Clinical trial NCT00017095: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Breast Cancer
Keywords: stage II breast cancer
stage IIIA breast cancer
stage IIIB breast cancer
stage IIIC breast cancer
inflammatory breast cancer
Lead sponsor: European Organisation for Research and Treatment of Cancer - EORTC
Sponsor class: NETWORK
Collaborators: name: Swedish Breast Cancer Group
name: Swiss Group for Clinical Cancer Research
name: Anglo Celtic Cooperative Oncology Group
First posted: 2003-01-27
Enrollment: 1856
Sex: FEMALE
Maximum age (years): 70
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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 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

Primary outcomes:
measure: Progression-free survival
timeFrame: from randomization till first evidence of progression
Secondary outcomes:
measure: Distant metastasis-free survival
timeFrame: randomization till first evidence recurrence
measure: Overall survival
timeFrame: randomization till death
measure: Clinical and pathological responses
timeFrame: after 3rd and 6d cycle of chemotherapy
measure: Clinical response according to RECIST criteria without pathologic response
timeFrame: after 3rd and 6d cycle of chemotherapy
measure: Toxicity according to CTC v2.0
timeFrame: from randomization
measure: 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
timeFrame: after 3 and 6 cycles of chemotherapy
measure: Tumor assessment using cDNA microarray technology
timeFrame: end of treatment
Other outcomes:
Locations:
city: Brussels
country: Belgium
facility: Institut Jules Bordet
city: Liege
country: Belgium
facility: CHU Liege - Domaine Universitaire du Sart Tilman
city: Wilrijk
country: Belgium
facility: Algemeen Ziekenhuis Sint-Augustinus
city: Angers
country: France
facility: Centre Paul Papin
city: Bordeaux
country: France
facility: Institut Bergonie
city: Dijon
country: France
facility: Centre de Lutte Contre le Cancer Georges-Francois Leclerc
city: La Roche Sur Yon
country: France
facility: Centre Hospitalier Departemental
city: Montpellier
country: France
facility: Centre Regional de Lutte Contre le Cancer - Centre Val d'Aurelle
city: Nantes-Saint Herblain
country: France
facility: Centre Regional Rene Gauducheau
city: Rouen
country: France
facility: Centre Henri Becquerel
city: Saint Cloud
country: France
facility: Centre Rene Huguenin
city: Strasbourg
country: France
facility: Centre Paul Strauss
city: Vandoeuvre-les-Nancy
country: France
facility: Centre Alexis Vautrin
city: Amsterdam
country: Netherlands
facility: Onze Lieve Vrouwe Gasthuis
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Rotterdam
country: Netherlands
facility: Daniel Den Hoed Cancer Center at Erasmus Medical Center
city: Gdansk
country: Poland
facility: Medical University of Gdansk
city: Warsaw
country: Poland
facility: Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology
city: Coimbra
country: Portugal
facility: Hospitais da Universidade de Coimbra (HUC)
city: Lisbon
country: Portugal
facility: Instituto Portugues de Oncologia de Francisco Gentil - Centro Regional de Oncologia de Lisboa, S.A.
city: Ljubljana
country: Slovenia
facility: Institute of Oncology - Ljubljana
city: Gothenburg (Goteborg)
country: Sweden
facility: Sahlgrenska University Hospital at Gothenburg University
city: Lund
country: Sweden
facility: Lund University Hospital
city: Malmo
country: Sweden
facility: Malmo University Hospital
city: Molndal
country: Sweden
facility: Sahlgrenska University Hospital - Molndal at Gothenburg University
city: Orebro
country: Sweden
facility: Orebro University Hospital
city: Stockholm
country: Sweden
facility: Karolinska University Hospital - Huddinge
city: Uppsala
country: Sweden
facility: Uppsala University Hospital
city: Aarau
country: Switzerland
facility: Kantonspital Aarau
city: Bern
country: Switzerland
facility: Swiss Institute for Applied Cancer Research
city: Bern
country: Switzerland
facility: Inselspital Bern
city: Geneva
country: Switzerland
facility: Hopital Cantonal Universitaire de Geneve
city: Lausanne
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois
city: Zurich
country: Switzerland
facility: UniversitaetsSpital Zuerich
city: Newcastle Upon Tyne
country: United Kingdom
facility: Northern Centre for Cancer Treatment at Newcastle General Hospital
state: England
city: Southampton
country: United Kingdom
facility: Royal South Hants Hospital
state: England
city: Dundee
country: United Kingdom
facility: Ninewells Hospital and Medical School
state: Scotland
city: Edinburgh
country: United Kingdom
facility: Edinburgh Cancer Centre at Western General Hospital
state: Scotland
city: Edinburgh
country: United Kingdom
facility: Scottish Cancer Therapy Network
state: Scotland
Study officials:
affiliation: Institut Bergonie, Bordeaux
name: Herve Bonnefoi
role: STUDY_CHAIR
References:
citation: Bonnefoi H, Potti A, Delorenzi M, Mauriac L, Campone M, Tubiana-Hulin M, Petit T, Rouanet P, Jassem J, Blot E, Becette V, Farmer P, Andre S, Acharya CR, Mukherjee S, Cameron D, Bergh J, Nevins JR, Iggo RD. Retraction--Validation of gene signatures that predict the response of breast cancer to neoadjuvant chemotherapy: a substudy of the EORTC 10994/BIG 00-01 clinical trial. Lancet Oncol. 2011 Feb;12(2):116. doi: 10.1016/S1470-2045(11)70011-0. No abstract available.
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