6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer (PERSEPHONE): 4-year disease-free survival results of a randomised phase 3 non-inferiority trial

Research output: Contribution to journalArticle

Authors

  • PERSEPHONE Steering Committee and Trial Investigators

Colleges, School and Institutes

External organisations

  • Department of Oncology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK; Cambridge Breast Cancer Research Unit, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, UK; National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK. Electronic address: hme22@cam.ac.uk.
  • Warwick Clinical Trials Unit, University of Warwick, Coventry
  • Cambridge Clinical Trials Unit-Cancer Theme, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, UK.
  • Department of Oncology, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, UK; Department of Oncology, North West Anglia NHS Foundation Trust, Peterborough City Hospital, Peterborough, UK.
  • Department of Oncology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK; Department of Oncology, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, UK.
  • Department of Oncology, James Paget University Hospital, Norfolk, UK; Department of Oncology, Norfolk & Norwich University Hospital, Norwich, UK.
  • Medical Oncology, Mount Vernon Cancer Centre, Northwood, UK.
  • Michael J. Seckl, Imperial College London; Yenting Ngai, Stephen Nash, and Allan Hackshaw, Cancer Research UK and University College London Cancer Trials Centre; Christian H. Ottensmeier, University of Southampton and Southampton University Hospitals, Southampton; Michael Cullen, Queen Elizabeth Hospital Birmingham; Joyce Thompson, Heart of England Birmingham; Gary Middleton, University of Birmingham, Birmingham; Peter Schmid, Brighton and Sussex Medical School, Brighton; Dakshinamoorthy Muthukumar, Colchester Hospital, Colchester; Susan Harden, Cambridge University Hospital, Cambridge; Kate M. Fife, Peterborough City Hospital, Peterborough; Barbara Crosse, Calderdale and Huddersfield NHS Foundation Trust, Huddersfield; and Paul Taylor, University Hospital South Manchester, Manchester, United Kingdom.
  • Cancer Research UK Clinical Trials Unit (CRCTU), Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK. c.main@bham.ac.uk.
  • Department of Paediatric Oncology, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
  • Department of Oncology, Royal Derby Hospital, Derby, England.
  • Department of Medical Oncology, Guy's and St Thomas' NHS Foundation Trust, London, UK.
  • National Cancer Research Institute Consumer Liaison Group (NCRI CLG); Independent Cancer Patients Voice (ICPV); London UK
  • Department of Cardiology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK; Freeman Hospital, Newcastle upon Tyne, UK.
  • Oncology Global Drug Development, Novartis, Basel, Switzerland.
  • Metabolic Research Laboratories, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK; Department of Histopathology, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, UK.
  • Department of Histopathology, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, UK; National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK.
  • Pharmacy, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, UK.
  • Department of Oncology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK; Cambridge Breast Cancer Research Unit, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, UK; National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK.
  • Department of Oncology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK; Cambridge Breast Cancer Research Unit, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, UK; National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK; Cancer Research UK Cambridge Institute, University of Cambridge Li Ka Shing Centre, Cambridge, UK.
  • Cancer Edinburgh Research Centre, The Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.
  • Institute of Health Economics, Edmonton, Canada.
  • Academic Unit of Health Economics, University of Leeds, Leeds, UK; Health Economics Group, Institute of Health Research, University of Exeter Medical School, Exeter, UK.
  • Research & Development, The NIHR Manchester Clinical Research Facility at The Christie NHS Foundation Trust, Manchester, UK; Division of Cancer Sciences, Faculty of Biology, Medicine and Health, ManchesterAcademic Health Science Centre, University of Manchester, Manchester, UK.

Abstract

Background: Adjuvant trastuzumab significantly improves outcomes for patients with HER2-positive early breast cancer. The standard treatment duration is 12 months but shorter treatment could provide similar efficacy while reducing toxicities and cost. We aimed to investigate whether 6-month adjuvant trastuzumab treatment is non-inferior to the standard 12-month treatment regarding disease-free survival.

Methods: This study is an open-label, randomised phase 3 non-inferiority trial. Patients were recruited from 152 centres in the UK. We randomly assigned patients with HER2-positive early breast cancer, aged 18 years or older, and with a clear indication for chemotherapy, by a computerised minimisation process (1:1), to receive either 6-month or 12-month trastuzumab delivered every 3 weeks intravenously (loading dose of 8 mg/kg followed by maintenance doses of 6 mg/kg) or subcutaneously (600 mg), given in combination with chemotherapy (concurrently or sequentially). The primary endpoint was disease-free survival, analysed by intention to treat, with a non-inferiority margin of 3% for 4-year disease-free survival. Safety was analysed in all patients who received trastuzumab. This trial is registered with EudraCT (number 2006–007018–39), ISRCTN (number 52968807), and ClinicalTrials.gov (number NCT00712140).

Findings: Between Oct 4, 2007, and July 31, 2015, 2045 patients were assigned to 12-month trastuzumab treatment and 2044 to 6-month treatment (one patient was excluded because they were double randomised). Median follow-up was 5·4 years (IQR 3·6–6·7) for both treatment groups, during which a disease-free survival event occurred in 265 (13%) of 2043 patients in the 6-month group and 247 (12%) of 2045 patients in the 12-month group. 4-year disease-free survival was 89·4% (95% CI 87·9–90·7) in the 6-month group and 89·8% (88·3–91·1) in the 12-month group (hazard ratio 1·07 [90% CI 0·93–1·24], non-inferiority p=0·011), showing non-inferiority of the 6-month treatment. 6-month trastuzumab treatment resulted in fewer patients reporting severe adverse events (373 [19%] of 1939 patients vs 459 [24%] of 1894 patients, p=0·0002) or stopping early because of cardiotoxicity (61 [3%] of 1939 patients vs 146 [8%] of 1894 patients, p<0·0001).

Interpretation: We have shown that 6-month trastuzumab treatment is non-inferior to 12-month treatment in patients with HER2-positive early breast cancer, with less cardiotoxicity and fewer severe adverse events. These results support consideration of reduced duration trastuzumab for women at similar risk of recurrence as to those included in the trial.

Funding: UK National Institute for Health Research, Health Technology Assessment Programme.

Bibliographic note

Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Details

Original languageEnglish
Pages (from-to)2599-2612
Number of pages14
JournalThe Lancet
Volume393
Issue number10191
Early online date6 Jun 2019
Publication statusPublished - 29 Jun 2019

Keywords

  • Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Immunological/administration & dosage, Breast Neoplasms/drug therapy, Chemotherapy, Adjuvant, Disease-Free Survival, Drug Administration Schedule, Female, Humans, Infusions, Intravenous, Injections, Subcutaneous, Middle Aged, Prospective Studies, Receptor, ErbB-2/metabolism, Trastuzumab/administration & dosage, Treatment Outcome, United Kingdom, Young Adult

ASJC Scopus subject areas