
==== Front
J Clin Oncol
J Clin Oncol
jco
JCO
Journal of Clinical Oncology
0732-183X
1527-7755
Wolters Kluwer Health

39018515
JCO.24.00178
10.1200/JCO.24.00178
CLINICAL TRIAL UPDATES
Breast Cancer
Tailored Dose-Dense Versus Standard Adjuvant Chemotherapy for High-Risk Early Breast Cancer: End-of-Study Results of the Randomized PANTHER Trial
https://orcid.org/0000-0002-4122-9624
Matikas Alexios MD, PhD 1 2
Möbus Volker MD, PhD 3
https://orcid.org/0000-0002-4462-3694
Greil Richard MD, PhD 4
https://orcid.org/0000-0002-9597-6465
Andersson Anne MD, PhD 5
Steger Günther G. MD 6
https://orcid.org/0000-0002-1233-1267
Untch Michael MD, PhD 7
Fornander Tommy MD, PhD 1
Malmström Per MD, PhD 8 9
Schmatloch Sabine MD 10
Johansson Hemming BSc 1
https://orcid.org/0000-0001-7897-4006
Hellström Mats BSc 2
https://orcid.org/0000-0001-9840-9266
Brandberg Yvonne PhD 1
https://orcid.org/0000-0003-1002-2118
Gnant Michael MD, PhD 11
https://orcid.org/0000-0001-6488-4958
Loibl Sibylle MD, PhD 12
https://orcid.org/0000-0001-8952-9987
Foukakis Theodoros MD, PhD 1 2
https://orcid.org/0000-0001-5526-1847
Bergh Jonas MD, PhD 1 2
the SweBCG, ABCSG and GBG
1 Oncology/Pathology Department, Karolinska Institutet, Stockholm, Sweden
2 Breast Center, Karolinska Comprehensive Cancer Center, Stockholm, Sweden
3 Department of Medicine II, Hematology & Oncology, University of Frankfurt, Frankfurt, Germany
4 3rd Medical Department, Paracelsus Medical University and Salzburg Cancer Research Institute, Cancer Cluster Salzburg and AGMT, Salzburg, Austria
5 Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden
6 Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria
7 Helios Klinikum Berlin-Buch, Berlin, Germany
8 Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
9 Department of Haematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden
10 Elisabeth Hospital, Kassel, Germany
11 Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
12 German Breast Group, Neu-Isenburg, Germany
Lohman Niklas
Söderberg Martin
Malmström Per
Einbeigi Zakaria
Karlsson Per
Linderholm Barbro
Holmberg Stig
Dabrosin Lotta
Hedayati Elham
Villman Kenneth
Rotstein Sam
Wallberg Birgitta
Fornander Tommy
Lindman Henrik
Ahlgren Johan
Edlund Per
Carlsson Lena
Bengtsson Nils-Olof
Karlsson Eva
Schmatloch Sabine
Kögel Matthias
Kohls Andreas
Grischke Eva-Maria
Baake Gerold
Hoffmann Gerald
Dietrich Maria
Möbus Volker
Adrion Ralf
Heyl Volker
Schnappauf Benjamin
Göhler Thomas
Ziemendorff Gabriele
Thalmann Ingo
Schumacher Claudia
Weiss Erich
Tomé Oliver
Bauer Wolfgang
Ober Angelika
Schneeweiss Andeas
Höffkes HG
Forstbauer Helmut
Solomayer Erich-Franz
Augustin Doris
Schultz Holger
Adhami Barmak
Niedermeier Michael
Ulmer Hans Ulrich
Hocke Andrea
Kusche Manfred
Hackenberg Reinhard
Rossmann Andreas
Lantzsch Tilmann
Schulze‐Tollert Jürgen
Lerchenmüller Christoph
Ladda Ekkehart
Wierick Elke
Tessen Hans Werner
Raudies Gerd
Sallmann Alexandra
Martin Berhardt
Uleer Christoph
Lübbe Kristina Maria
Felberbaum Ricardo
Wiest Wolfgang
Sütterlin Marc
Thomssen Christoph
Göhring Uwe-Jochen
Tesch Hans
Gatzweiler Axel
Janni Wolfgang
Schmidt Marcus
Werner Andeas
Bauer Lelia
Tulusan Agustinus
Park Tjong-Won
Berghorn Michael
Noesselt Thomas
Henschen Stephan
Stöger Herbert
Marth Christian
Pichler Angelika
Fridrik Michael
Ömer Volker
Lang Alois
Greil Richard
Weiß Harald
Andel Johannes
Thaler Josef
Galid Arik
Sevelda Paul
Singer Christian
Steger Günther
Melbinger‐Zeinitzer Elisabeth
Keckstein Jörg
Keil Felix
Tinchon Christoph
Kubista Ernst
Stierer Michael
Neumann Hans Jörg
Bauernhofer Thomas
Tschurtschenthaler Gertraud
Samonigg Hellmut
Theodoros Foukakis; e-mail: theodoros.foukakis@ki.se.
10 9 2024
17 7 2024
17 7 2024
42 26 30773082
30 1 2024
4 3 2024
5 4 2024
© 2024 by American Society of Clinical Oncology
2024
American Society of Clinical Oncology
https://creativecommons.org/licenses/by-nc-nd/4.0/ Creative Commons Attribution Non-Commercial No Derivatives 4.0 License: https://creativecommons.org/licenses/by-nc-nd/4.0/

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.

