors No bilateral breast cancer Frozen tumor sample available 1 incisional biopsy OR 2 trucut biopsies from a 14G needle Hormone receptor status: Not specified PATIENT CHARACTERISTICS: Age: 70 and under Sex: Female Menopausal status: Not specified Performance status: WHO 0-1 Life expectancy: Not specified Hematopoietic: Neutrophil count greater than 1,500/mm^3 Platelet count greater than 100,000/mm^3 Hepatic: Bilirubin less than 1.2 mg/dL SGOT less than 60 IU/L Renal: Creatinine less than 1.35 mg/dL Cardiovascular: LVEF normal by echocardiography or MUGA Other: No other malignancy within the past 5 years except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix No serious uncontrolled medical condition No uncontrolled psychiatric or addictive disorders Not pregnant or nursing Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy: Not specified Chemotherapy: No prior chemotherapy Endocrine therapy: Not specified Radiotherapy: No prior radiotherapy Surgery: See Disease Characteristics

Ages Eligible for Study
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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
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: non taxane based chemotherapy<br>either FEC 100 or Canadian CEF or Tailored FEC for 6 cycles | Biological: filgrastim<br> <br> Drug: cyclophosphamide<br> <br> Drug: epirubicin hydrochloride<br> <br> Drug: fluorouracil<br> <br> Genetic: microarray analysis<br> <br> Other: immunohistochemistry staining method<br> <br> Other: laboratory biomarker analysis<br> <br> Procedure: biopsy<br> <br> Procedure: conventional surgery<br> <br> Procedure: neoadjuvant therapy<br> <br> Radiation: radiation therapy<br> <br> |
| Experimental: taxane based chemotherapy<br>Docetaxel for 3 cycles followed by Epirubicin/Docetaxel for 3 cycles | Drug: docetaxel<br> <br> Drug: epirubicin hydrochloride<br> <br> Genetic: microarray analysis<br> <br> Other: immunohistochemistry staining method<br> <br> Other: laboratory biomarker analysis<br> <br> Procedure: biopsy<br> <br> Procedure: conventional surgery<br> <br> Procedure: neoadjuvant therapy<br> <br> Radiation: radiation therapy<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival |  | from randomization till first evidence of progression | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Distant metastasis-free survival |  | randomization till first evidence recurrence | 
| Overall survival |  | randomization till death | 
| Clinical and pathological responses |  | after 3rd and 6d cycle of chemotherapy | 
| Clinical response according to RECIST criteria without pathologic response |  | after 3rd and 6d cycle of chemotherapy | 
| Toxicity according to CTC v2.0 |  | from randomization | 
| Agreement between p53 assessment by IHC method and functional test in yeast by analyzing the correlation between p52 and tumor status after 3 and 6 cycles of chemotherapy |  | after 3 and 6 cycles of chemotherapy | 
| Tumor assessment using cDNA microarray technology |  | end of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage II breast cancer, stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer, inflammatory breast cancer