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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

Lookup NU author(s): Dr Chris PlummerORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licenseBackground: 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 (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.

Publication metadata

Author(s): Earl HM, Hiller L, Vallier A-L, Loi S, McAdam K, Hughes-Davies L, Harnett AN, Ah-See M-L, Simcock R, Rea D, Raj S, Woodings P, Harries M, Howe D, Raynes K, Higgins HB, Wilcox M, Plummer C, Mansi J, Gounaris I, Mahler-Araujo B, Provenzano E, Chhabra A, Abraham JE, Caldas C, Hall PS, McCabe C, Hulme C, Miles D, Wardley AM, Cameron DA, Dunn JA, Agarwal R, Algurafi H, Allerton R, Archer C, Armstrong A, Bale C, Barraclough L, Barthakur U, Bedi C, Benstead K, Bloomfield D, Bowen R, Bradley C, Brown J, Butt M, Churn M, Cleator S, Cliff J, Crellin P, Daly M, De Silva-Minor S, Dhadda A, Din O, Down S, Earl H, Eaton D, Eichholz A, Epurescu D, Goh C, Goodman A, Grieve R, Hadaki M, Harper-Wynne C, Hayward L, Humphreys A, Innes H, Jafri M, Jegannathen A, Kelleher M, Kristeleit H, Lee D, Lupton S, MacGregor C, Malik Z, Marshall J, McGolick T, Mehra R, Mithal N, Moss C, Moss A, Mukesh M, Neal A, Nelmes D, Neville-Webbe H, Newby J, O'Reilly S, Ostler P, Persic M, Pettit L, Raja F, Reed C, Rigg A, Roe H, Shah N, Simmonds P, Sims E, Smith S, Storey N, Taylor W, Thanvi N, Tipples K, Vaidya J, Varughese M, Vinayan A, Walji N, Waters S, Wright K, Yahya S

Publication type: Article

Publication status: Published

Journal: The Lancet

Year: 2019

Volume: 393

Issue: 10191

Pages: 2599-2612

Print publication date: 29/06/2019

Online publication date: 06/06/2019

Acceptance date: 02/04/2019

Date deposited: 11/07/2019

ISSN (print): 0140-6736

ISSN (electronic): 1474-547X

Publisher: Lancet Publishing Group


DOI: 10.1016/S0140-6736(19)30650-6

PubMed id: 31178152


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