Although dose-dense adjuvant chemotherapy administered once every 2 weeks leads to superior outcomes compared with standard regimens once every 3 weeks, the observed improvement is largely limited to studies using the suboptimal paclitaxel schedule once every 3 weeks as control. PANTHER is an international phase III trial which compared sequential epirubicin/cyclophosphamide and docetaxel administered either once every 2 or once every 3 weeks, with tailored dosing at the dose-dense schedule according to hematologic toxicity. In this end-of-study analysis, the median follow-up was 10.3 years. Compared with standard adjuvant chemotherapy, dose-dense treatment improved breast cancer recurrence-free survival (hazard ratio [HR], 0.80 [95% CI, 0.65 to 0.98]; P = .030), event-free survival (HR, 0.78 [95% CI, 0.65 to 0.94]; P = .009), and distant disease-free survival (HR, 0.79 [95% CI, 0.64 to 0.98]; P = .030) while the improvement in overall survival was not statistically significant (HR, 0.82 [95% CI, 0.65 to 1.04]; P = .109). To our knowledge, this is the first trial that confirms the benefit of a dose-dense regimen over a control regimen containing docetaxel once every 3 weeks.

OPEN-ACCESSTRUE
==== Body
pmcINTRODUCTION

The dose-dense sequential administration of an anthracycline and a taxane after surgery for early breast cancer reduces breast cancer recurrence and mortality, with the same relative risk reduction regardless of clinical and pathologic factors.1 However, the relative effect of the administered drugs is unknown. Previous trials have used paclitaxel once every 3 weeks as control,2,3 which is inferior to alternatives such as paclitaxel once per week or docetaxel once every 3 weeks.4 We have previously reported the primary efficacy analysis of the PANTHER trial, which compared adjuvant tailored and dose-dense (tDD) chemotherapy with standard interval treatment.5 After a median follow-up of 5.3 years, the primary and secondary time-to-event outcomes all favored the experimental group, although only the difference in event-free survival (EFS) was significant. Herein, we present the protocol-predefined final efficacy results of PANTHER.

METHODS

Details regarding the design of the PANTHER study (ClinicalTrials.gov identifier: NCT00798070) have been previously presented.5 PANTHER was conducted in 86 sites in Sweden, Germany, and Austria and enrolled women age 18-65 years who had undergone primary surgery for nonmetastatic, high-risk breast cancer (node-positive or node-negative, hormone receptor–negative breast cancer at least 20 mm in size and grade 3 or patients younger than 35 years). Patients allocated to the experimental group received epirubicin and cyclophosphamide once every 2 weeks for four cycles, followed by four cycles of docetaxel once every 2 weeks (tDD epirubicin, cyclophosphamide [EC]/D). Dose tailoring for each cycle in the experimental group was decided according to a predefined algorithm on the basis of hematologic and nonhematologic toxicities5 (Data Supplement, Tables S1 and S2, online only). Patients allocated to the control group received three cycles of fluorouracil and EC once every 3 weeks, followed by three cycles of docetaxel once every 3 weeks (fluorouracil, epirubicin, cyclophosphamide [FEC]/D). Patients received radiotherapy, endocrine therapy, and trastuzumab (97.9% of human epidermal growth factor receptor 2 [HER2]–positive patients6) according to national and local guidelines. Patient follow-up during years 5-10 was performed per protocol in Sweden and Austria with annual visits and by annual visits (50%) or patient reporting (40%) or both (10%) in Germany. The protocol was approved by ethics review boards at the participating sites and relevant health authorities. All patients provided written informed consent before inclusion. The study was conducted according to the Declaration of Helsinki.

Study outcomes (breast cancer recurrence free survival [BCRFS], EFS, distant disease-free survival [DDFS], and overall survival [OS]) followed the standardized definitions applicable at the time the study was conducted7 and have been previously described.5 Statistical methods follow the primary efficacy analysis.5 Cox proportional hazards models were adjusted for site and hormone receptor status, as specified in the protocol.

