236 www.thelancet.com/oncology Vol 12 March 2011 Articles Lancet Oncol 2011; 12: 236–44 Published Online February 25, 2011 DOI:10.1016/S1470- 2045(11)70033-X See Comment pages 203 and 209 Department of Medical Oncology, San Raffaele Institute, Milan, Italy (Prof L Gianni MD); Laboratory of Biostatistics, University of Athens, and Frontier Science Foundation-Hellas, Athens, Greece (Prof U Dafni ScD); Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA (Prof R D Gelber PhD); Medical Oncology Clinic and Breast European Adjuvant Study Team (BrEAST) Data Centre, Jules Bordet Institute, Université Libre de Bruxelles, Brussels, Belgium (E Azambuja PhD); F Hoffmann-La Roche, Basel, Switzerland (S Muehlbauer PhD); Department of Medicine, European Institute of Oncology, Milan, Italy, and Oncology Institute of Southern Switzerland, Bellinzona, Switzerland (Prof A Goldhirsch MD); Department of Gynaecology and Obstetrics and Multidisciplinary Breast Cancer Center, Helios Klinikum Berlin-Buch, Germany (Prof M Untch MD); Breast Unit, Royal Marsden Hospital, and Institute of Cancer Research, London, UK (Prof I Smith MD); Division of Hematology/ Oncology, Massachusetts General Hospital Cancer Center, Boston, MA, USA (Prof J Baselga MD); Department of Gynecology and Obstetrics, Klinikum Offenbach, Germany (Prof C Jackisch MD); Universityof Edinburgh and Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial Luca Gianni, Urania Dafni, Richard D Gelber, Evandro Azambuja, Susanne Muehlbauer, Aron Goldhirsch, Michael Untch, Ian Smith, José Baselga, Christian Jackisch, David Cameron, Max Mano, José Luiz Pedrini, Andrea Veronesi, Cesar Mendiola, Anna Pluzanska, Vladimir Semiglazov, Eduard Vrdoljak, Michael J Eckart, Zhenzhou Shen, George Skiadopoulos, Marion Procter, Kathleen I Pritchard, Martine J Piccart-Gebhart, and Richard Bell, for the Herceptin Adjuvant (HERA) Trial Study Team Summary Background Treatment with adjuvant trastuzumab for 1 year improves disease-free survival and overall survival in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. We aimed to assess disease-free survival and overall survival after a median follow-up of 4 years for patients enrolled on the Herceptin Adjuvant (HERA) trial. Methods The HERA trial is an international, multicentre, randomised, open-label, phase 3 trial comparing treatment with trastuzumab for 1 and 2 years with observation after standard neoadjuvant, adjuvant chemotherapy, or both in patients with HER2-positive early breast cancer. The primary endpoint was disease-free survival. After a positive first interim analysis at a median follow-up of 1 year for the comparison of treatment with trastuzumab for 1 year with observation, event-free patients in the observation group were allowed to cross over to receive trastuzumab. We report trial outcomes for the 1-year trastuzumab and observation groups at a median follow-up of 48·4 months (IQR 42·0–56·5) and assess the effect of the extensive crossover to trastuzumab. Our analysis was by intention-to- treat. The HERA trial is registered with the European Clinical Trials Database, number 2005-002385-11. Findings The HERA trial population comprised 1698 patients randomly assigned to the observation group and 1703 to the 1-year trastuzumab group. Intention-to-treat analysis of disease-free survival showed a significant benefit in favour of patients in the 1-year trastuzumab group (4-year disease-free survival 78·6%) compared with the observation group (4-year disease-free survival 72·2%; hazard ratio [HR] 0·76; 95% CI 0·66–0·87; p<0·0001). Intention-to-treat analysis of overall survival showed no significant difference in the risk of death (4-year overall survival 89·3% vs 87·7%, respectively; HR 0·85; 95% CI 0·70–1·04; p=0·11). Overall, 885 patients (52%) of the 1698 patients in the observation group crossed over to receive trastuzumab, and began treatment at median 22·8 months (range 4·5–52·7) from randomisation. In a non-randomised comparison, patients in the selective-crossover cohort had fewer disease- free survival events than patients remaining in the observation group (adjusted HR 0·68; 95% CI 0·51–0·90; p=0·0077). Higher incidences of grade 3–4 and fatal adverse events were noted on 1-year trastuzumab than in the observation group. The most common grade 3 or 4 adverse events, each in less than 1% of patients, were congestive cardiac failure, hypertension, arthralgia, back pain, central-line infection, hot flush, headache, and diarrhoea. Interpretation Treatment with adjuvant trastuzumab for 1 year after chemotherapy is associated with significant clinical benefit at 4-year median follow-up. The substantial selective crossover of patients in the observation group to trastuzumab was associated with improved outcomes for this cohort. Funding F Hoffmann-La Roche, Michelangelo Foundation. Introduction The human epidermal growth factor receptor 2 (HER2) gene is amplified, overexpressed, or both in 15–25% of breast cancers 1,2 and is associated with aggressive disease. 3 Trastuzumab (Herceptin; F Hoffmann-La Roche, Basel, Switzerland), a humanised monoclonal antibody that targets the extracellular domain of the HER2 receptor, 4 has established clinical benefits in women with HER2-positive breast cancer in metastatic and early disease settings. 5–15 The Herceptin Adjuvant (HERA) trial (Breast International Group 01-01) is an ongoing, international, multicentre, randomised, phase 3 trial comparing treatment with trastuzumab for 1 and 2 years with observation after standard neoadjuvant/adjuvant chemotherapy in women with HER2-positive early breast cancer. 5102 women were enrolled into the HERA trial, and a planned interim analysis at a median follow-up of 1 year showed that the addition of trastuzumab to standard adjuvant chemotherapy significantly improved disease-free survival compared with chemotherapy alone (hazard ratio [HR] 0·54; 95% CI 0·43–0·67). 9 These results led to a protocol amendment, which allowed patients in the observation