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

European Organisation for Research and Treatment of Cancer (EORTC)

Status and phase: Completed; Phase 3

Conditions: Breast Cancer

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

Study type: Interventional

Funder types: Other; NETWORK

Identifiers

NCT00017095

SAKK-EORTC-10994

SBGC-EORTC-10994

ACCOG-EORTC-10994

EORTC-10994

EORTC-10994-p53

BIG-1-00

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 1,856 patients

Sex: Female

Ages: Under 70 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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1,856 participants in 2 patient groups

non taxane based chemotherapy

Active Comparator group

Description:

either FEC 100 or Canadian CEF or Tailored FEC for 6 cycles

Treatment:

Procedure: biopsy

Procedure: neoadjuvant therapy

Genetic: microarray analysis

Drug: epirubicin hydrochloride

Procedure: conventional surgery

Other: laboratory biomarker analysis

Drug: fluorouracil

Other: immunohistochemistry staining method

Biological: filgrastim

Drug: cyclophosphamide

Radiation: radiation therapy

taxane based chemotherapy

Experimental group

Description:

Docetaxel for 3 cycles followed by Epirubicin/Docetaxel for 3 cycles

Treatment:

Procedure: biopsy

Procedure: neoadjuvant therapy

Genetic: microarray analysis

Drug: epirubicin hydrochloride

Procedure: conventional surgery

Other: laboratory biomarker analysis

Other: immunohistochemistry staining method

Radiation: radiation therapy

Drug: docetaxel