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Showing content from https://pubmed.ncbi.nlm.nih.gov/31178152/ below:

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

Clinical Trial

. 2019 Jun 29;393(10191):2599-2612. doi: 10.1016/S0140-6736(19)30650-6. Epub 2019 Jun 6. 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 Louise Hiller², Anne-Laure Vallier³, Shrushma Loi², Karen McAdam⁴, Luke Hughes-Davies⁵, Adrian N Harnett⁶, Mei-Lin Ah-See⁷, Richard Simcock⁸, Daniel Rea⁹, Sanjay Raj¹⁰, Pamela Woodings¹¹, Mark Harries¹², Donna Howe², Kerry Raynes², Helen B Higgins², Maggie Wilcox¹³, Chris Plummer¹⁴, Janine Mansi¹², Ioannis Gounaris¹⁵, Betania Mahler-Araujo¹⁶, Elena Provenzano¹⁷, Anita Chhabra¹⁸, Jean E Abraham¹⁹, Carlos Caldas²⁰, Peter S Hall²¹, Christopher McCabe²², Claire Hulme²³, David Miles⁷, Andrew M Wardley²⁴, David A Cameron²¹, Janet A Dunn²; PERSEPHONE Steering Committee and Trial Investigators

Collaborators, Affiliations

Collaborators

PERSEPHONE Steering Committee and Trial Investigators: Roshan Agarwal, Hafiz Algurafi, Rozenn Allerton, Caroline Archer, Anne Armstrong, Catherine Bale, Lisa Barraclough, Urmila Barthakur, Carolyn Bedi, Kim Benstead, David Bloomfield, Rebecca Bowen, Chris Bradley, Jane Brown, Mohammad Butt, Mark Churn, Susan Cleator, Joanne Cliff, Perric Crellin, Margaret Daly, Shiroma De Silva-Minor, Amandeep Dhadda, Omar Din, Sue Down, Helena Earl, David Eaton, Andrew Eichholz, Daniel Epurescu, Chee Goh, Andrew Goodman, Robert Grieve, Maher Hadaki, Catherine Harper-Wynne, Mark Harries, Larry Hayward, Alison Humphreys, Helen Innes, Mariam Jafri, Apurna Jegannathen, Muireann Kelleher, Hartmut Kristeleit, Daniela Lee, Susan Lupton, Carol MacGregor, Zafar Malik, Janine Mansi, Jennifer Marshall, Karen McAdam, Trevor McGolick, Rakesh Mehra, David Miles, Natasha Mithal, Charlotte Moss, Aian Moss, Mukesh Mukesh, Anthony Neal, Daniel Nelmes, Helen Neville-Webbe, Jacqueline Newby, Susan O'Reilly, Peter Ostler, Mojca Persic, Laura Pettit, Sanjay Raj, Fharat Raja, Daniel Rea, Catherine Reed, Anne Rigg, Helen Roe, Nihal Shah, Peter Simmonds, Eliot Sims, Sarah Smith, Nicola Storey, Wendy Taylor, Narottam Thanvi, Karen Tipples, Jayant Vaidya, Mohini Varughese, Anup Vinayan, Nawaz Walji, Simon Waters, Pamela Woodings, Kathryn Wright, Sundus Yahya

Affiliations

¹ 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.
² Warwick Clinical Trials Unit, University of Warwick, Coventry, UK.
³ Cambridge Clinical Trials Unit-Cancer Theme, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, UK.
⁴ 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.
⁵ 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.
⁶ Department of Oncology, James Paget University Hospital, Norfolk, UK; Department of Oncology, Norfolk & Norwich University Hospital, Norwich, UK.
⁷ Medical Oncology, Mount Vernon Cancer Centre, Northwood, UK.
⁸ Sussex Cancer Centre, Brighton and Sussex University Hospitals NHS, Brighton, UK.
⁹ Cancer Research UK Clinical Trials Unit and Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
¹⁰ Department of Oncology, Southampton University Hospital NHS Foundation Trust, Southampton, UK.
¹¹ Department of Oncology, Royal Derby Hospital, Derby, UK.
¹² Department of Medical Oncology, Guy's and St Thomas' NHS Foundation Trust, London, UK.
¹³ Independent Cancer Patients Voice, London, UK.
¹⁴ Department of Cardiology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK; Freeman Hospital, Newcastle upon Tyne, UK.
¹⁵ Oncology Global Drug Development, Novartis, Basel, Switzerland.
¹⁶ 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.
¹⁷ 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.
¹⁸ Pharmacy, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, UK.
¹⁹ 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.
²⁰ 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.
²¹ Cancer Edinburgh Research Centre, The Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.
²² Institute of Health Economics, Edmonton, Canada.
²³ Academic Unit of Health Economics, University of Leeds, Leeds, UK; Health Economics Group, Institute of Health Research, University of Exeter Medical School, Exeter, UK.
²⁴ 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.

PMID: 31178152
PMCID: PMC6615016
DOI: 10.1016/S0140-6736(19)30650-6

Item in Clipboard

Clinical Trial

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

Helena M Earl et al. Lancet. 2019.

. 2019 Jun 29;393(10191):2599-2612. doi: 10.1016/S0140-6736(19)30650-6. Epub 2019 Jun 6. Authors Helena M Earl¹, Louise Hiller², Anne-Laure Vallier³, Shrushma Loi², Karen McAdam⁴, Luke Hughes-Davies⁵, Adrian N Harnett⁶, Mei-Lin Ah-See⁷, Richard Simcock⁸, Daniel Rea⁹, Sanjay Raj¹⁰, Pamela Woodings¹¹, Mark Harries¹², Donna Howe², Kerry Raynes², Helen B Higgins², Maggie Wilcox¹³, Chris Plummer¹⁴, Janine Mansi¹², Ioannis Gounaris¹⁵, Betania Mahler-Araujo¹⁶, Elena Provenzano¹⁷, Anita Chhabra¹⁸, Jean E Abraham¹⁹, Carlos Caldas²⁰, Peter S Hall²¹, Christopher McCabe²², Claire Hulme²³, David Miles⁷, Andrew M Wardley²⁴, David A Cameron²¹, Janet A Dunn²; PERSEPHONE Steering Committee and Trial Investigators Collaborators

PERSEPHONE Steering Committee and Trial Investigators: Roshan Agarwal, Hafiz Algurafi, Rozenn Allerton, Caroline Archer, Anne Armstrong, Catherine Bale, Lisa Barraclough, Urmila Barthakur, Carolyn Bedi, Kim Benstead, David Bloomfield, Rebecca Bowen, Chris Bradley, Jane Brown, Mohammad Butt, Mark Churn, Susan Cleator, Joanne Cliff, Perric Crellin, Margaret Daly, Shiroma De Silva-Minor, Amandeep Dhadda, Omar Din, Sue Down, Helena Earl, David Eaton, Andrew Eichholz, Daniel Epurescu, Chee Goh, Andrew Goodman, Robert Grieve, Maher Hadaki, Catherine Harper-Wynne, Mark Harries, Larry Hayward, Alison Humphreys, Helen Innes, Mariam Jafri, Apurna Jegannathen, Muireann Kelleher, Hartmut Kristeleit, Daniela Lee, Susan Lupton, Carol MacGregor, Zafar Malik, Janine Mansi, Jennifer Marshall, Karen McAdam, Trevor McGolick, Rakesh Mehra, David Miles, Natasha Mithal, Charlotte Moss, Aian Moss, Mukesh Mukesh, Anthony Neal, Daniel Nelmes, Helen Neville-Webbe, Jacqueline Newby, Susan O'Reilly, Peter Ostler, Mojca Persic, Laura Pettit, Sanjay Raj, Fharat Raja, Daniel Rea, Catherine Reed, Anne Rigg, Helen Roe, Nihal Shah, Peter Simmonds, Eliot Sims, Sarah Smith, Nicola Storey, Wendy Taylor, Narottam Thanvi, Karen Tipples, Jayant Vaidya, Mohini Varughese, Anup Vinayan, Nawaz Walji, Simon Waters, Pamela Woodings, Kathryn Wright, Sundus Yahya

