{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T03:55:29Z","timestamp":1788580529370,"version":"build-2803163510"},"reference-count":161,"publisher":"National Institute for Health and Care Research","issue":"40","license":[{"start":{"date-parts":[[2020,8,1]],"date-time":"2020-08-01T00:00:00Z","timestamp":1596240000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/www.nationalarchives.gov.uk\/doc\/non-commercial-government-licence\/non-commercial-government-licence.htm"}],"funder":[{"DOI":"10.13039\/501100000664","name":"Health Technology Assessment programme","doi-asserted-by":"publisher","award":["06\/303\/98"],"award-info":[{"award-number":["06\/303\/98"]}],"id":[{"id":"10.13039\/501100000664","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journalslibrary.nihr.ac.uk"],"crossmark-restriction":false},"short-container-title":["Health Technol Assess"],"abstract":"Background<\/jats:title>The addition of adjuvant trastuzumab to chemotherapy has significantly improved outcomes for people with human epidermal growth factor receptor 2 (HER2)-positive, early, potentially curable breast cancer. Twelve months\u2019 trastuzumab, tested in registration trials, was adopted as standard adjuvant treatment in 2006. Subsequently, similar outcomes were demonstrated using 9 weeks of trastuzumab. Shorter durations were therefore tested for non-inferiority.<\/jats:p><\/jats:sec>Objectives<\/jats:title>To establish whether or not 6 months\u2019 adjuvant trastuzumab is non-inferior to 12 months\u2019 in the treatment of HER2-positive early breast cancer using a primary end point of 4-year disease-free survival.<\/jats:p><\/jats:sec>Design<\/jats:title>This was a Phase III randomised controlled non-inferiority trial.<\/jats:p><\/jats:sec>Setting<\/jats:title>The setting was 152 NHS hospitals.<\/jats:p><\/jats:sec>Participants<\/jats:title>A total of 4088 patients with HER2-positive early breast cancer who it was planned would receive both chemotherapy and trastuzumab took part.<\/jats:p><\/jats:sec>Intervention<\/jats:title>Randomisation (1\u2009:\u20091) to 6 months\u2019 or 12 months\u2019 trastuzumab treatment.<\/jats:p><\/jats:sec>Main outcomes<\/jats:title>The primary end point was disease-free survival. The secondary end points were overall survival, cost-effectiveness and cardiac function during treatment with trastuzumab. Assuming a 4-year disease-free survival rate of 80% with 12 months\u2019 trastuzumab, 4000 patients were required to demonstrate non-inferiority of 6 months\u2019 trastuzumab (5% one-sided significance, 85% power), defining the non-inferiority limit as no worse than 3% below the standard arm. Costs and quality-adjusted life-years were estimated using a within-trial analysis and a lifetime decision-analytic model.<\/jats:p><\/jats:sec>Results<\/jats:title>Between 4 October 2007 and 31 July 2015, 2045 patients were randomised to 12 months\u2019 trastuzumab and 2043 were randomised to 6 months\u2019 trastuzumab. Sixty-nine per cent of patients had ER-positive disease; 90% received anthracyclines (49% with taxanes; 41% without taxanes); 10% received taxanes without anthracyclines; 54% received trastuzumab sequentially after chemotherapy; and 85% received adjuvant chemotherapy (58% were node negative). At 6.1 years\u2019 median follow-up, with 389 (10%) deaths and 566 (14%) disease-free survival events, the 4-year disease-free survival rates for the 4088 patients were 89.5% (95% confidence interval 88.1% to 90.8%) in the 6-month group and 90.3% (95% confidence interval 88.9% to 91.5%) in the 12-month group (hazard ratio 1.10, 90% confidence interval 0.96 to 1.26; non-inferiorityp<\/jats:italic>\u2009=\u20090.01), demonstrating non-inferiority of 6 months\u2019 trastuzumab. Congruent results were found for overall survival (non-inferiorityp<\/jats:italic>\u2009=\u20090.0003) and landmark analyses 6 months from starting trastuzumab [non-inferiorityp<\/jats:italic>\u2009=\u20090.03 (disease-free-survival) andp<\/jats:italic>\u2009=\u20090.006 (overall survival)]. Six months\u2019 trastuzumab resulted in fewer patients reporting adverse events of severe grade [365\/1929 (19%) vs. 460\/1935 (24%) for 12-month patients;p<\/jats:italic>\u2009=\u20090.0003] or stopping early because of cardiotoxicity [61\/1977 (3%) vs. 146\/1941 (8%) for 12-month patients;p<\/jats:italic>\u2009<\u20090.0001]. Health economic analysis showed that 6 months\u2019 trastuzumab resulted in significantly lower lifetime costs than and similar lifetime quality-adjusted life-years to 12 months\u2019 trastuzumab, and thus there is a high probability that 6 months\u2019 trastuzumab is cost-effective compared with 12 months\u2019 trastuzumab. Patient-reported experiences in the trial highlighted fatigue and aches and pains most frequently.<\/jats:p><\/jats:sec>Limitations<\/jats:title>The type of chemotherapy and timing of trastuzumab changed during the recruitment phase of the study as standard practice altered.<\/jats:p><\/jats:sec>Conclusions<\/jats:title>PERSEPHONE demonstrated that, in the treatment of HER2-positive early breast cancer, 6 months\u2019 adjuvant trastuzumab is non-inferior to 12 months\u2019. Six months\u2019 treatment resulted in significantly less cardiac toxicity and fewer severe adverse events.<\/jats:p><\/jats:sec>Future work<\/jats:title>Ongoing translational work investigates patient and tumour genetic determinants of toxicity, and trastuzumab efficacy. An individual patient data meta-analysis with PHARE and other trastuzumab duration trials is planned.<\/jats:p><\/jats:sec>Trial registration<\/jats:title>Current Controlled Trials ISRCTN52968807, EudraCT 2006-007018-39 and ClinicalTrials.gov NCT00712140.<\/jats:p><\/jats:sec>Funding<\/jats:title>This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment<\/jats:italic>; Vol. 24, No. 40. See the NIHR Journals Library website for further project information.<\/jats:p><\/jats:sec>","DOI":"10.3310\/hta24400","type":"journal-article","created":{"date-parts":[[2020,9,3]],"date-time":"2020-09-03T12:58:07Z","timestamp":1599137887000},"page":"1-190","update-policy":"https:\/\/doi.org\/10.3310\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":19,"title":["Six versus 12 months\u2019 adjuvant trastuzumab in patients with HER2-positive early breast cancer: the PERSEPHONE non-inferiority RCT"],"prefix":"10.3310","volume":"24","clinical-trial-number":[{"clinical-trial-number":"isrctn52968807","registry":"10.18810\/isrctn","type":"results"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1549-8094","authenticated-orcid":true,"given":"Helena","family":"Earl","sequence":"first","affiliation":[{"name":"Department of Oncology, University of Cambridge, Addenbrooke\u2019s Hospital, Cambridge, UK"},{"name":"Cambridge Breast Cancer Research Unit, Cambridge University 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