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

• Sponsor: European Organisation for Research and Treatment of Cancer - EORTC (Other)
• Overall Status: Completed
• CT.gov ID: NCT00017095
• Collaborator: Swedish Breast Cancer Group (Other), Swiss Group for Clinical Cancer Research (Other), Anglo Celtic Cooperative Oncology Group (Other)
• Enrollment: 1,856
• Locations: 39
• Arms: 2
• Patients Per Site: 47.6

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	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

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 Design

• Study Type: Interventional
• Actual Enrollment: 1856 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (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
• Study Start Date: Mar 1, 2001
• Actual Primary Completion Date: Nov 1, 2006

Arms and Interventions

Arm	Intervention/Treatment
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

Outcome Measures

Primary Outcome Measures

1. Progression-free survival [from randomization till first evidence of progression]

Secondary Outcome Measures

1. Distant metastasis-free survival [randomization till first evidence recurrence]

2. Overall survival [randomization till death]

3. Clinical and pathological responses [after 3rd and 6d cycle of chemotherapy]

4. Clinical response according to RECIST criteria without pathologic response [after 3rd and 6d cycle of chemotherapy]

5. Toxicity according to CTC v2.0 [from randomization]

6. 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]

7. Tumor assessment using cDNA microarray technology [end of treatment]

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 70 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	Institut Jules Bordet	Brussels		Belgium	1000
2	CHU Liege - Domaine Universitaire du Sart Tilman	Liege		Belgium	B-4000
3	Algemeen Ziekenhuis Sint-Augustinus	Wilrijk		Belgium	2610
4	Centre Paul Papin	Angers		France	49036
5	Institut Bergonie	Bordeaux		France	33076
6	Centre de Lutte Contre le Cancer Georges-Francois Leclerc	Dijon		France	21079
7	Centre Hospitalier Departemental	La Roche Sur Yon		France	F-85025
8	Centre Regional de Lutte Contre le Cancer - Centre Val d'Aurelle	Montpellier		France	34298
9	Centre Regional Rene Gauducheau	Nantes-Saint Herblain		France	44805
10	Centre Henri Becquerel	Rouen		France	76038
11	Centre Rene Huguenin	Saint Cloud		France	92211
12	Centre Paul Strauss	Strasbourg		France	67085
13	Centre Alexis Vautrin	Vandoeuvre-les-Nancy		France	54511
14	Onze Lieve Vrouwe Gasthuis	Amsterdam		Netherlands	1091 HA
15	Leiden University Medical Center	Leiden		Netherlands	2300 CA
16	Daniel Den Hoed Cancer Center at Erasmus Medical Center	Rotterdam		Netherlands	3008 AE
17	Medical University of Gdansk	Gdansk		Poland	80-211
18	Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology	Warsaw		Poland	02-781
19	Hospitais da Universidade de Coimbra (HUC)	Coimbra		Portugal	3049
20	Instituto Portugues de Oncologia de Francisco Gentil - Centro Regional de Oncologia de Lisboa, S.A.	Lisbon		Portugal	1099-023 Codex
21	Institute of Oncology - Ljubljana	Ljubljana		Slovenia	Sl-1000
22	Sahlgrenska University Hospital at Gothenburg University	Gothenburg (Goteborg)		Sweden	S-413 45
23	Lund University Hospital	Lund		Sweden	S-22185
24	Malmo University Hospital	Malmo		Sweden	S-20502
25	Sahlgrenska University Hospital - Molndal at Gothenburg University	Molndal		Sweden	S-43180
26	Orebro University Hospital	Orebro		Sweden	70185
27	Karolinska University Hospital - Huddinge	Stockholm		Sweden	S-171 76
28	Uppsala University Hospital	Uppsala		Sweden	S-75185
29	Kantonspital Aarau	Aarau		Switzerland	5001
30	Swiss Institute for Applied Cancer Research	Bern		Switzerland	CH-3008
31	Inselspital Bern	Bern		Switzerland	CH-3010
32	Hopital Cantonal Universitaire de Geneve	Geneva		Switzerland	CH-1211
33	Centre Hospitalier Universitaire Vaudois	Lausanne		Switzerland	CH-1011
34	UniversitaetsSpital Zuerich	Zurich		Switzerland	CH-8091
35	Northern Centre for Cancer Treatment at Newcastle General Hospital	Newcastle Upon Tyne	England	United Kingdom	NE4 6BE
36	Royal South Hants Hospital	Southampton	England	United Kingdom	SO14 0YG
37	Ninewells Hospital and Medical School	Dundee	Scotland	United Kingdom	DD1 9SY
38	Edinburgh Cancer Centre at Western General Hospital	Edinburgh	Scotland	United Kingdom	EH4 2XU
39	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

Study Documents (Full-Text)

None provided.

More Information

Publications

• 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.
• 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.

• Responsible Party: European Organisation for Research and Treatment of Cancer - EORTC
• ClinicalTrials.gov Identifier: NCT00017095
• Other Study ID Numbers: EORTC-10994-p53; EORTC-10994; ACCOG-EORTC-10994; SAKK-EORTC-10994; SBGC-EORTC-10994; BIG-1-00
• First Posted: Jan 27, 2003
• Last Update Posted: Oct 24, 2013
• Last Verified: Oct 1, 2013

• 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; Cyclophosphamide; Docetaxel; Fluorouracil; Epirubicin

Study Results

No Results Posted as of Oct 24, 2013