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
- 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.
- 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
- 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. 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
- Endocrine therapy* (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.
PROJECTED ACCRUAL: A total of 6,600 patients will be accrued for this study.
Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Distant metastasis-free survival at 5 years
Emiel J. T. Rutgers, MD, PhD, FRCS
The Netherlands Cancer Institute
Belgium: Federal Agency for Medicines and Health Products, FAMHP