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

October 23, 2013 updated by: European Organisation for Research and Treatment of Cancer - EORTC

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

1856

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 70 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure
Time Frame
Distant metastasis-free survival
Time Frame: randomization till first evidence recurrence
randomization till first evidence recurrence
Overall survival
Time Frame: randomization till death
randomization till death
Clinical and pathological responses
Time Frame: after 3rd and 6d cycle of chemotherapy
after 3rd and 6d cycle of chemotherapy
Clinical response according to RECIST criteria without pathologic response
Time Frame: after 3rd and 6d cycle of chemotherapy
after 3rd and 6d cycle of chemotherapy
Toxicity according to CTC v2.0
Time Frame: from randomization
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
Time Frame: after 3 and 6 cycles of chemotherapy
after 3 and 6 cycles of chemotherapy
Tumor assessment using cDNA microarray technology
Time Frame: end of treatment
end of treatment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

European Organisation for Research and Treatment of Cancer - EORTC

Collaborators

Swiss Group for Clinical Cancer Research
Swedish Breast Cancer Group
Anglo Celtic Cooperative Oncology Group

Investigators

  • Study Chair: Herve Bonnefoi, Institut Bergonie, Bordeaux

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

March 1, 2001

Primary Completion (Actual)

November 1, 2006

Study Registration Dates

First Submitted

June 6, 2001

First Submitted That Met QC Criteria

January 26, 2003

First Posted (Estimate)

January 27, 2003

Study Record Updates

Last Update Posted (Estimate)

October 24, 2013

Last Update Submitted That Met QC Criteria

October 23, 2013

Last Verified

October 1, 2013

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • EORTC-10994-p53
  • EORTC-10994
  • ACCOG-EORTC-10994
  • SAKK-EORTC-10994
  • SBGC-EORTC-10994
  • BIG-1-00

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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