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

Abstract

Purpose: MINDACT demonstrated that 46% of patients with early breast cancer at high clinical but low genomic risk on the basis of MammaPrint may safely avoid adjuvant chemotherapy. A second random assignment (R-C) compared docetaxel-capecitabine with an anthracycline-based regimen.

Patients and methods: R-C randomly assigned patients 1:1 between standard anthracycline-based regimens, with or without taxanes (control) and experimental docetaxel 75 mg/m2 intravenously plus oral capecitabine 825 mg/m2 two times per day for 14 days (DC) every 3 weeks for 6 cycles. The primary end point was disease-free survival (DFS). Secondary end points included overall survival and safety.

Results: Of 2,832 patients, 1,301 (45%) were randomly assigned, and 97% complied with R-C assignment. In the control arm, 29.6% only received taxanes (0.5% of N0 patients). DFS events (n = 148) were much less than required (n = 422) as a result of a lower-than-expected accrual and event rate. At 5 years of median follow-up, DFS was not different between DC (n = 652) and control (n = 649; 90.7% [95% CI, 88% to 92.8%] v 88.8% [95% CI, 85.9% to 91.1%]; hazard ratio [HR], 0.83 [95% CI, 0.60 to 1.15]; P = .26). Overall survival (HR, 0.91 [95% CI, 0.54 to 1.53]) and DFS in the clinical high and genomic high-risk subgroup (86.1% v 88.1%; HR, 0.83 [95% CI, 0.58 to 1.21]) were similar in both arms. DC led to more grade 1 neuropathy (27.1% v 11.2%) and more grade 2 hand/foot syndrome (28.5% v 3.3%) and diarrhea (13.7% v 5.8%). Serious cardiac events occurred in 9 patients (control, n = 4; DC, n = 5). Fifty-three patients developed second cancers (control, n = 32; DC, n = 21; leukemia: 2 v 1). Five treatment-related deaths occurred (control, 2 [0.3%]; DC, 3 [0.5%]).

Conclusion: Although underpowered, this second randomization in MINDACT did not show any improvement in outcome or safety with the use of DC compared with anthracycline-based chemotherapy.

Trial registration: ClinicalTrials.gov NCT00433589.

Conflict of interest statement

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

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/journal/jco/site/ifc.

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Suzette Delaloge

Consulting or Advisory Role: AstraZeneca

Research Funding: AstraZeneca (Inst), Pfizer (Inst), Genentech (Inst), Puma (Inst), Eli Lilly (Inst), Novartis (Inst), Sanofi (Inst)

Travel, Accommodations, Expenses: Pfizer, AstraZeneca, Roche

Martine Piccart

Consulting or Advisory Role: AstraZeneca, Eli Lilly, MSD Oncology, Novartis, Pfizer, Genentech, Crescendo Biologics, Periphagen, HUYA Bioscience International, Debiopharm Group, Odonate Therapeutics, G1 Therapeutics, Menarini, Seattle Genetics, Camel-IDS, Immunomedics, Oncolytics, Radius Health

Research Funding: AstraZeneca (Inst), Eli Lilly (Inst), MSD Oncology (Inst), Novartis (Inst), Pfizer (Inst), Genentech (Inst), Radius Health (Inst), Synthon (Inst), Servier (Inst)

Other Relationship: Radius Health

Laura J. van 't Veer

Employment: Agendia

Leadership: Agendia

Stock and Other Ownership Interests: Agendia

Etienne Brain

Honoraria: Pfizer, Roche, Mylan, Bristol-Myers Squibb

Consulting or Advisory Role: Clinigen Group, Bristol-Myers Squibb (Inst), Bristol-Myers Squibb, Pfizer, Samsung, Pfizer, TLC PharmaChem, G1 Therapeutics

Travel, Accommodations, Expenses: Roche, Pierre Fabre, Pfizer, AstraZeneca, Novartis

Aleksandra Dudek-Peric

Employment: Terumo (I)

Miguel Gil-Gil

Honoraria: Roche, Pfizer, Novartis, Eisai

Consulting or Advisory Role: Daiichi Sankyo, Genomic Health

Travel, Accommodations, Expenses: Roche, Daiichi Sankyo, Pfizer, Kern

Florentine S. Hilbers

Research Funding: Novartis (Inst), Pfizer (Inst), Genentech (Inst)

Zaman Khalil

Consulting or Advisory Role: Amgen (Inst), AstraZeneca (Inst), Celgene (Inst), Genomic Health (Inst), Eli Lilly (Inst), Novartis (Inst), Pfizer (Inst), Eisai (Inst), Roche (Inst), MSD Oncology (Inst)

Travel, Accommodations, Expenses: Roche, Pfizer, Celgene, AstraZeneca, Roche

Susan Knox

Stock and Other Ownership Interests: Eli Lilly

Travel, Accommodations, Expenses: Roche

Sherko Kuemmel

Consulting or Advisory Role: Genentech, Genomic Health, Novartis, AstraZeneca, Amgen, Celgene, Somatex, Daiichi Sankyo, Puma Biotechnology, PFM Medical, Pfizer, MSD Oncology, Eli Lilly, Sonoscape

Travel, Accommodations, Expenses: Roche, Daiichi Sankyo

Jean-Yves Pierga

Consulting or Advisory Role: Genentech, Novartis, Ipsen, AstraZeneca, Pfizer, Puma Biotechnology, Genentech (Inst), MSD Oncology, Genomic Health, Illumina, MSD Oncology (Inst), Daiichi Sankyo

Research Funding: Roche (Inst)

Travel, Accommodations, Expenses: AstraZeneca, Amgen

Isabel T. Rubio

Honoraria: Roche

Alastair M. Thompson

Honoraria: Novartis (I), Pfizer

Research Funding: Genentech (Inst)

Travel, Accommodations, Expenses: Novartis (I), Pfizer

Giuseppe Viale

Honoraria: MSD Oncology, Pfizer

Consulting or Advisory Role: Dako, Genentech, Astellas Pharma, Novartis, Bayer, Daiichi Sankyo, MSD Oncology

Speakers' Bureau: Genentech

Research Funding: Genentech, Ventana Medical Systems (Inst), Dako (Inst), Agilent Technologies (Inst)

Travel, Accommodations, Expenses: Roche, Celgene

Gabriele Zoppoli

Research Funding: ThermoFisher Scientific (Inst)

Patents, Royalties, Other Intellectual Property: AstraZeneca concerning methods for SLFN11 detection in cancer samples and its correlation with clinical outcome; Davide Bedognetti and Wouter Hendricxk from SIDRA Medicine, Doha, concerning in vitro experiments with SLFN11 and cancer models

Travel, Accommodations, Expenses: Novartis, Roche

Uncompensated Relationships: Breast International Group, Roche, International Breast Cancer Study Group, AstraZeneca, European Organisation for Research and Treatment of Cancer

Peter Vuylsteke

Honoraria: Genentech, Novartis, MSD Oncology, Bristol-Myers Squibb, Pfizer

Consulting or Advisory Role: Pfizer

Travel, Accommodations, Expenses: Pfizer

Konstantinos Tryfonidis

Employment: MSD Oncology

Stock and Other Ownership Interests: MSD Oncology

Jan Bogaerts

Stock and Other Ownership Interests: Bristol-Myers Squibb

Travel, Accommodations, Expenses: AstraZeneca

Fatima Cardoso

Consulting or Advisory Role: Roche, Novartis, Pfizer, AstraZeneca, Teva, Astellas Pharma, Merus, Celgene, Eisai, Daiichi Sankyo, Genentech, Merck Sharp & Dohme, Sanofi, Pierre Fabre, Macrogenics, Amgen, GE Healthcare, GlaxoSmithKline, Mylan, Mundipharma, Seattle Genetics, Samsung Bioepis, Medscape, Prime Oncology

Travel, Accommodations, Expenses: Pfizer, Roche, AstraZeneca

No other potential conflicts of interest were reported.

Figures

FIG 1.

CONSORT diagram of randomization in the MINDACT study. (a) The control anthracycline arm was different for patients with LN0 breast cancer and for patients with lymph node (LN)–positive disease, as standard therapies were different for each subgroup at that time and evolved over time during the trial. For LN0 disease, anthracycline-based regimens without taxanes were used and included: cyclophosphamide, doxorubicin, and fluorouracil (FAC or CAF); cyclophosphamide, epirubicin, and fluorouracil (FEC); or 4 cycles of epirubicin followed by 4 cycles of cyclophosphamide, methotrexate, and fluorouracil. For LN-positive disease, the standard regimen was a sequence of 3 cycles of FEC 100 followed by 3 cycles of docetaxel. (b) One patient was found to be ineligible as a result of M1 status at baseline and was censored at time 0 in the analysis of disease-free survival and distant metastases–free survival end points.

FIG 2.

Efficacy end points in the chemotherapy randomization arms of MINDACT. (A) Disease-free survival (DFS; intent-to-treat [ITT] randomization [R-C] population). (B) Distant metastases–free survival (DMFS; ITT R-C population). (C) Overall survival (OS; ITT R-C population). (D) DFS (clinical-high risk [cH]/genomic-high risk [gH]). (E) DMFS (cH/gH). (F) OS (cH/gH). DC, docetaxel-capecitabine; HR, hazard ratio; KM, Kaplan-Meier.

FIG 3.

Forest plots of disease-free survival, by stratification factors. cH, clinical high risk; cL, clinical low risk; DC, docetaxel-capecitabine; gH, genomic high risk; gL, genomic low risk; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; SLNB, sentinel lymph node biopsy.

FIG A1.

Forest plots of overall survival, by stratification factors, among patients randomly assigned between an anthracycline-based chemotherapy regimen (control) and docetaxel-capecitabine (DC). cH, clinical high risk; cL, clinical low risk; gH, genomic high risk; gL, genomic low risk; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; SLNB, sentinel lymph node biopsy.