David Cameron1, Martine J Piccart-Gebhart2, Richard D Gelber3, Marion Procter4, Aron Goldhirsch5, Evandro de Azambuja6, Gilberto Castro7, Michael Untch8, Ian Smith9, Luca Gianni10, Jose Baselga11, Nedal Al-Sakaff12, Sabine Lauer12, Eleanor McFadden4, Brian Leyland-Jones13, Richard Bell14, Mitch Dowsett9, Christian Jackisch15. 1. University of Edinburgh Cancer Research Centre, Western General Hospital, Edinburgh, UK. Electronic address: d.cameron@ed.ac.uk. 2. Department of Medicine, Université Libre de Bruxelles, Brussels, Belgium. 3. BrEAST Data Centre, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Harvard TH Chan School of Public Health and Frontier Science and Technology Research Foundation, Boston, MA, USA. 4. Frontier Science Scotland Ltd, Kincraig, Kingussie, UK. 5. European Institute of Oncology, Milan, Italy. 6. Medical Oncology Clinic, Université Libre de Bruxelles, Brussels, Belgium. 7. Clinical Oncology, Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil. 8. Helios Klinikum Berlin Buch, Multidisciplinary Breast Cancer Center, Berlin, Germany. 9. Breast Unit, Royal Marsden Hospital, and The Institute of Cancer Research, London, UK. 10. Department of Medical Oncology, San Raffaele Hospital, Scientific Institute, Milan, Italy. 11. Memorial Sloan-Kettering Cancer Center, New York, NY, USA. 12. F Hoffmann-La Roche, Basel, Switzerland. 13. Avera Cancer Institute Center for Precision Oncology, Sioux Falls, SD, USA. 14. Deakin University, Waurn Ponds, VIC, Australia. 15. Department of Gynecology and Obstetrics, Sana Klinikum Offenbach, Offenbach, Germany.
Abstract
BACKGROUND: Clinical trials have shown that trastuzumab, a recombinant monoclonal antibody against HER2 receptor, significantly improves overall survival and disease-free survival in women with HER2-positive early breast cancer, but long-term follow-up data are needed. We report the results of comparing observation with two durations of trastuzumab treatment at a median follow-up of 11 years, for patients enrolled in the HERA (HERceptin Adjuvant) trial. METHODS:HERA (BIG 1-01) is an international, multicentre, open-label, phase 3 randomised trial of 5102 women with HER2-positive early breast cancer, who were enrolled from hospitals in 39 countries between Dec 7, 2001, and June 20, 2005. After completion of all primary therapy (including, surgery, chemotherapy, and radiotherapy as indicated), patients were randomly assigned (1:1:1) to receive trastuzumab for 1 year (once at 8 mg/kg of bodyweight intravenously, then 6 mg/kg once every 3 weeks) or for 2 years (with the same dose schedule), or to the observation group. Primary endpoint is disease-free survival, and analyses are in the intention-to-treat population. Hazard ratios (HRs) were estimated from Cox models, and survival curves were estimated by the Kaplan-Meier method. Comparison of 2 years versus 1 year of trastuzumab is based on 366-day landmark analyses. This study is registered with ClinicalTrials.gov (NCT00045032). FINDINGS: Of the 5102 women randomly assigned in the HERA trial, three patients had no evidence of having provided written informed consent to participate. We followed up the intention-to-treat population of 5099 patients (1697 in observation, 1702 in 1-year trastuzumab, and 1700 in 2-years trastuzumab groups). After a median follow-up of 11 years (IQR 10·09-11·53), random assignment to 1 year of trastuzumab significantly reduced the risk of a disease-free survival event (HR 0·76, 95% CI 0·68-0·86) and death (0·74, 0·64-0·86) compared with observation. 2 years of adjuvant trastuzumab did not improve disease free-survival outcomes compared with 1 year of this drug (HR 1·02, 95% CI 0·89-1·17). Estimates of 10-year disease-free survival were 63% for observation, 69% for 1 year of trastuzumab, and 69% for 2 years of trastuzumab. 884 (52%) patients assigned to the observation group selectively crossed over to receive trastuzumab. Cardiac toxicity remained low in all groups and occurred mostly during the treatment phase. The incidence of secondary cardiac endpoints was 122 (7·3%) in the 2-years trastuzumab group, 74 (4·4%) in the 1-year trastuzumab group, and 15 (0·9%) in the observation group. INTERPRETATION: 1 year of adjuvant trastuzumab after chemotherapy for patients with HER2-positive early breast cancer significantly improves long-term disease-free survival, compared with observation. 2 years of trastuzumab had no additional benefit. FUNDING: F Hoffmann-La Roche (Roche).
RCT Entities:
BACKGROUND: Clinical trials have shown that trastuzumab, a recombinant monoclonal antibody against HER2 receptor, significantly improves overall survival and disease-free survival in women with HER2-positive early breast cancer, but long-term follow-up data are needed. We report the results of comparing observation with two durations of trastuzumab treatment at a median follow-up of 11 years, for patients enrolled in the HERA (HERceptin Adjuvant) trial. METHODS:HERA (BIG 1-01) is an international, multicentre, open-label, phase 3 randomised trial of 5102 women with HER2-positive early breast cancer, who were enrolled from hospitals in 39 countries between Dec 7, 2001, and June 20, 2005. After completion of all primary therapy (including, surgery, chemotherapy, and radiotherapy as indicated), patients were randomly assigned (1:1:1) to receive trastuzumab for 1 year (once at 8 mg/kg of bodyweight intravenously, then 6 mg/kg once every 3 weeks) or for 2 years (with the same dose schedule), or to the observation group. Primary endpoint is disease-free survival, and analyses are in the intention-to-treat population. Hazard ratios (HRs) were estimated from Cox models, and survival curves were estimated by the Kaplan-Meier method. Comparison of 2 years versus 1 year of trastuzumab is based on 366-day landmark analyses. This study is registered with ClinicalTrials.gov (NCT00045032). FINDINGS: Of the 5102 women randomly assigned in the HERA trial, three patients had no evidence of having provided written informed consent to participate. We followed up the intention-to-treat population of 5099 patients (1697 in observation, 1702 in 1-year trastuzumab, and 1700 in 2-years trastuzumab groups). After a median follow-up of 11 years (IQR 10·09-11·53), random assignment to 1 year of trastuzumab significantly reduced the risk of a disease-free survival event (HR 0·76, 95% CI 0·68-0·86) and death (0·74, 0·64-0·86) compared with observation. 2 years of adjuvant trastuzumab did not improve disease free-survival outcomes compared with 1 year of this drug (HR 1·02, 95% CI 0·89-1·17). Estimates of 10-year disease-free survival were 63% for observation, 69% for 1 year of trastuzumab, and 69% for 2 years of trastuzumab. 884 (52%) patients assigned to the observation group selectively crossed over to receive trastuzumab. Cardiac toxicity remained low in all groups and occurred mostly during the treatment phase. The incidence of secondary cardiac endpoints was 122 (7·3%) in the 2-years trastuzumab group, 74 (4·4%) in the 1-year trastuzumab group, and 15 (0·9%) in the observation group. INTERPRETATION: 1 year of adjuvant trastuzumab after chemotherapy for patients with HER2-positive early breast cancer significantly improves long-term disease-free survival, compared with observation. 2 years of trastuzumab had no additional benefit. FUNDING: F Hoffmann-La Roche (Roche).
Authors: Ian Smith; Marion Procter; Richard D Gelber; Sébastien Guillaume; Andrea Feyereislova; Mitch Dowsett; Aron Goldhirsch; Michael Untch; Gabriella Mariani; Jose Baselga; Manfred Kaufmann; David Cameron; Richard Bell; Jonas Bergh; Robert Coleman; Andrew Wardley; Nadia Harbeck; Roberto I Lopez; Peter Mallmann; Karen Gelmon; Nicholas Wilcken; Erik Wist; Pedro Sánchez Rovira; Martine J Piccart-Gebhart Journal: Lancet Date: 2007-01-06 Impact factor: 79.321
Authors: Edith A Perez; Edward H Romond; Vera J Suman; Jong-Hyeon Jeong; Nancy E Davidson; Charles E Geyer; Silvana Martino; Eleftherios P Mamounas; Peter A Kaufman; Norman Wolmark Journal: J Clin Oncol Date: 2011-07-18 Impact factor: 44.544
Authors: 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; Richard Bell Journal: Lancet Oncol Date: 2011-02-25 Impact factor: 41.316
Authors: Luca Gianni; Tadeusz Pienkowski; Young-Hyuck Im; Ling-Ming Tseng; Mei-Ching Liu; Ana Lluch; Elżbieta Starosławska; Juan de la Haba-Rodriguez; Seock-Ah Im; Jose Luiz Pedrini; Brigitte Poirier; Paolo Morandi; Vladimir Semiglazov; Vichien Srimuninnimit; Giulia Valeria Bianchi; Domenico Magazzù; Virginia McNally; Hannah Douthwaite; Graham Ross; Pinuccia Valagussa Journal: Lancet Oncol Date: 2016-05-11 Impact factor: 41.316
Authors: Dennis Slamon; Wolfgang Eiermann; Nicholas Robert; Tadeusz Pienkowski; Miguel Martin; Michael Press; John Mackey; John Glaspy; Arlene Chan; Marek Pawlicki; Tamas Pinter; Vicente Valero; Mei-Ching Liu; Guido Sauter; Gunter von Minckwitz; Frances Visco; Valerie Bee; Marc Buyse; Belguendouz Bendahmane; Isabelle Tabah-Fisch; Mary-Ann Lindsay; Alessandro Riva; John Crown Journal: N Engl J Med Date: 2011-10-06 Impact factor: 91.245
Authors: Martine J Piccart-Gebhart; Marion Procter; Brian Leyland-Jones; Aron Goldhirsch; Michael Untch; Ian Smith; Luca Gianni; Jose Baselga; Richard Bell; Christian Jackisch; David Cameron; Mitch Dowsett; Carlos H Barrios; Günther Steger; Chiun-Shen Huang; Michael Andersson; Moshe Inbar; Mikhail Lichinitser; István Láng; Ulrike Nitz; Hiroji Iwata; Christoph Thomssen; Caroline Lohrisch; Thomas M Suter; Josef Rüschoff; Tamás Suto; Victoria Greatorex; Carol Ward; Carolyn Straehle; Eleanor McFadden; M Stella Dolci; Richard D Gelber Journal: N Engl J Med Date: 2005-10-20 Impact factor: 91.245
Authors: Edward H Romond; Edith A Perez; John Bryant; Vera J Suman; Charles E Geyer; Nancy E Davidson; Elizabeth Tan-Chiu; Silvana Martino; Soonmyung Paik; Peter A Kaufman; Sandra M Swain; Thomas M Pisansky; Louis Fehrenbacher; Leila A Kutteh; Victor G Vogel; Daniel W Visscher; Greg Yothers; Robert B Jenkins; Ann M Brown; Shaker R Dakhil; Eleftherios P Mamounas; Wilma L Lingle; Pamela M Klein; James N Ingle; Norman Wolmark Journal: N Engl J Med Date: 2005-10-20 Impact factor: 91.245
Authors: Evandro de Azambuja; Marion J Procter; Dirk J van Veldhuisen; Dominique Agbor-Tarh; Otto Metzger-Filho; Jutta Steinseifer; Michael Untch; Ian E Smith; Luca Gianni; Jose Baselga; Christian Jackisch; David A Cameron; Richard Bell; Brian Leyland-Jones; Mitch Dowsett; Richard D Gelber; Martine J Piccart-Gebhart; Thomas M Suter Journal: J Clin Oncol Date: 2014-06-09 Impact factor: 44.544
Authors: Aron Goldhirsch; Richard D Gelber; Martine J Piccart-Gebhart; Evandro de Azambuja; Marion Procter; Thomas M Suter; Christian Jackisch; David Cameron; Harald A Weber; Dominik Heinzmann; Lissandra Dal Lago; Eleanor McFadden; Mitch Dowsett; Michael Untch; Luca Gianni; Richard Bell; Claus-Henning Köhne; Anita Vindevoghel; Michael Andersson; A Murray Brunt; Douglas Otero-Reyes; Santai Song; Ian Smith; Brian Leyland-Jones; Jose Baselga Journal: Lancet Date: 2013-07-18 Impact factor: 79.321
Authors: Tessa G Steenbruggen; Mette S van Ramshorst; Marleen Kok; Sabine C Linn; Carolien H Smorenburg; Gabe S Sonke Journal: Drugs Date: 2017-08 Impact factor: 9.546
Authors: Heikki Joensuu; Judith Fraser; Hans Wildiers; Riikka Huovinen; Päivi Auvinen; Meri Utriainen; Paul Nyandoto; Kenneth K Villman; Päivi Halonen; Helena Granstam-Björneklett; Lotta Lundgren; Liisa Sailas; Taina Turpeenniemi-Hujanen; Minna Tanner; Jeffrey Yachnin; Diana Ritchie; Oskar Johansson; Teppo Huttunen; Patrick Neven; Peter Canney; Vernon J Harvey; