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
  Purpose

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.


Condition Intervention Phase
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
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by European Organisation for Research and Treatment of Cancer - EORTC:

Primary Outcome Measures:
  • Progression-free survival [ Time Frame: from randomization till first evidence of progression ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • 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 ]

Enrollment: 1856
Study Start Date: March 2001
Primary Completion Date: November 2006 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: non taxane based chemotherapy
either FEC 100 or Canadian CEF or Tailored FEC for 6 cycles
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
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

  Hide Detailed Description

Detailed 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.

  Eligibility

Ages Eligible for Study:   up to 70 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00017095

  Hide Study Locations
Locations
Belgium
Institut Jules Bordet
Brussels, Belgium, 1000
CHU Liege - Domaine Universitaire du Sart Tilman
Liege, Belgium, B-4000
Algemeen Ziekenhuis Sint-Augustinus
Wilrijk, Belgium, 2610
France
Centre Paul Papin
Angers, France, 49036
Institut Bergonie
Bordeaux, France, 33076
Centre de Lutte Contre le Cancer Georges-Francois Leclerc
Dijon, France, 21079
Centre Hospitalier Departemental
La Roche Sur Yon, France, F-85025
Centre Regional de Lutte Contre le Cancer - Centre Val d'Aurelle
Montpellier, France, 34298
Centre Regional Rene Gauducheau
Nantes-Saint Herblain, France, 44805
Centre Henri Becquerel
Rouen, France, 76038
Centre Rene Huguenin
Saint Cloud, France, 92211
Centre Paul Strauss
Strasbourg, France, 67085
Centre Alexis Vautrin
Vandoeuvre-les-Nancy, France, 54511
Netherlands
Onze Lieve Vrouwe Gasthuis
Amsterdam, Netherlands, 1091 HA
Leiden University Medical Center
Leiden, Netherlands, 2300 CA
Daniel Den Hoed Cancer Center at Erasmus Medical Center
Rotterdam, Netherlands, 3008 AE
Poland
Medical University of Gdansk
Gdansk, Poland, 80-211
Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology
Warsaw, Poland, 02-781
Portugal
Hospitais da Universidade de Coimbra (HUC)
Coimbra, Portugal, 3049
Instituto Portugues de Oncologia de Francisco Gentil - Centro Regional de Oncologia de Lisboa, S.A.
Lisbon, Portugal, 1099-023 Codex
Slovenia
Institute of Oncology - Ljubljana
Ljubljana, Slovenia, Sl-1000
Sweden
Sahlgrenska University Hospital at Gothenburg University
Gothenburg (Goteborg), Sweden, S-413 45
Lund University Hospital
Lund, Sweden, S-22185
Malmo University Hospital
Malmo, Sweden, S-20502
Sahlgrenska University Hospital - Molndal at Gothenburg University
Molndal, Sweden, S-43180
Orebro University Hospital
Orebro, Sweden, 70185
Karolinska University Hospital - Huddinge
Stockholm, Sweden, S-171 76
Uppsala University Hospital
Uppsala, Sweden, S-75185
Switzerland
Kantonspital Aarau
Aarau, Switzerland, 5001
Inselspital Bern
Bern, Switzerland, CH-3010
Swiss Institute for Applied Cancer Research
Bern, Switzerland, CH-3008
Hopital Cantonal Universitaire de Geneve
Geneva, Switzerland, CH-1211
Centre Hospitalier Universitaire Vaudois
Lausanne, Switzerland, CH-1011
UniversitaetsSpital Zuerich
Zurich, Switzerland, CH-8091
United Kingdom
Northern Centre for Cancer Treatment at Newcastle General Hospital
Newcastle Upon Tyne, England, United Kingdom, NE4 6BE
Royal South Hants Hospital
Southampton, England, United Kingdom, SO14 0YG
Ninewells Hospital and Medical School
Dundee, Scotland, United Kingdom, DD1 9SY
Edinburgh Cancer Centre at Western General Hospital
Edinburgh, Scotland, United Kingdom, EH4 2XU
Scottish Cancer Therapy Network
Edinburgh, Scotland, United Kingdom, EH5 3SQ
Sponsors and Collaborators
European Organisation for Research and Treatment of Cancer - EORTC
Swedish Breast Cancer Group
Swiss Group for Clinical Cancer Research
Anglo Celtic Cooperative Oncology Group
Investigators
Study Chair: Herve Bonnefoi Institut Bergonie, Bordeaux
  More Information

Additional Information:
Publications:
Bonnefoi HR, Bogaerts J, Piccart M, et al.: Phase III trial (EORTC 10994/BIG 00-01) assessing the value of p53 using a functional assay to predict sensitivity to a taxane versus nontaxane primary chemotherapy in breast cancer: final analysis. [Abstract] J Clin Oncol 28 (Suppl 18): A-LBA503, 2010.
Bonnefoi H, Zimmer AS, Piccart M, et al.: P53 functional assay in yeast: evaluation in 1856 patients in a large prospective clinical trial: EORTC 10994/BIG 00-01. [Abstract] 31st Annual San Antonio Breast Cancer Symposium, December 10-14, 2008, San Antonio, Texas. A-1067, 2008.
Karina M, Bogaerts J, Piccart M, et al.: Preliminary safety data of the EORTC 10994/BIG 00-01 neoadjuvant trial comparing 3 cycles of docetaxel followed by 3 cycles of epirubicin-docetaxel versus 6 cycles of FEC 100 in patients with locally advanced/inflammatory or large operable breast cancer. [Abstract] Breast Cancer Res Treat 100 (Suppl 1): A-3067, S146-7, 2006.
Bonnefoi H, Farmer P, Delorenzi M, et al.: Is there a regimen-specific gene signature predicting for pathological complete response after neoadjuvant chemotherapy in hormone-negative breast cancer patients? A microarray substudy of 101 patients included in EORTC 10994/BIG 00-01 trial. [Abstract] Breast Cancer Research and Treatment 94 (Suppl 1): A-1040, 2005.
Farmer P, Iggo R, Becette V, et al.: High quality gene expression microarray data from a multicentre prospective trial: results of the first microarray analysis in the EORTC 10994/ BIG 00-01 study. [Abstract] Eur J Cancer 2 (Suppl 3): A-155, 99, 2004.

Responsible Party: European Organisation for Research and Treatment of Cancer - EORTC
ClinicalTrials.gov Identifier: NCT00017095     History of Changes
Other Study ID Numbers: EORTC-10994-p53, EORTC-10994, ACCOG-EORTC-10994, SAKK-EORTC-10994, SBGC-EORTC-10994, BIG-1-00
Study First Received: June 6, 2001
Last Updated: October 23, 2013
Health Authority: United States: Federal Government

Keywords provided by European Organisation for Research and Treatment of Cancer - EORTC:
stage II breast cancer
stage IIIA breast cancer
stage IIIB breast cancer
stage IIIC breast cancer
inflammatory breast cancer

Additional relevant MeSH terms:
Breast Neoplasms
Inflammatory Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Docetaxel
Cyclophosphamide
Fluorouracil
Epirubicin
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Myeloablative Agonists
Antimetabolites
Antimetabolites, Antineoplastic
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on October 01, 2014