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
NCT ID: NCT00017095
Last Updated: 2013-10-24
Study Results
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Basic Information
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COMPLETED
PHASE3
1856 participants
INTERVENTIONAL
2001-03-31
Brief Summary
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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
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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.
Conditions
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Keywords
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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non taxane based chemotherapy
either FEC 100 or Canadian CEF or Tailored FEC for 6 cycles
filgrastim
cyclophosphamide
epirubicin hydrochloride
fluorouracil
microarray analysis
immunohistochemistry staining method
laboratory biomarker analysis
biopsy
conventional surgery
neoadjuvant therapy
radiation therapy
taxane based chemotherapy
Docetaxel for 3 cycles followed by Epirubicin/Docetaxel for 3 cycles
docetaxel
epirubicin hydrochloride
microarray analysis
immunohistochemistry staining method
laboratory biomarker analysis
biopsy
conventional surgery
neoadjuvant therapy
radiation therapy
Interventions
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filgrastim
cyclophosphamide
docetaxel
epirubicin hydrochloride
fluorouracil
microarray analysis
immunohistochemistry staining method
laboratory biomarker analysis
biopsy
conventional surgery
neoadjuvant therapy
radiation therapy
Eligibility Criteria
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Inclusion Criteria
* 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
70 Years
FEMALE
No
Sponsors
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Swedish Breast Cancer Group
OTHER
Swiss Cancer Institute
OTHER
Anglo Celtic Cooperative Oncology Group
OTHER
European Organisation for Research and Treatment of Cancer - EORTC
NETWORK
Responsible Party
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Principal Investigators
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Herve Bonnefoi
Role: STUDY_CHAIR
Institut Bergonie, Bordeaux
Locations
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Institut Jules Bordet
Brussels, , Belgium
CHU Liege - Domaine Universitaire du Sart Tilman
Liège, , Belgium
Algemeen Ziekenhuis Sint-Augustinus
Wilrijk, , Belgium
Centre Paul Papin
Angers, , France
Institut Bergonie
Bordeaux, , France
Centre de Lutte Contre le Cancer Georges-Francois Leclerc
Dijon, , France
Centre Hospitalier Departemental
La Roche-sur-Yon, , France
Centre Regional de Lutte Contre le Cancer - Centre Val d'Aurelle
Montpellier, , France
Centre Regional Rene Gauducheau
Nantes-Saint Herblain, , France
Centre Henri Becquerel
Rouen, , France
Centre Rene Huguenin
Saint-Cloud, , France
Centre Paul Strauss
Strasbourg, , France
Centre Alexis Vautrin
Vandœuvre-lès-Nancy, , France
Onze Lieve Vrouwe Gasthuis
Amsterdam, , Netherlands
Leiden University Medical Center
Leiden, , Netherlands
Daniel Den Hoed Cancer Center at Erasmus Medical Center
Rotterdam, , Netherlands
Medical University of Gdansk
Gdansk, , Poland
Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology
Warsaw, , Poland
Hospitais da Universidade de Coimbra (HUC)
Coimbra, , Portugal
Instituto Portugues de Oncologia de Francisco Gentil - Centro Regional de Oncologia de Lisboa, S.A.
Lisbon, , Portugal
Institute of Oncology - Ljubljana
Ljubljana, , Slovenia
Sahlgrenska University Hospital at Gothenburg University
Gothenburg (Goteborg), , Sweden
Lund University Hospital
Lund, , Sweden
Malmo University Hospital
Malmo, , Sweden
Sahlgrenska University Hospital - Molndal at Gothenburg University
Mölndal, , Sweden
Orebro University Hospital
Örebro, , Sweden
Karolinska University Hospital - Huddinge
Stockholm, , Sweden
Uppsala University Hospital
Uppsala, , Sweden
Kantonspital Aarau
Aarau, , Switzerland
Swiss Institute for Applied Cancer Research
Bern, , Switzerland
Inselspital Bern
Bern, , Switzerland
Hopital Cantonal Universitaire de Geneve
Geneva, , Switzerland
Centre Hospitalier Universitaire Vaudois
Lausanne, , Switzerland
UniversitaetsSpital Zuerich
Zurich, , Switzerland
Northern Centre for Cancer Treatment at Newcastle General Hospital
Newcastle upon Tyne, England, United Kingdom
Royal South Hants Hospital
Southampton, England, United Kingdom
Ninewells Hospital and Medical School
Dundee, Scotland, United Kingdom
Edinburgh Cancer Centre at Western General Hospital
Edinburgh, Scotland, United Kingdom
Scottish Cancer Therapy Network
Edinburgh, Scotland, United Kingdom
Countries
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References
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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.
Desmedt C, Di Leo A, de Azambuja E, Larsimont D, Haibe-Kains B, Selleslags J, Delaloge S, Duhem C, Kains JP, Carly B, Maerevoet M, Vindevoghel A, Rouas G, Lallemand F, Durbecq V, Cardoso F, Salgado R, Rovere R, Bontempi G, Michiels S, Buyse M, Nogaret JM, Qi Y, Symmans F, Pusztai L, D'Hondt V, Piccart-Gebhart M, Sotiriou C. Multifactorial approach to predicting resistance to anthracyclines. J Clin Oncol. 2011 Apr 20;29(12):1578-86. doi: 10.1200/JCO.2010.31.2231. Epub 2011 Mar 21.
Bonnefoi H, Piccart M, Bogaerts J, Mauriac L, Fumoleau P, Brain E, Petit T, Rouanet P, Jassem J, Blot E, Zaman K, Cufer T, Lortholary A, Lidbrink E, Andre S, Litiere S, Lago LD, Becette V, Cameron DA, Bergh J, Iggo R; EORTC 10994/BIG 1-00 Study Investigators. TP53 status for prediction of sensitivity to taxane versus non-taxane neoadjuvant chemotherapy in breast cancer (EORTC 10994/BIG 1-00): a randomised phase 3 trial. Lancet Oncol. 2011 Jun;12(6):527-39. doi: 10.1016/S1470-2045(11)70094-8. Epub 2011 May 11.
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.
Collingridge D. Expression of concern--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. 2010 Sep;11(9):813-4. doi: 10.1016/S1470-2045(10)70185-6. Epub 2010 Jul 26. No abstract available.
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.
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. 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. 2007 Dec;8(12):1071-1078. doi: 10.1016/S1470-2045(07)70345-5. Epub 2007 Nov 19.
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.
Chatzipli A, Bonnefoi H, MacGrogan G, Sentis J, Cameron D, Poncet C; EORTC 10994/BIG 1-00 Consortium; Iggo R. Patterns of genomic change in residual disease after neoadjuvant chemotherapy for estrogen receptor-positive and HER2-negative breast cancer. Br J Cancer. 2021 Nov;125(10):1356-1364. doi: 10.1038/s41416-021-01526-3. Epub 2021 Sep 3.
Bonnefoi H, Litiere S, Piccart M, MacGrogan G, Fumoleau P, Brain E, Petit T, Rouanet P, Jassem J, Moldovan C, Bodmer A, Zaman K, Cufer T, Campone M, Luporsi E, Malmstrom P, Werutsky G, Bogaerts J, Bergh J, Cameron DA; EORTC 10994/BIG 1-00 Study investigators. Pathological complete response after neoadjuvant chemotherapy is an independent predictive factor irrespective of simplified breast cancer intrinsic subtypes: a landmark and two-step approach analyses from the EORTC 10994/BIG 1-00 phase III trial. Ann Oncol. 2014 Jun;25(6):1128-36. doi: 10.1093/annonc/mdu118. Epub 2014 Mar 11.
Other Identifiers
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EORTC-10994
Identifier Type: -
Identifier Source: secondary_id
ACCOG-EORTC-10994
Identifier Type: -
Identifier Source: secondary_id
SAKK-EORTC-10994
Identifier Type: -
Identifier Source: secondary_id
SBGC-EORTC-10994
Identifier Type: -
Identifier Source: secondary_id
BIG-1-00
Identifier Type: -
Identifier Source: secondary_id
EORTC-10994-p53
Identifier Type: -
Identifier Source: org_study_id