RESULTS

Patient Characteristics

Between February 2007 and September 2011, 2017 patients were enrolled in the trial and 2003 patients comprise the intention-to-treat population (Data Supplement, Fig S1). The patients' clinical and demographic characteristics were balanced between the two treatment groups (Table 1).

TABLE 1. Baseline Patient Characteristics, Intention-To-Treat Population

Characteristic	Tailored Dose-Dense Chemotherapy (n = 1,001)	Standard Chemotherapy (n = 1,002)	
Median age (range)	51.1 (23.3-69.2)	50.7 (21.4-68.6)	
Menopausal status, No. (%)			
 Premenopausal	515 (51.4)	521 (52.0)	
 Postmenopausal ≤5 years	162 (16.2)	169 (16.9)	
 Postmenopausal >5 years	279 (27.9)	267 (26.6)	
 Missing	45 (4.5)	45 (4.5)	
Type of surgery, No. (%)			
 Mastectomy	460 (46.0)	472 (47.1)	
 Breast-conserving surgery	541 (54.0)	530 (52.9)	
Tumor size, cm, No. (%)			
 ≤2	413 (41.3)	413 (41.2)	
 2-5	507 (50.6)	520 (51.9)	
 >5	76 (7.6)	68 (6.8)	
 Missing	5 (0.5)	1 (0.1)	
No. of positive nodes, (%)			
 0	31 (3.1)	30 (3.0)	
 1-3	591 (59.0)	555 (55.4)	
 4-9	263 (26.3)	290 (28.9)	
 >9	116 (11.6)	127 (12.7)	
Tumor grade, No. (%)			
 1	59 (5.9)	54 (5.4)	
 2	484 (48.3)	512 (51.1)	
 3	453 (45.2)	435 (43.4)	
 Missing	5 (0.5)	1 (0.1)	
Hormone receptor status, No. (%)			
 ER or PR positive	805 (80.4)	795 (79.3)	
 ER and PR negative	195 (19.5)	206 (20.6)	
 Missing	1 (0.1)	1 (0.1)	
HER2 status, No. (%)			
 Negative	841 (84.0)	820 (81.8)	
 Positive	160 (16.0)	182 (18.2)	
Ki-67%, No. (%)			
 ≤20	294 (29.4)	294 (29.3)	
 >20	322 (32.2)	341 (34.0)	
 Missing	385 (38.4)	367 (36.6)	
Abbreviations: ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; PR, progesterone receptor.

Efficacy

In the experimental group, the median cumulative doses of epirubicin and docetaxel were 405 and 334 mg/m2, respectively, and 300 mg/m2 for both drugs in the control group. Reasons for premature treatment discontinuation are shown in the Data Supplement (Table S3). Cumulative epirubicin dose in the experimental group was not associated with BCRFS (P = .133).

After a median follow-up of 10.3 years (IQR, 9.1-10.5 years), there were 179 breast cancer relapses in the experimental and 218 in the control group. Treatment with tDD EC/D improved the primary end point of BCRFS (hazard ratio [HR], 0.80 [95% CI, 0.65 to 0.98]; P = .030; 10-year event rate 18.6% v 22.3%, absolute difference 3.7% ± 1.9%; Fig 1A). The improvement in BCRFS was noted across subgroups according to hormone receptor and HER2 expression, anatomic stage, and other demographic and pathologic factors (Fig 2). In addition, treatment with tDD EC/D improved EFS (HR, 0.78 [95% CI, 0.65 to 0.94]; P = .009; 10-year event rate 23.2% v 27.6%, absolute difference 4.4% ± 2.1%; Fig 1B) and DDFS (HR, 0.79 [95% CI, 0.64 to 0.98]; P = .030; 10-year event rate 17.2% v 20.9%, absolute difference 3.7% ± 1.9%; Fig 1C). At the end of study, there were 137 deaths in the tDD EC/D and 166 in the FEC/D group. The difference in OS was not statistically significant (HR, 0.82 [95% CI, 0.65 to 1.04]; P = .109; 10-year event rate 15.1% v 16.6%, absolute difference 1.5% ± 1.7%; Fig 1D and Data Supplement, Fig S2).

FIG 1. Cumulative incidence curves of efficacy end points in the intention-to-treat population. Cumulative incidence curves and 10-year event rates for breast cancer (A) relapse-free survival events, (B) event-free survival events, (C) distant disease-free survival events, and (D) overall survival events. Log-rank test refers to comparisons of crude, unadjusted event rates. D, docetaxel; EC, epirubicin, cyclophosphamide; FEC, fluorouracil, epirubicin, cyclophosphamide; tDD, tailored dose dense.

FIG 2. Subgroup analysis of breast cancer-free survival events. The size of each box is proportional to the size of the respective subgroup. Hormone receptor–positive includes estrogen receptor– and/or progesterone receptor–positive patients; hormone receptor–negative includes estrogen and progesterone receptor–negative patients. D, docetaxel; EC, epirubicin, cyclophosphamide; FEC, fluorouracil, epirubicin, cyclophosphamide; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; tDD, tailored dose dense.

There were no new safety signals,5,6,8 and no reported cases of acute myeloid leukemia or myelodysplastic syndrome since the primary analysis (three in the tDD EC/D and two in the FEC/D group).

DISCUSSION

In the protocol-predefined final efficacy analysis of the PANTHER trial, treatment with adjuvant tDD chemotherapy improved the primary end point of BCRFS and the secondary end points of EFS and DDFS compared with standard adjuvant chemotherapy. This is to our knowledge the first trial demonstrating improved outcomes with dose-dense chemotherapy when compared with a control of optimally dosed sequential EC and docetaxel once every 3 weeks.

Two of the most influential trials that compared sequential anthracyclines and taxanes once every 3 versus once every 2 weeks, the Cancer and Leukemia Group B 9741 and the Gruppo Italiano Mammella 2 trials, both used paclitaxel once every 3 weeks as control.2,3 These trials and PANTHER had largely similar populations in terms of nodal status, tumor stage, age, and hormone receptor expression. An important difference between the control groups lies, however, in the administered taxane. In a direct comparison, docetaxel once every 3 weeks, which was used in PANTHER, improved disease-free and OS compared with paclitaxel once every 3 weeks, both following four cycles of doxorubicin and cyclophosphamide.4 Intriguingly, a trial-level meta-analysis reported that dose-dense schedules are superior to standard interval treatment only when paclitaxel once every 3 weeks is used as control (for DFS, Pinteraction = .04 and for OS, Pinteraction = .001).9 Furthermore, compressing treatment intervals of anthracycline courses has failed to improve outcomes in most,10-13 but not all studies,14 despite in many cases anthracycline doses in control groups that would today be considered as suboptimal. These observations imply that the difference in long-term outcomes demonstrated by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) meta-analysis may be explained by a weaker control regimen and not by an inherent advantage of dose-dense cycles, as suggested by the Norton-Simon hypothesis.15,16 With the present results from the PANTHER trial, we dispel these concerns by comparing sequential anthracycline and taxane administered once every 2 weeks to the optimal taxane schedule according to the latest EBCTCG overview17 and solidify its role as the standard of care for primarily resected, nonmetastatic high-risk breast cancer.

A potential confounder to our findings is the higher cumulative chemotherapy dose patients in the experimental group received owing to dose tailoring and increased number of treatment cycles. However, the differences in median cumulative chemotherapy doses were below the clinically relevant thresholds established by the latest EBCTCG meta-analysis.17 Of note, there were no discernible differences between countries in terms of treatment cycles, median doses per cycle, or median cumulative doses. Finally, outcomes in the experimental group did not associate with cumulative epirubicin dose.18 As such, our hypothesis is that the driving force behind the improved outcomes in the experimental group is the dose-dense schedule.

In conclusion, tDD adjuvant chemotherapy improved BCRFS, EFS, and DDFS compared with standard adjuvant chemotherapy. These results demonstrate the superiority of dose-dense schedules regardless of comparator treatment.

ACKNOWLEDGMENT

A list of PANTHER collaborators can be found in Appendix 1 (online only).

SUPPORT

CLINICAL TRIAL INFORMATION

DATA SHARING STATEMENT

A data sharing statement provided by the authors is available with this article at DOI https://doi.org/10.1200/JCO.24.00178.

AUTHOR CONTRIBUTIONS

Conception and design: Alexios Matikas, Volker Möbus, Richard Greil, Michael Untch, Tommy Fornander, Per Malmström, Yvonne Brandberg, Michael Gnant, Sibylle Loibl, Theodoros Foukakis, Jonas Bergh

Administrative support: Mats Hellström, Sibylle Loibl, Jonas Bergh

Provision of study materials or patients: Volker Möbus, Richard Greil, Anne Andersson, Tommy Fornander, Per Malmström, Mats Hellström, Sibylle Loibl, Theodoros Foukakis, Jonas Bergh

Collection and assembly of data: Alexios Matikas, Volker Möbus, Richard Greil, Anne Andersson, Tommy Fornander, Per Malmström, Sabine Schmatloch, Mats Hellström, Michael Gnant, Sibylle Loibl, Theodoros Foukakis

Data analysis and interpretation: Alexios Matikas, Volker Möbus, Richard Greil, Michael Untch, Per Malmström, Hemming Johansson, Mats Hellström, Yvonne Brandberg, Michael Gnant, Theodoros Foukakis

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Tailored Dose-Dense Versus Standard Adjuvant Chemotherapy for High-Risk Early Breast Cancer: End-of-Study Results of the Randomized PANTHER 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/jco/authors/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

APPENDIX 1. List of PANTHER Collaborators

The Swedish Breast Cancer Group (SweBCG) members include: Niklas Lohman, Skånes universitetssjukhus, Malmö; Martin Söderberg, Skånes universitetssjukhus, Malmö; Per Malmström, Skånes universitetssjukhus, Lund; Zakaria Einbeigi, SU/Sahlgrenska; Per Karlsson, SU/Sahlgrenska; Barbro Linderholm, SU/Sahlgrenska; Stig Holmberg, SU/Sahlgrenska; Lotta Dabrosin, Universitetssjukhuset Linköping; Elham Hedayati, Universitetssjukhuset Linköping; Kenneth Villman, Universitetssjukhuset Örebro; Sam Rotstein, Karolinska universitetssjukhuset (DS); Birgitta Wallberg, Karolinska universitetssjukhuset (RH); Tommy Fornander, Karolinska universitetssjukhuset (SöS); Henrik Lindman, Akademiska sjukhuset Uppsala; Johan Ahlgren, Sjukhuset i Gävle; Per Edlund, Sjukhuset i Gävle; Lena Carlsson, Länssjukhuset Sundsvall; Nils‐Olof Bengtsson, Norrlands universitetssjukhus; Eva Karlsson, Centralsjukhuset Karlstad.

The German Breast Group (GBG) members include: Sabine Schmatloch, Elisabeth Krankenhaus; Matthias Kögel, Stadtkrankenhaus Worms; Andreas Kohls, Ev. Krankenhaus Ludwigsfelde‐Teltow; Eva‐Maria Grischke, Universitätsfrauenklinik Tübingen; Gerold Baake, Onkologische Praxis Pinneberg; Gerald Hoffmann, St Josefs‐Hospital; Maria Dietrich, Klinikum Fichtelgebirge; Volker Möbus, Klinikum Frankfurt Höchst GmbH; Ralf Adrion, Klinikum am Bruderwald, Bamberg; Volker Heyl, Asklepios Paulinen Klinik; Benjamin Schnappauf, Klinikum der J. W. Goethe Universität; Thomas Göhler, Gemeinschaftspraxis Dresden; Gabriele Ziemendorff, Klinikum Ludwigsburg; Ingo Thalmann, Klinikum am Steinenberg; Claudia Schumacher, St Elisabeth‐KKH; Dr Erich Weiss, Klinikum Sindelfingen‐Böblingen/Kliniken Böblingen; Dr Oliver Tomé, St Vincentius Kliniken Karlsruhe; Wolfgang Bauer, Klinikum Villingen‐Schwenningen; Angelika Ober, St Vincenz Krankenhaus; Andeas Schneeweiss, Universität Heidelberg; HG Höffkes, Klinikum Fulda; Helmut Forstbauer, Gesellschaft für onkologische Studien, Troisdorf; Erich‐Franz Solomayer, Universitätsfrauenklinik Homburg; Doris Augustin, Klinikum Deggendorf; Holger Schultz, Klinikum Berlin‐Buch; Barmak Adhami, Praxis Dr Adhami; Michael Niedermeier, Onkologische Praxis Memmingen; Hans Ulrich Ulmer, Städtisches Klinikum Karlsruhe; Andrea Hocke, Universitätsfrauenklinik Bonn; Manfred Kusche, Marienhospital Aachen; Reinhard Hackenberg, Klinikum Heilbronn; Andreas Rossmann, Klinikum Weiden; Tilmann Lantzsch, Krankenhaus St Elisabeth und St Barbara, Halle/Saale; Jürgen Schulze‐Tollert, Kreiskrankenhaus Freudenstadt; Christoph Lerchenmüller, Gemeinschaftspraxis Münster; Ekkehart Ladda, Praxis am Klinikum Neumarkt; Elke Wierick, Onkologische Tagesklinik Lohsa; Hans Werner Tessen, Onkologische Schwerpunktpraxis Goslar; Gerd Raudies, Klinikum Bietigheim; Alexandra Sallmann, Klinikum Rheinfelden; Berhardt Martin, Klinikum Tuttlingen; Christoph Uleer, Gemienschaftspraxis Hildesheim; Kristina Maria Lübbe, Henriettenstiftung Hannover; Ricardo Felberbaum, Klinikum Kempten; Wolfgang Wiest, St Vincenz und Elisabeth‐Hospital Mainz; Marc Sütterlin, Universitätsfrauenklinik Mannheim; Christoph Thomssen, Universitätsfrauenklinik Halle/Saale; Uwe‐Jochen Göhring, Johanniter Krankenhaus Bonn; Hans Tesch, Onkologische Gemeinschaftspraxis Frankfurt; Axel Gatzweiler, Krankenhaus St Joseph‐Stift Dresden; Wolfgang Janni, Universitätsfrauenklinik Ulm; Marcus Schmidt, Universitätsfrauenklinik Mainz; Andeas Werner, Diakonissen Krankenhaus Dresden; Lelia Bauer, Klinikum Weinheim; Agustinus Tulusan, Klinikum Bayreuth; Tjong‐Won Park, Medizinische Hochschule Hannover; Michael Berghorn, Krankernhaus Celle; Thomas Noesselt, Klinikum Hameln; Stephan Henschen, Klinikum Schwerin.

