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

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ClinicalTrials.gov Identifier: NCT00433589

Recruitment Status : Completed

First Posted : February 12, 2007

Last Update Posted : November 17, 2022

View this study on the modernized ClinicalTrials.gov

Sponsor:

Collaborators:

Agendia

Breast International Group

Roche Pharma AG

Novartis

Sanofi

Information provided by (Responsible Party):

European Organisation for Research and Treatment of Cancer - EORTC

Tracking Information

First Submitted Date ^ICMJE

February 8, 2007

First Posted Date ^ICMJE

February 12, 2007

Last Update Posted Date

November 17, 2022

Study Start Date ^ICMJE

February 2007

Actual Primary Completion Date

March 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures ^ICMJE

Distant metastasis-free survival at 5 years [ Time Frame: from enrollment/randomization ]
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).
Disease-free survival (DFS) [ Time Frame: from enrollment/randomization ]
o The primary endpoint for the chemotherapy randomization (R-C) is disease free survival (DFS).
DFS [ Time Frame: from enrollment/randomization ]
The primary test for the endocrine randomization (R-E) is DFS.

Original Primary Outcome Measures ^ICMJE

Distant metastasis-free survival at 5 years
Disease-free survival (DFS)

Change History

Current Secondary Outcome Measures ^ICMJE

Proportion of patients treated with chemotherapy based on clinical prognosis compared to 70-gene signature prognosis [ Time Frame: from enrollment ]
For R-T randomization
Overall survival at 5 years [ Time Frame: from enrollment/randomization ]
For R-T randomization
DFS at 5 years [ Time Frame: from enrollment/randomization ]
For R-T randomization
Safety (early and late) [ Time Frame: from registration ]
For R-C randomization
Overall survival at 5 years [ Time Frame: from enrollment/randomization ]
For R-C randomization
DMFS at 5 years [ Time Frame: from enrollment/randomization ]
For R-C randomization
Overall survival at 5 years [ Time Frame: from enrollment/randomization ]
For R-E randomization
DMFS at 5 years [ Time Frame: from enrollment/randomization ]
For R-E randomization

Original Secondary Outcome Measures ^ICMJE

Proportion of women treated with chemotherapy per clinical prognosis compared to 70-gene signature prognosis
Overall survival at 5 years
DFS at 5 years
Safety (early and late)

Current Other Pre-specified Outcome Measures

Not Provided

Original Other Pre-specified Outcome Measures

Not Provided

Descriptive Information

Brief Title ^ICMJE

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

Official Title ^ICMJE

MINDACT (Microarray In Node-Negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy): A Prospective, Randomized Study Comparing the 70-Gene Signature With the Common Clinical-Pathological Criteria in Selecting Patients for Adjuvant Chemotherapy in Breast Cancer With 0 to 3 Positive Nodes

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.

Detailed Description

OBJECTIVES:

Primary

Compare a molecular profiling approach (70-gene signature) vs usual clinical assessment in assigning adequate risk categories (and the need to receive adjuvant chemotherapy or not) to breast cancer patients with 0-3 positive lymph nodes.
Compare the efficacy and long-term toxicities of docetaxel and capecitabine vs standard anthracycline-based chemotherapy regimens in these patients.
Determine the best endocrine treatment strategy (i.e., letrozole for 7 years vs sequential tamoxifen for 2 years followed by letrozole for 5 years) in these patients.

Secondary

Compare both relative (hazard ratio) and absolute (percentage at 5 years) efficacy of these regimens, in terms of disease-free survival (DFS), distant metastasis-free survival (DMFS), and overall survival (OS), in these patients.
Determine overall estimates of efficacy (DFS, DMFS, OS) for each treatment strategy according to clinical-pathological prognosis and molecular prognosis in these patients.
Estimate the percentage of patients receiving chemotherapy per each prognostic method.
Identify predictive gene expression profiles of clinical response/resistance to anthracycline-based and docetaxel-capecitabine chemotherapy in these patients.
Compare novel gene expression signatures predicting clinical response in patients treated with sequential tamoxifen-letrozole vs letrozole alone.
Compare the OS distributions in patients treated with these regimens.
Compare the early and late toxicities of these regimens in these patients.
Evaluate adjuvant endocrine treatment success or failure in the subgroup of postmenopausal patients with endocrine-responsive disease.
Compare the safety profile of these two endocrine therapy regimens in these patients.

OUTLINE: This is a partially randomized, open-label, prospective, multicenter study.

Patients with both clinical high-risk (CHR) and genomic high-risk (GHR) disease are assigned to receive chemotherapy. Patients with both clinical low-risk (CLR) and genomic low-risk (GLR) disease do not receive chemotherapy. Patients with discordant risk between the 2 decision-making tools (standard clinical-pathological criteria vs 70-gene signature criteria) are randomized to receive chemotherapy or not. Patients with HER-2 positive tumors which have both methods discordant and were randomized to no chemotherapy, can receive adjuvant trastuzumab alone or with adjuvant endocrine therapy (if hormonal receptor positive), if decided by the treating physician. Patients with HER-2 positive tumors that are classified low-risk by both methods can receive adjuvant trastuzumab alone or with adjuvant endocrine therapy (if hormonal receptor positive), if decided by the treating physician and if no issues for trastuzumab reimbursement exist in the investigator's country.

Chemotherapy: Patients are stratified according to participating center, risk group (GHR/CLR vs GLR/CHR), hormone receptor status (estrogen receptor [ER] positive and/or progesterone receptor [PR] positive vs ER and PR negative), age (< 50 years vs at least 50 years), HER2/neu status (positive vs negative vs unknown), method of axillary evaluation (sentinel only vs dissection), and type of surgery (mastectomy vs quadrantectomy/tumorectomy). In case PR is unknown, the patient will be stratified to the hormone receptor (HR) negative group if ER is negative, and to the HR positive group if ER is positive.

Three randomizations took place:

One randomization on the discordant groups (where clinical risk did not match genomic risk) in treatment decision (R-T).
One randomization for patients who are candidates for chemotherapy (R-C): randomization between anthracycline based chemotherapy and taxane/capecitabine chemotherapy.
One randomization for patients who are candidates for endocrine therapy (R-E): randomization between 2 years of tamoxifen followed by 5 years of letrozole and 7 years of letrozole.

For the treatment decision randomization, patients for whom both methods are discordant will be randomized (R-T) between chemotherapy-decision-making according to clinical criteria (using Adjuvant! Online) or chemotherapy-decision-making according to genomic prognosis using the 70-gene signature.

For the chemotherapy randomization, patients are randomized to 1 of 2 treatment arms.

Arm I (anthracycline-based): Patients may receive 1 of the following regimens*:
- FEC 100: Patients receive fluorouracil IV, epirubicin hydrochloride IV, and cyclophosphamide IV on day 1. Treatment repeats every 3 weeks for 6 courses.
- Canadian CEF: Patients receive oral cyclophosphamide on days 1-14 (or IV on days 1 and 8) and epirubicin hydrochloride IV and fluorouracil IV on days 1 and 8. Treatment repeats every 4 weeks for 6 courses.
- CAF: Patients receive cyclophosphamide IV, doxorubicin hydrochloride IV, and fluorouracil IV on day 1. Treatment repeats every 4 weeks for 6 courses.
- FAC: Patients receive cyclophosphamide IV and doxorubicin hydrochloride IV on day 1 and fluorouracil IV on days 1 and 8. Treatment repeats every 3 weeks for 6 courses.
- E-CMF: Patients receive epirubicin hydrochloride IV on day 1. Treatment repeats every 3 weeks for 4 courses. Patients then receive cyclophosphamide IV, methotrexate IV, and fluorouracil IV on days 1 and 8. Treatment repeats every 4 weeks for 4 courses.

NOTE: *Patients who refuse randomization may be treated with another chemotherapy regimen and still be included in the study.

Arm II (docetaxel and capecitabine): Patients receive docetaxel IV over 1 hour on day 1 and oral capecitabine twice daily on days 1-14. Treatment repeats every 3 weeks for 6 courses.

For the endocrine therapy randomization (all postmenopausal and some premenopausal** patients who have endocrine-responsive tumors***): Patients are stratified according to participating center, risk group (GHR/CHR vs GHR/CLR vs GLR/CHR vs GLR/CLR), adjuvant chemotherapy (no vs nonrandomized vs arm I vs arm II), endocrine sensitivity (both ER and PR positive vs either ER or PR positive), age (< 50 years vs at least 50 years), HER2/neu status (positive vs negative vs unknown), method of axillary evaluation (sentinel only vs dissection), and type of surgery (mastectomy vs quadrantectomy/tumorectomy). In case PR is unknown, the patient will be stratified to the HR negative group if ER is negative, and to the HR positive group if ER is positive.

Therapy begins after prior surgery in patients who did not receive chemotherapy and after chemotherapy in those who did. Patients are randomized to 1 of 2 treatment arms.

Arm I: Patients receive oral tamoxifen citrate once daily for 2 years. Patients then receive oral letrozole once daily for 5 years.
Arm II: Patients receive oral letrozole once daily for 7 years. NOTE: *The first dose of endocrine therapy should be administered within 4 weeks following the randomization (R-E) date. If treatment has not started within 300 days after definitive surgery, the patient becomes ineligible for randomized endocrine therapy.

NOTE: **Premenopausal women (< 50 years) must undergo adequate ovarian suppression (gonadotropin releasing hormone, bilateral oophorectomy, or bilateral ovarian radiation).

NOTE: ***Patients who have endocrine-responsive tumors but refuse randomization should receive standard endocrine therapy and may remain on study.

After completion of study treatment, patients are followed annually for at least 15 years.

FINAL ACCRUAL: A total of 6,694 patients have been accrued for this study.

Study Type ^ICMJE

Interventional

Study Phase ^ICMJE

Phase 3

Study Design ^ICMJE

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment

Condition ^ICMJE

Breast Cancer

Intervention ^ICMJE

Drug: anthracycline-based
Drug: docetaxel and capecitabine
Drug: tamoxifen
Drug: Letrozole

Study Arms ^ICMJE

Active Comparator: Chemotherapy randomization: Arm I (anthracycline-based)
- FEC 100
- Canadian CEF
- CAF
- FAC
- E-CMF
Intervention: Drug: anthracycline-based
Experimental: Chemotherapy randomization: Arm II (docetaxel and capecitabine)
- Docetaxel
- Capecitabine
Intervention: Drug: docetaxel and capecitabine
Active Comparator: Endocrine therapy randomization: Arm I
2 years of tamoxifen followed by 5 years of letrozole
Interventions:
- Drug: tamoxifen
- Drug: Letrozole
Experimental: Endocrine therapy randomization: Arm II
7 years of letrozole

Intervention: Drug: Letrozole
Active Comparator: Treatment decision randomization: Arm I
chemotherapy-decision-making according to clinical criteria (using Adjuvant! Online)
Interventions:
- Drug: anthracycline-based
- Drug: docetaxel and capecitabine
Experimental: Treatment decision randomization: Arm II
chemotherapy-decision-making according to genomic prognosis using the 70-gene signature
Interventions:
- Drug: anthracycline-based
- Drug: docetaxel and capecitabine

Publications *

* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.

Recruitment Information

Recruitment Status ^ICMJE

Completed

Estimated Enrollment ^ICMJE

6600

Original Enrollment ^ICMJE

6000

Actual Study Completion Date ^ICMJE

March 2020

Actual Primary Completion Date

March 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria ^ICMJE

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

Sex/Gender ^ICMJE

Sexes Eligible for Study:

Female

Ages ^ICMJE

18 Years to 120 Years (Adult, Older Adult)

Accepts Healthy Volunteers ^ICMJE

Contacts ^ICMJE

Contact information is only displayed when the study is recruiting subjects

Listed Location Countries ^ICMJE

Netherlands

Removed Location Countries

Administrative Information

NCT Number ^ICMJE

NCT00433589

Other Study ID Numbers ^ICMJE

EORTC-10041
2005-002625-31 ( EudraCT Number )
BIG-3-04
EU-20676
NOVARTIS-EORTC-10041
ROCHE-EORTC-10041
SANOFI-AVENTIS-EORTC-10041

Has Data Monitoring Committee

Not Provided

U.S. FDA-regulated Product

Not Provided

IPD Sharing Statement ^ICMJE

Not Provided

Current Responsible Party

European Organisation for Research and Treatment of Cancer - EORTC

Original Responsible Party

Not Provided

Current Study Sponsor ^ICMJE

European Organisation for Research and Treatment of Cancer - EORTC

Original Study Sponsor ^ICMJE

Same as current

Collaborators ^ICMJE

Agendia
Breast International Group
Roche Pharma AG
Novartis
Sanofi

Investigators ^ICMJE

Study Chair:	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

PRS Account

European Organisation for Research and Treatment of Cancer - EORTC

Verification Date

November 2022

^ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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