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

This study has been completed.
Sponsor:
Collaborators:
Swedish Breast Cancer Group
Swiss Group for Clinical Cancer Research
Anglo Celtic Cooperative Oncology Group
Information provided by (Responsible Party):
European Organisation for Research and Treatment of Cancer - EORTC
ClinicalTrials.gov Identifier:
NCT00017095
First received: June 6, 2001
Last updated: October 23, 2013
Last verified: October 2013

June 6, 2001
October 23, 2013
March 2001
November 2006   (final data collection date for primary outcome measure)
Progression-free survival [ Time Frame: from randomization till first evidence of progression ] [ Designated as safety issue: No ]
Not Provided
Complete list of historical versions of study NCT00017095 on ClinicalTrials.gov Archive Site
  • Distant metastasis-free survival [ Time Frame: randomization till first evidence recurrence ] [ Designated as safety issue: No ]
  • Overall survival [ Time Frame: randomization till death ] [ Designated as safety issue: No ]
  • Clinical and pathological responses [ Time Frame: after 3rd and 6d cycle of chemotherapy ] [ Designated as safety issue: No ]
  • Clinical response according to RECIST criteria without pathologic response [ Time Frame: after 3rd and 6d cycle of chemotherapy ] [ Designated as safety issue: No ]
  • Toxicity according to CTC v2.0 [ Time Frame: from randomization ] [ Designated as safety issue: Yes ]
  • 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 [ Time Frame: after 3 and 6 cycles of chemotherapy ] [ Designated as safety issue: No ]
  • Tumor assessment using cDNA microarray technology [ Time Frame: end of treatment ] [ Designated as safety issue: No ]
Not Provided
Not Provided
Not Provided
 
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
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

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.

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.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Breast Cancer
  • 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
  • Active Comparator: non taxane based chemotherapy
    either FEC 100 or Canadian CEF or Tailored FEC for 6 cycles
    Interventions:
    • Biological: filgrastim
    • Drug: cyclophosphamide
    • 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
  • Experimental: taxane based chemotherapy
    Docetaxel for 3 cycles followed by Epirubicin/Docetaxel for 3 cycles
    Interventions:
    • Drug: docetaxel
    • Drug: epirubicin hydrochloride
    • Genetic: microarray analysis
    • Other: immunohistochemistry staining method
    • Other: laboratory biomarker analysis
    • Procedure: biopsy
    • Procedure: conventional surgery
    • Procedure: neoadjuvant therapy
    • Radiation: radiation therapy

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
1856
Not Provided
November 2006   (final data collection date for primary outcome measure)

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
Female
up to 70 Years
No
Contact information is only displayed when the study is recruiting subjects
Belgium,   France,   Netherlands,   Poland,   Portugal,   Slovenia,   Sweden,   Switzerland,   United Kingdom
 
NCT00017095
EORTC-10994-p53, EORTC-10994, ACCOG-EORTC-10994, SAKK-EORTC-10994, SBGC-EORTC-10994, BIG-1-00
Not Provided
European Organisation for Research and Treatment of Cancer - EORTC
European Organisation for Research and Treatment of Cancer - EORTC
  • Swedish Breast Cancer Group
  • Swiss Group for Clinical Cancer Research
  • Anglo Celtic Cooperative Oncology Group
Study Chair: Herve Bonnefoi Institut Bergonie, Bordeaux
European Organisation for Research and Treatment of Cancer - EORTC
October 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP