Antroula Papakonstantinou1, Alexios Matikas1, Nils Olof Bengtsson2, Per Malmström3,4, Elham Hedayati1, Guenther Steger5,6, Michael Untch7, Laila Hübbert8,9, Hemming Johansson1, Mats Hellström1, Michael Gnant10, Sibylle Loibl11, Richard Greil12,13, Volker Moebus14, Theodoros Foukakis1, Jonas Bergh1. 1. Department of Oncology-Pathology, Karolinska Institute and University Hospital, Stockholm, Sweden. 2. University Hospital Umeå, Umeå, Sweden. 3. Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden. 4. Department of Hematology, Oncology, and Radiation Physics, Skåne University Hospital, Lund, Sweden. 5. Medical Oncology, Medical University of Vienna, Vienna, Austria. 6. Gaston H. Glock Research Center, Medical University of Vienna, Vienna, Austria. 7. Department of Obstetrics and Gynecology, Helios Hospital Berlin-Buch, Berlin, Germany. 8. Department of Medical and Health Sciences, Division of Cardiovascular Medicine, Linkoping University, Linkoping, Sweden. 9. Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden. 10. Department of Surgery, Medical University of Vienna, Vienna, Austria. 11. German Breast Group, Neu-Isenburg, Germany. 12. Third Medical Department, Paracelsus Medical University, Salzburg, Austria. 13. Salzburg Cancer Research Institute, Cancer Cluster Salzburg, Salzburg, Austria. 14. Department of Medicine II, Hematology & Oncology, Goethe University of Frankfurt, Frankfurt, Germany.
Abstract
BACKGROUND:Dose-dense (DD) adjuvant chemotherapy improves outcomes in early breast cancer (BC). However, there are no phase 3 randomized data to inform on its combination with trastuzumab for patients with human epidermal growth factor receptor 2 (HER2)-positive disease. METHODS: This was a protocol-predefined secondary analysis of the randomized phase 3 Pan-European Tailored Chemotherapy (PANTHER) trial. Women 65 years old or younger with node-positive or high-risk, node-negative BC were randomized 1:1 to either tailored (according to hematologic nadirs) and DD epirubicin and cyclophosphamide followed by docetaxel or standard 5-fluorouracil, epirubicin, and cyclophosphamide plus docetaxel every 3 weeks. Patients with HER2-positive disease received 1 year of adjuvant trastuzumab. The primary endpoint was BC relapse-free survival. In addition, HER2-positive patients and an equal number of HER2-negative patients matched for age, treatment group, and institution who were enrolled at Swedish sites were asked to participate in a predefined study of cardiac safety and underwent echocardiography or multigated acquisition scanning and electrocardiography at the baseline and at 4 and 6 years of follow-up. RESULTS: There were 342 HER2-positive patients; 335 received at least 1 dose of trastuzumab, and 29 patients discontinued trastuzumab prematurely. Relapse-free survival was not statistically significantly in favor of the tailored and DD group (hazard ratio, 0.68; 95% confidence interval, 0.37-1.27; P = .231). Cardiac outcomes after 4 and 6 years of follow-up did not differ significantly between HER2-positive and HER2-negative patients or between the 2 treatment groups. CONCLUSIONS: The combination of DD chemotherapy and trastuzumab decreased the relative risk for relapse by 32% in comparison with standard treatment, a statistically nonsignificant difference. Its efficacy and safety merit further evaluation as part of both escalation and de-escalation strategies.
RCT Entities:
BACKGROUND: Dose-dense (DD) adjuvant chemotherapy improves outcomes in early breast cancer (BC). However, there are no phase 3 randomized data to inform on its combination with trastuzumab for patients with humanepidermal growth factor receptor 2 (HER2)-positive disease. METHODS: This was a protocol-predefined secondary analysis of the randomized phase 3 Pan-European Tailored Chemotherapy (PANTHER) trial. Women 65 years old or younger with node-positive or high-risk, node-negative BC were randomized 1:1 to either tailored (according to hematologic nadirs) and DD epirubicin and cyclophosphamide followed by docetaxel or standard 5-fluorouracil, epirubicin, and cyclophosphamide plus docetaxel every 3 weeks. Patients with HER2-positive disease received 1 year of adjuvant trastuzumab. The primary endpoint was BC relapse-free survival. In addition, HER2-positive patients and an equal number of HER2-negative patients matched for age, treatment group, and institution who were enrolled at Swedish sites were asked to participate in a predefined study of cardiac safety and underwent echocardiography or multigated acquisition scanning and electrocardiography at the baseline and at 4 and 6 years of follow-up. RESULTS: There were 342 HER2-positive patients; 335 received at least 1 dose of trastuzumab, and 29 patients discontinued trastuzumab prematurely. Relapse-free survival was not statistically significantly in favor of the tailored and DD group (hazard ratio, 0.68; 95% confidence interval, 0.37-1.27; P = .231). Cardiac outcomes after 4 and 6 years of follow-up did not differ significantly between HER2-positive and HER2-negative patients or between the 2 treatment groups. CONCLUSIONS: The combination of DD chemotherapy and trastuzumab decreased the relative risk for relapse by 32% in comparison with standard treatment, a statistically nonsignificant difference. Its efficacy and safety merit further evaluation as part of both escalation and de-escalation strategies.
Authors: Ioannis Zerdes; Michele Simonetti; Alexios Matikas; Luuk Harbers; Balazs Acs; Ceren Boyaci; Ning Zhang; Dimitrios Salgkamis; Susanne Agartz; Pablo Moreno-Ruiz; Yalai Bai; David L Rimm; Johan Hartman; Artur Mezheyeuski; Jonas Bergh; Nicola Crosetto; Theodoros Foukakis Journal: NPJ Breast Cancer Date: 2021-11-19