Genetic Testing or Clinical Assessment in Determining the Need for Chemotherapy in Women With Breast Cancer That Involves No More Than 3 Lymph Nodes

NCT00433589 | Completed Phase 3

• 7 other identifiers: EORTC-100412005-002625-31BIG-3-04EU-20676NOVARTIS-EORTC-10041ROCHE-EORTC-10041SANOFI-AVENTIS-EORTC-10041
• Study Type: interventional
• Target: 6,600
• Locations: 1 country
• Sites: 1

Brief Summary

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. Estrogen can cause the growth of breast cancer cells. Hormone therapy using tamoxifen may fight breast cancer by blocking the use of estrogen by the tumor cells. Letrozole may fight breast cancer by lowering the amount of estrogen the body makes. Giving chemotherapy and hormone therapy after surgery may kill any tumor cells that remain after surgery. It is not yet known whether genetic testing is more effective than clinical assessment in determining the need for chemotherapy in treating breast cancer. PURPOSE: This randomized phase III trial is studying genetic testing to see how well it works compared with clinical assessment in determining the need for chemotherapy in women with breast cancer that is either node-negative or involves no more than 3 lymph nodes.

Conditions

Breast Cancer

Keywords

invasive ductal breast carcinoma; invasive lobular breast carcinoma; stage IA breast cancer; stage IB breast cancer; stage II breast cancer; estrogen receptor-positive breast cancer; progesterone receptor-positive breast cancer

Outcome Measures

Primary Outcomes (3)

• Distant metastasis-free survival at 5 years

  o The primary endpoint for chemotherapy versus no chemotherapy (R-T) is that the 5-year distant metastasis free survival (DMFS) of 92% will be tested (a one-sided test).

  from enrollment/randomization

• Disease-free survival (DFS)

  o The primary endpoint for the chemotherapy randomization (R-C) is disease free survival (DFS).

  from enrollment/randomization

• DFS

  The primary test for the endocrine randomization (R-E) is DFS.

  from enrollment/randomization

Secondary Outcomes (8)

• Proportion of patients treated with chemotherapy based on clinical prognosis compared to 70-gene signature prognosis

  from enrollment

• Overall survival at 5 years

  from enrollment/randomization

• DFS at 5 years

  from enrollment/randomization

• Safety (early and late)

  from registration

• Overall survival at 5 years

  from enrollment/randomization

Study Arms (6)

Chemotherapy randomization: Arm I (anthracycline-based)

ACTIVE COMPARATOR

* FEC 100 * Canadian CEF * CAF * FAC * E-CMF

Drug: anthracycline-based

Chemotherapy randomization: Arm II (docetaxel and capecitabine)

EXPERIMENTAL

* Docetaxel * Capecitabine

Drug: docetaxel and capecitabine

Endocrine therapy randomization: Arm I

ACTIVE COMPARATOR

2 years of tamoxifen followed by 5 years of letrozole

Drug: tamoxifen; Drug: Letrozole

Endocrine therapy randomization: Arm II

EXPERIMENTAL

7 years of letrozole

Drug: Letrozole

Treatment decision randomization: Arm I

ACTIVE COMPARATOR

chemotherapy-decision-making according to clinical criteria (using Adjuvant! Online)

Drug: anthracycline-based; Drug: docetaxel and capecitabine

Treatment decision randomization: Arm II

EXPERIMENTAL

chemotherapy-decision-making according to genomic prognosis using the 70-gene signature

Drug: anthracycline-based; Drug: docetaxel and capecitabine

Interventions

anthracycline-based DRUG

Chemotherapy randomization: Arm I (anthracycline-based); Treatment decision randomization: Arm I; Treatment decision randomization: Arm II

docetaxel and capecitabine DRUG

Chemotherapy randomization: Arm II (docetaxel and capecitabine); Treatment decision randomization: Arm I; Treatment decision randomization: Arm II

tamoxifen DRUG

Endocrine therapy randomization: Arm I

Letrozole DRUG

Endocrine therapy randomization: Arm I; Endocrine therapy randomization: Arm II

Eligibility Criteria

• Age: 18 Years - 120 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

DISEASE CHARACTERISTICS: * Histologically confirmed invasive breast cancer meeting the following criteria: * T1, T2, or operable T3 disease * Zero to three positive lymph nodes and no distant metastases * Unilateral tumor * Multifocal tumors are allowed provided that they have identical histology * Ductal carcinoma in situ or lobular carcinoma in situ allowed * Operable disease * Must have undergone breast-conserving surgery or mastectomy with either a sentinel node procedure or full axillary clearance * Radiotherapy is mandatory in the case of breast-conserving surgery * Unresectable positive deep margins and will receive adjuvant radiotherapy provided that all other margins negative allowed * Patients eligible for inclusion in the chemotherapy randomization must meet one of the following criteria: * High-risk of recurrence according to both the clinical-pathological criteria and the 70-gene signature * High risk of recurrence according to the clinical-pathological criteria and low-risk of recurrence according to the 70-gene signature and are randomized to use the clinical-pathological criteria for chemotherapy decision * Low-risk of recurrence according to the clinical-pathological criteria and high-risk of recurrence according to the 70-gene signature and are randomized to use the 70-gene signature for chemotherapy decision * Patients eligible for inclusion in the endocrine therapy randomization must meet all of the following criteria: * Endocrine-responsive disease * Hormone receptor-positive disease (estrogen receptor-positive, progesterone receptor-positive, or both) PATIENT CHARACTERISTICS: * Female * WHO performance status 0-1 * Neutrophil count \> 1,500/mm\^3 * Platelet count \> 100,000/mm\^3 * Creatinine clearance at least 50 mL/min OR creatinine up to 1.5 times upper limit of normal (ULN) * ALT and AST up to 2.5 times ULN * Alkaline phosphatase up to 2.5 times ULN * Bilirubin up to 2.0 times ULN * Normal echocardiogram (ECHO) compatible with chemotherapy treatment * No serious cardiac illness or medical condition including, but not limited to, any of the following: * History of documented congestive heart failure * High-risk uncontrolled arrhythmias * Angina pectoris requiring antianginal medication * Clinically significant valvular heart disease * Evidence of transmural infarction on ECG * Poorly controlled hypertension (e.g., systolic blood pressure \[BP\] \> 180 mm Hg or diastolic BP \> 100 mm Hg) * Symptomatic coronary artery disease or a myocardial infarction within the past 12 months * Other risk factors that contraindicate the use of anthracycline-based chemotherapy * No serious uncontrolled infection or other serious uncontrolled disease * No other cancer within the past 5 years except for adequately treated carcinoma in situ of the cervix, nonmelanoma skin cancer, lobular or ductal carcinoma in situ of the breast, or any invasive cancer (other than breast cancer) * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective barrier contraception * No psychological, familial, sociological, or geographical condition that would preclude study treatment * No psychiatric disability * No history of uncontrolled seizures or CNS disorders * Patients eligible for inclusion in the chemotherapy randomization must meet all of the following additional criteria: * LVEF normal by ECHO or MUGA * No prior severe hypersensitivity reaction to drugs formulated with polysorbate 80 * Must have physical integrity of the upper gastrointestinal tract * Able to swallow tablets * No malabsorption syndrome * No prior thromboembolic disorder, deep vein thrombosis, or pulmonary emboli (for patients eligible for inclusion in the endocrine therapy randomization) PRIOR CONCURRENT THERAPY: * See Disease Characteristics * No prior neoadjuvant chemotherapy, neoadjuvant endocrine therapy, or radiotherapy for primary breast cancer * No participation in another investigational drug study within the past 4 weeks * No systemic hormone replacement therapy (with or without progestins) for more than 3 months in duration * Patients eligible for inclusion in the chemotherapy randomization must meet all of the following additional criteria: * Interval between definitive surgery and start of chemotherapy 8-18 weeks * No prior organ allografts requiring immunosuppressive therapy * No concurrent sorivudine or chemically related analogues, such as brivudine * Patients eligible for inclusion in the endocrine therapy randomization must meet all of the following additional criteria: * No prior high-dose systemic corticosteroids (except as antiemetic treatment), immunotherapy, or biological response modifiers (e.g., interferon) * No prior adjuvant antiestrogen therapy for \> 1 month immediately after surgery, radiotherapy, and/or chemotherapy * No hormone replacement therapy within the past 4 weeks * No antiestrogens (e.g., tamoxifen or raloxifen) as chemoprevention or osteoporosis treatment for breast cancer within the past 18 months * No concurrent primary prophylaxis with filgrastim (G-CSF), sargramostim (GM-CSF), or pegfilgrastim * No other concurrent treatment during endocrine therapy, including the following: * Anticancer therapy (anti-estrogens, aromatase inhibitors, chemotherapy) * Investigational agents * Raloxifene or other selective estrogen-receptor modulators * Hormonal contraceptives (including depot injections and implants) * Intrauterine devices, including progesterone-coated, allowed * Oral or transdermal hormonal treatments, including estrogen, progesterone, androgen, or aromatase inhibitor * Local vaginal (topical) estrogens with minimal systemic absorption allowed for severe vaginal dryness/dyspareunia * Concurrent bisphosphonates allowed

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• European Organisation for Research and Treatment of Cancer - EORTC: lead
• Agendia: collaborator
• Breast International Group: collaborator
• Roche Pharma AG: collaborator
• Novartis: collaborator
• Sanofi: collaborator

Study Sites (1)

Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital

Amsterdam, Netherlands

Location

Related Publications (11)

• Mook S, Bonnefoi H, Pruneri G, Larsimont D, Jaskiewicz J, Sabadell MD, MacGrogan G, Van't Veer LJ, Cardoso F, Rutgers EJ. Daily clinical practice of fresh tumour tissue freezing and gene expression profiling; logistics pilot study preceding the MINDACT trial. Eur J Cancer. 2009 May;45(7):1201-1208. doi: 10.1016/j.ejca.2009.01.004. Epub 2009 Feb 14.

  PMID: 19232484 BACKGROUND

• Cardoso F, Van't Veer L, Rutgers E, Loi S, Mook S, Piccart-Gebhart MJ. Clinical application of the 70-gene profile: the MINDACT trial. J Clin Oncol. 2008 Feb 10;26(5):729-35. doi: 10.1200/JCO.2007.14.3222.

  PMID: 18258980 BACKGROUND

• Cardoso F, Piccart-Gebhart M, Van't Veer L, Rutgers E; TRANSBIG Consortium. The MINDACT trial: the first prospective clinical validation of a genomic tool. Mol Oncol. 2007 Dec;1(3):246-51. doi: 10.1016/j.molonc.2007.10.004. Epub 2007 Oct 22.

  PMID: 19383299 BACKGROUND

• Mook S, Van't Veer LJ, Rutgers EJ, Piccart-Gebhart MJ, Cardoso F. Individualization of therapy using Mammaprint: from development to the MINDACT Trial. Cancer Genomics Proteomics. 2007 May-Jun;4(3):147-55.

  PMID: 17878518 BACKGROUND

• Bogaerts J, Cardoso F, Buyse M, Braga S, Loi S, Harrison JA, Bines J, Mook S, Decker N, Ravdin P, Therasse P, Rutgers E, van 't Veer LJ, Piccart M; TRANSBIG consortium. Gene signature evaluation as a prognostic tool: challenges in the design of the MINDACT trial. Nat Clin Pract Oncol. 2006 Oct;3(10):540-51. doi: 10.1038/ncponc0591.

  PMID: 17019432 BACKGROUND

• Viale G, Slaets L, Bogaerts J, Rutgers E, Van't Veer L, Piccart-Gebhart MJ, de Snoo FA, Stork-Sloots L, Russo L, Dell'Orto P, van den Akker J, Glas A, Cardoso F; TRANSBIG Consortium & the MINDACT Investigators. High concordance of protein (by IHC), gene (by FISH; HER2 only), and microarray readout (by TargetPrint) of ER, PgR, and HER2: results from the EORTC 10041/BIG 03-04 MINDACT trial. Ann Oncol. 2014 Apr;25(4):816-823. doi: 10.1093/annonc/mdu026.

  PMID: 24667714 RESULT

• Rutgers E, Piccart-Gebhart MJ, Bogaerts J, Delaloge S, Veer LV, Rubio IT, Viale G, Thompson AM, Passalacqua R, Nitz U, Vindevoghel A, Pierga JY, Ravdin PM, Werutsky G, Cardoso F. The EORTC 10041/BIG 03-04 MINDACT trial is feasible: results of the pilot phase. Eur J Cancer. 2011 Dec;47(18):2742-9. doi: 10.1016/j.ejca.2011.09.016. Epub 2011 Nov 1.

  PMID: 22051734 RESULT

• Alaeikhanehshir S, Ajayi T, Duijnhoven FH, Poncet C, Olaniran RO, Lips EH, van 't Veer LJ, Delaloge S, Rubio IT, Thompson AM, Cardoso F, Piccart M, Rutgers EJT. Locoregional Breast Cancer Recurrence in the European Organisation for Research and Treatment of Cancer 10041/BIG 03-04 MINDACT Trial: Analysis of Risk Factors Including the 70-Gene Signature. J Clin Oncol. 2024 Apr 1;42(10):1124-1134. doi: 10.1200/JCO.22.02690. Epub 2024 Jan 19.

  PMID: 38241603 DERIVED

• Piccart M, van 't Veer LJ, Poncet C, Lopes Cardozo JMN, Delaloge S, Pierga JY, Vuylsteke P, Brain E, Vrijaldenhoven S, Neijenhuis PA, Causeret S, Smilde TJ, Viale G, Glas AM, Delorenzi M, Sotiriou C, Rubio IT, Kummel S, Zoppoli G, Thompson AM, Matos E, Zaman K, Hilbers F, Fumagalli D, Ravdin P, Knox S, Tryfonidis K, Peric A, Meulemans B, Bogaerts J, Cardoso F, Rutgers EJT. 70-gene signature as an aid for treatment decisions in early breast cancer: updated results of the phase 3 randomised MINDACT trial with an exploratory analysis by age. Lancet Oncol. 2021 Apr;22(4):476-488. doi: 10.1016/S1470-2045(21)00007-3. Epub 2021 Mar 12.

  PMID: 33721561 DERIVED

• Delaloge S, Piccart M, Rutgers E, Litiere S, van 't Veer LJ, van den Berkmortel F, Brain E, Dudek-Peric A, Gil-Gil M, Gomez P, Hilbers FS, Khalil Z, Knox S, Kuemmel S, Kunz G, Lesur A, Pierga JY, Ravdin P, Rubio IT, Saghatchian M, Smilde TJ, Thompson AM, Viale G, Zoppoli G, Vuylsteke P, Tryfonidis K, Poncet C, Bogaerts J, Cardoso F; MINDACT investigators and the TRANSBIG Consortium. Standard Anthracycline Based Versus Docetaxel-Capecitabine in Early High Clinical and/or Genomic Risk Breast Cancer in the EORTC 10041/BIG 3-04 MINDACT Phase III Trial. J Clin Oncol. 2020 Apr 10;38(11):1186-1197. doi: 10.1200/JCO.19.01371. Epub 2020 Feb 21.

  PMID: 32083990 DERIVED

• Cardoso F, van't Veer LJ, Bogaerts J, Slaets L, Viale G, Delaloge S, Pierga JY, Brain E, Causeret S, DeLorenzi M, Glas AM, Golfinopoulos V, Goulioti T, Knox S, Matos E, Meulemans B, Neijenhuis PA, Nitz U, Passalacqua R, Ravdin P, Rubio IT, Saghatchian M, Smilde TJ, Sotiriou C, Stork L, Straehle C, Thomas G, Thompson AM, van der Hoeven JM, Vuylsteke P, Bernards R, Tryfonidis K, Rutgers E, Piccart M; MINDACT Investigators. 70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer. N Engl J Med. 2016 Aug 25;375(8):717-29. doi: 10.1056/NEJMoa1602253.

  PMID: 27557300 DERIVED

Related Links

• Clinical trial summary from the EORTC website

MeSH Terms

Conditions

Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Lobular

Interventions

Docetaxel; Capecitabine; Tamoxifen; Letrozole

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Carcinoma, Ductal; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms, Ductal, Lobular, and Medullary

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Stilbenes; Benzylidene Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Nitriles; Triazoles; Azoles

Study Officials

• Emiel Rutgers, MD, PhD

  The Netherlands Cancer Institute

  STUDY CHAIR

• Martine Piccart-Gebhart, MD, PhD

  Jules Bordet Institute

  STUDY CHAIR

• Fatima Cardoso, MD

  Champalimaud Cancer Center

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 8, 2007
• First Posted: February 12, 2007
• Study Start: February 1, 2007
• Primary Completion: March 1, 2020
• Study Completion: March 1, 2020
• Last Updated: November 17, 2022

Record last verified: 2022-11

Locations

NL (1)