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

Breast Cancer Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00017095
• Other study ID #: EORTC-10994-p53
• Secondary ID: EORTC-10994ACCOG
• Status: Completed
• Phase: Phase 3
• First received: June 6, 2001
• Last updated: October 23, 2013
• Start date: March 2001

Study information

• Verified date: October 2013
• Source: European Organisation for Research and Treatment of Cancer - EORTC
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1856
• Est. primary completion date: November 2006
• Accepts healthy volunteers: No
• Gender: Female
• Age group: N/A to 70 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Biological:
• filgrastim

Drug:
• cyclophosphamide

• docetaxel

• epirubicin hydrochloride

• fluorouracil

Genetic:
• microarray analysis

Other:
• immunohistochemistry staining method

• laboratory biomarker analysis

Procedure:
• biopsy

• conventional surgery

• neoadjuvant therapy

Radiation:
• radiation therapy

Locations

Country	Name	City	State
Belgium	Institut Jules Bordet	Brussels
Belgium	CHU Liege - Domaine Universitaire du Sart Tilman	Liege
Belgium	Algemeen Ziekenhuis Sint-Augustinus	Wilrijk
France	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	Vandoeuvre-les-Nancy
Netherlands	Onze Lieve Vrouwe Gasthuis	Amsterdam
Netherlands	Leiden University Medical Center	Leiden
Netherlands	Daniel Den Hoed Cancer Center at Erasmus Medical Center	Rotterdam
Poland	Medical University of Gdansk	Gdansk
Poland	Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology	Warsaw
Portugal	Hospitais da Universidade de Coimbra (HUC)	Coimbra
Portugal	Instituto Portugues de Oncologia de Francisco Gentil - Centro Regional de Oncologia de Lisboa, S.A.	Lisbon
Slovenia	Institute of Oncology - Ljubljana	Ljubljana
Sweden	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	Molndal
Sweden	Orebro University Hospital	Orebro
Sweden	Karolinska University Hospital - Huddinge	Stockholm
Sweden	Uppsala University Hospital	Uppsala
Switzerland	Kantonspital Aarau	Aarau
Switzerland	Inselspital Bern	Bern
Switzerland	Swiss Institute for Applied Cancer Research	Bern
Switzerland	Hopital Cantonal Universitaire de Geneve	Geneva
Switzerland	Centre Hospitalier Universitaire Vaudois	Lausanne
Switzerland	UniversitaetsSpital Zuerich	Zurich
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	Northern Centre for Cancer Treatment at Newcastle General Hospital	Newcastle Upon Tyne	England
United Kingdom	Royal South Hants Hospital	Southampton	England

Sponsors (4)

Lead Sponsor	Collaborator
European Organisation for Research and Treatment of Cancer - EORTC	Anglo Celtic Cooperative Oncology Group, Swedish Breast Cancer Group, Swiss Group for Clinical Cancer Research

Countries where clinical trial is conducted

Belgium,  France,  Netherlands,  Poland,  Portugal,  Slovenia,  Sweden,  Switzerland,  United Kingdom, 

References & Publications (10)

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 i

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, André S, Litière S, Lago LD, Becette V, Cameron DA, Bergh J, Iggo R; EORTC 10994/BIG 1-00 Study Investigat — View 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, André 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. — View 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, André S, Acharya CR, Mukherjee S, Cameron D, Bergh J, Nevins JR, Iggo RD. Validation of gene signatures that predict the re — View Citation

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 Antoni

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

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/S1470-204 — View Citation

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. — View Citation

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.

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/infla

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free survival		from randomization till first evidence of progression	No
Secondary	Distant metastasis-free survival		randomization till first evidence recurrence	No
Secondary	Overall survival		randomization till death	No
Secondary	Clinical and pathological responses		after 3rd and 6d cycle of chemotherapy	No
Secondary	Clinical response according to RECIST criteria without pathologic response		after 3rd and 6d cycle of chemotherapy	No
Secondary	Toxicity according to CTC v2.0		from randomization	Yes
Secondary	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		after 3 and 6 cycles of chemotherapy	No
Secondary	Tumor assessment using cDNA microarray technology		end of treatment	No