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
Authors: Helena M Earl, Louise Hiller, Anne-Laure Vallier, Shrushma Loi, Karen McAdam, Luke Hughes-Davies, Adrian N Harnett, Mei-Lin Ah-See, Richard Simcock, Daniel Rea, Sanjay Raj, Pamela Woodings, Mark Harries, Donna Howe, Kerry Raynes, Helen B Higgins, Maggie Wilcox, Chris Plummer, Janine Mansi, Ioannis Gounaris, Betania Mahler–Araujo, Elena Provenzano, Anita Chhabra, Jean E Abraham, Carlos Caldas, Peter S Hall, Christopher McCabe, Claire Hulme, David Miles, Andrew M Wardley, David A Cameron, Janet A Dunn, 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
Journal: The Lancet (2019)

BackgroundAdjuvant 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.MethodsThis 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).FindingsBetween 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).InterpretationWe 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.FundingUK National Institute for Health Research, Health Technology Assessment Programme.