The Austrian Breast & Colorectal Cancer Study Group (ABCSG) members include: Herbert Stöger, MUG ‐ Med. Univ.‐Klinik Graz; Christian Marth, MUI ‐ Univ. Klinik f. Frauenheilkunde Innsbruck; Angelika Pichler, LKH Leoben; Michael Fridrik, AKH Linz; Volker Ömer, KH BHS Linz; Alois Lang, LKH Rankweil; Richard Greil, LKH Salzburg/PMU; Harald Weiß, KH BHB St Veit/Glan; Johannes Andel, LKH Steyr; Josef Thaler, Klinikum Wels – Grieskirchen GmbH; Arik Galid, Brustzentrum Hanusch‐KH; Paul Sevelda, KH Hietzing Wien; Christian Singer, MUW ‐ Med. Univ.‐Klinik f. Frauenheilk.; Günther Steger, MUW ‐ Med. Univ.‐Klinik f. Inn. Med. I; Elisabeth Melbinger‐Zeinitzer, LKH Wolfsberg; Jörg Keckstein, LKH Villach; Felix Keil, LKH Leoben; Christoph Tinchon, LKH Leoben; Ernst Kubista, MUW ‐ Med. Univ.‐Klinik f. Frauenheilk.; Michael Stierer, Brustzentrum Hanusch‐KH; Hans Jörg Neumann, KH BHB St Veit/Glan; Thomas Bauernhofer, LKH Leoben; Gertraud Tschurtschenthaler, KH BHS Linz; Hellmut Samonigg, MUG ‐ Med. Univ.‐Klinik Graz.

Supported by grants from the Swedish Cancer Society (Cancerfonden), from the Swedish Breast Cancer Association (Bröstcancerförbundet), from the research funds at Radiumhemmet, and from Amgen, Roche, and Sanofi-Aventis to the Swedish Breast Cancer Group (SweBCG) at Karolinska University Hospital, the German Breast Group (GBG), and the Austrian Breast & Colorectal Cancer Study Group (ABCSG).

NCT00798070 (PANTHER)

* J.B. and T.F. contributed equally to this work.

Alexios Matikas

Honoraria: Veracyte

Speakers' Bureau: Roche, Seagen (Inst)

Research Funding: AstraZeneca (Inst), Novartis (Inst), Veracyte (Inst), MSD (Inst)

Volker Moebus

Consulting or Advisory Role: IQVIA

Richard Greil

Stock and Other Ownership Interests: Novo Nordisk (Inst), Lilly (Inst)

Honoraria: Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, Bristol Myers Squibb, MSD, Sandoz, AbbVie, Gilead Sciences, Daiichi Sankyo, Sanofi

Consulting or Advisory Role: Celgene, Novartis, Roche, Bristol Myers Squibb, Takeda, AbbVie, AstraZeneca, Janssen, MSD, Merck, Gilead Sciences, Daiichi Sankyo, Sanofi

Research Funding: Celgene (Inst), Merck (Inst), Takeda (Inst), AstraZeneca (Inst), Novartis (Inst), Amgen (Inst), Bristol Myers Squibb (Inst), MSD (Inst), Sandoz (Inst), Gilead Sciences (Inst), Roche (Inst), Daiichi Sankyo Europe GmbH (Inst), AbbVie

Travel, Accommodations, Expenses: Roche, Amgen, Janssen-Cilag, AstraZeneca, Novartis, MSD, Celgene, Gilead Sciences, Bristol Myers Squibb, AbbVie, Daiichi Sankyo

Günther G. Steger

Honoraria: Pfizer, Lilly, Novartis, Roche, AstraZeneca/Daiichi Sankyo, Teva

Consulting or Advisory Role: Pfizer, Lilly, Novartis

Travel, Accommodations, Expenses: Roche, Teva

Michael Untch

Honoraria: AstraZeneca (Inst), Daiji Sankyo (Inst), Roche Pharma AG (Inst), Pfizer (Inst), Pierre Fabre (Inst), Sanofi (Inst), Agendia (Inst), Art tempi (Inst), Novartis (Inst), Eisai Europe (Inst), Gilead Sciences (Inst), Lilly (Inst), Amgen (Inst), Seagen (Inst), Baxter (Inst), AstraZeneca

Consulting or Advisory Role: Amgen (Inst), Lilly (Inst), Novartis (Inst), MSD Oncology (Inst), Pfizer (Inst), Roche Pharma AG (Inst), Agendia (Inst), Pierre Fabre (Inst), Daiichi Sankyo Europe GmbH (Inst), Novartis (Inst), AstraZeneca (Inst), Myriad Genetics (Inst), GlaxoSmithKline (Inst), Art tempi (Inst), Gilead Sciences (Inst), Sanofi Aventis GmbH (Inst), Medac (Inst), Stemline Therapeutics

Tommy Fornander

Stock and Other Ownership Interests: Pfizer

Per Malmström

Patents, Royalties, Other Intellectual Property: Participation in royalty sharing agreements PFS Genomics United States

Sabine Schmatloch

Other Relationship: Roche Pharma AG

Michael Gnant

Employment: Sandoz

Honoraria: Novartis, AstraZeneca, Lilly, Pierre Fabre, MSD, Amgen, Daiichi Sankyo Europe GmbH, EPG Health, Menarini

Consulting or Advisory Role: Daiichi-Sankyo, Veracyte, AstraZeneca, Lilly, Menarini, MSD Oncology, Novartis

Expert Testimony: Veracyte, Lilly

Travel, Accommodations, Expenses: Novartis, Lilly

Other Relationship: ABCSG GmbH, ABCSG Research Services GmbH

Sibylle Loibl

Consulting or Advisory Role: Pfizer (Inst), Roche (Inst), Novartis (Inst), Seagen (Inst), Celgene (Inst), Lilly (Inst), AstraZeneca/MedImmune (Inst), Bristol Myers Squibb (Inst), Merck KGaA (Inst), AbbVie (Inst), Amgen (Inst), Daiichi Sankyo (Inst), Pierre Fabre (Inst), GlaxoSmithKline (Inst), EirGenix (Inst), Eisai Europe (Inst), Relay Therapeutics (Inst), Sanofi (Inst), Olema Pharmaceuticals (Inst), Menarini Group (Inst), MSD Oncology (Inst)

Speakers' Bureau: AstraZeneca (Inst), Daiichi Sankyo Europe GmbH (Inst), Novartis (Inst), Pfizer (Inst), Roche (Inst), Gilead Sciences (Inst), Seagen (Inst)

Research Funding: AbbVie (Inst), AstraZeneca (Inst), Celgene (Inst), Novartis (Inst), Pfizer (Inst), Roche (Inst), Daiichi Sankyo (Inst), Gilead Sciences (Inst), MolecularHealth (Inst), Menarini Group (Inst)

Patents, Royalties, Other Intellectual Property: Patent Pending EP14153692.0 (Inst), Patent Pending EP21152186.9 (Inst), Patent Issued EP15702464.7 (Inst), Patent Pending EP19808852.8 (Inst), Digital Ki67 Evaluator, VM Scope GmbH (Inst)

Theodoros Foukakis

Honoraria: UpToDate

Consulting or Advisory Role: Roche (Inst), AstraZeneca (Inst), Gilead Sciences (Inst)

Research Funding: AstraZeneca (Inst), Novartis (Inst), Veracyte (Inst)

Jonas Bergh

Stock and Other Ownership Interests: Stratipath AB

Honoraria: Roche, AstraZeneca

Research Funding: Amgen (Inst), AstraZeneca (Inst), Bayer (Inst), Merck (Inst), Pfizer (Inst), Roche (Inst), Sanofi (Inst)

Other Relationship: UpToDate

No other potential conflicts of interest were reported.

Alexios Matikas

Honoraria: Veracyte

Speakers' Bureau: Roche, Seagen (Inst)

Research Funding: AstraZeneca (Inst), Novartis (Inst), Veracyte (Inst), MSD (Inst)

Volker Moebus

Consulting or Advisory Role: IQVIA

Richard Greil

Stock and Other Ownership Interests: Novo Nordisk (Inst), Lilly (Inst)

Honoraria: Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, Bristol Myers Squibb, MSD, Sandoz, AbbVie, Gilead Sciences, Daiichi Sankyo, Sanofi

Consulting or Advisory Role: Celgene, Novartis, Roche, Bristol Myers Squibb, Takeda, AbbVie, AstraZeneca, Janssen, MSD, Merck, Gilead Sciences, Daiichi Sankyo, Sanofi