Affiliations

¹ 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.
² Warwick Clinical Trials Unit, University of Warwick, Coventry, UK.
³ Cambridge Clinical Trials Unit-Cancer Theme, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, UK.
⁴ 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.
⁵ 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.
⁶ Department of Oncology, James Paget University Hospital, Norfolk, UK; Department of Oncology, Norfolk & Norwich University Hospital, Norwich, UK.
⁷ Medical Oncology, Mount Vernon Cancer Centre, Northwood, UK.
⁸ Sussex Cancer Centre, Brighton and Sussex University Hospitals NHS, Brighton, UK.
⁹ Cancer Research UK Clinical Trials Unit and Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
¹⁰ Department of Oncology, Southampton University Hospital NHS Foundation Trust, Southampton, UK.
¹¹ Department of Oncology, Royal Derby Hospital, Derby, UK.
¹² Department of Medical Oncology, Guy's and St Thomas' NHS Foundation Trust, London, UK.
¹³ Independent Cancer Patients Voice, London, UK.
¹⁴ Department of Cardiology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK; Freeman Hospital, Newcastle upon Tyne, UK.
¹⁵ Oncology Global Drug Development, Novartis, Basel, Switzerland.
¹⁶ 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.
¹⁷ 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.
¹⁸ Pharmacy, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, UK.
¹⁹ 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.
²⁰ 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.
²¹ Cancer Edinburgh Research Centre, The Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.
²² Institute of Health Economics, Edmonton, Canada.
²³ Academic Unit of Health Economics, University of Leeds, Leeds, UK; Health Economics Group, Institute of Health Research, University of Exeter Medical School, Exeter, UK.
²⁴ 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.

PMID: 31178152
PMCID: PMC6615016
DOI: 10.1016/S0140-6736(19)30650-6

Item in Clipboard

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.

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Figures
Figure 1

Trial profile *Seven patients were…

Figure 1

Trial profile *Seven patients were found to be ineligible after randomisation (four had…

Figure 1

Trial profile *Seven patients were found to be ineligible after randomisation (four had previous cancer or ductal carcinoma in situ treated with surgery and radiotherapy, two were HER2 negative, and one had primary cancer confined to the axilla). †11 patients were found to be ineligible after randomisation (seven had previous cancer or ductal carcinoma in situ treated with surgery and radiotherapy, one was HER2 negative, two had metastatic disease, and one had received >9 cycles of trastuzumab).

Figure 2

Kaplan-Meier plots of disease-free survival…

Figure 2

Kaplan-Meier plots of disease-free survival (A) and overall survival (B) for 6-month and…

Figure 2

Kaplan-Meier plots of disease-free survival (A) and overall survival (B) for 6-month and 12-month trastuzumab treatment groups

Figure 3

Forest plots of disease-free survival…

Figure 3

Forest plots of disease-free survival for all patients (A) and patients who received…

Figure 3

Forest plots of disease-free survival for all patients (A) and patients who received adjuvant treatment (B) FISH=fluorescence in-situ hybridisation. ER=oestrogen receptor.

Figure 4

Kaplan-Meier plots of landmark analysis…

Figure 4

Kaplan-Meier plots of landmark analysis from 6-months after starting trastuzumab treatment (A) Disease-free…

Figure 4

Kaplan-Meier plots of landmark analysis from 6-months after starting trastuzumab treatment (A) Disease-free survival. (B) Overall survival.