Research Funding: Celgene (Inst), Merck (Inst), Takeda (Inst), AstraZeneca (Inst), Novartis (Inst), Amgen (Inst), Bristol Myers Squibb (Inst), MSD (Inst), Sandoz (Inst), Gilead Sciences (Inst), Roche (Inst), Daiichi Sankyo Europe GmbH (Inst), AbbVie

Travel, Accommodations, Expenses: Roche, Amgen, Janssen-Cilag, AstraZeneca, Novartis, MSD, Celgene, Gilead Sciences, Bristol Myers Squibb, AbbVie, Daiichi Sankyo

Günther G. Steger

Honoraria: Pfizer, Lilly, Novartis, Roche, AstraZeneca/Daiichi Sankyo, Teva

Consulting or Advisory Role: Pfizer, Lilly, Novartis

Travel, Accommodations, Expenses: Roche, Teva

Michael Untch

Honoraria: AstraZeneca (Inst), Daiji Sankyo (Inst), Roche Pharma AG (Inst), Pfizer (Inst), Pierre Fabre (Inst), Sanofi (Inst), Agendia (Inst), Art tempi (Inst), Novartis (Inst), Eisai Europe (Inst), Gilead Sciences (Inst), Lilly (Inst), Amgen (Inst), Seagen (Inst), Baxter (Inst), AstraZeneca

Consulting or Advisory Role: Amgen (Inst), Lilly (Inst), Novartis (Inst), MSD Oncology (Inst), Pfizer (Inst), Roche Pharma AG (Inst), Agendia (Inst), Pierre Fabre (Inst), Daiichi Sankyo Europe GmbH (Inst), Novartis (Inst), AstraZeneca (Inst), Myriad Genetics (Inst), GlaxoSmithKline (Inst), Art tempi (Inst), Gilead Sciences (Inst), Sanofi Aventis GmbH (Inst), Medac (Inst), Stemline Therapeutics

Tommy Fornander

Stock and Other Ownership Interests: Pfizer

Per Malmström

Patents, Royalties, Other Intellectual Property: Participation in royalty sharing agreements PFS Genomics United States

Sabine Schmatloch

Other Relationship: Roche Pharma AG

Michael Gnant

Employment: Sandoz

Honoraria: Novartis, AstraZeneca, Lilly, Pierre Fabre, MSD, Amgen, Daiichi Sankyo Europe GmbH, EPG Health, Menarini

Consulting or Advisory Role: Daiichi-Sankyo, Veracyte, AstraZeneca, Lilly, Menarini, MSD Oncology, Novartis

Expert Testimony: Veracyte, Lilly

Travel, Accommodations, Expenses: Novartis, Lilly

Other Relationship: ABCSG GmbH, ABCSG Research Services GmbH

Sibylle Loibl

Consulting or Advisory Role: Pfizer (Inst), Roche (Inst), Novartis (Inst), Seagen (Inst), Celgene (Inst), Lilly (Inst), AstraZeneca/MedImmune (Inst), Bristol Myers Squibb (Inst), Merck KGaA (Inst), AbbVie (Inst), Amgen (Inst), Daiichi Sankyo (Inst), Pierre Fabre (Inst), GlaxoSmithKline (Inst), EirGenix (Inst), Eisai Europe (Inst), Relay Therapeutics (Inst), Sanofi (Inst), Olema Pharmaceuticals (Inst), Menarini Group (Inst), MSD Oncology (Inst)

Speakers' Bureau: AstraZeneca (Inst), Daiichi Sankyo Europe GmbH (Inst), Novartis (Inst), Pfizer (Inst), Roche (Inst), Gilead Sciences (Inst), Seagen (Inst)

Research Funding: AbbVie (Inst), AstraZeneca (Inst), Celgene (Inst), Novartis (Inst), Pfizer (Inst), Roche (Inst), Daiichi Sankyo (Inst), Gilead Sciences (Inst), MolecularHealth (Inst), Menarini Group (Inst)

Patents, Royalties, Other Intellectual Property: Patent Pending EP14153692.0 (Inst), Patent Pending EP21152186.9 (Inst), Patent Issued EP15702464.7 (Inst), Patent Pending EP19808852.8 (Inst), Digital Ki67 Evaluator, VM Scope GmbH (Inst)

Theodoros Foukakis

Honoraria: UpToDate

Consulting or Advisory Role: Roche (Inst), AstraZeneca (Inst), Gilead Sciences (Inst)

Research Funding: AstraZeneca (Inst), Novartis (Inst), Veracyte (Inst)

Jonas Bergh

Stock and Other Ownership Interests: Stratipath AB

Honoraria: Roche, AstraZeneca

Research Funding: Amgen (Inst), AstraZeneca (Inst), Bayer (Inst), Merck (Inst), Pfizer (Inst), Roche (Inst), Sanofi (Inst)

Other Relationship: UpToDate

No other potential conflicts of interest were reported.
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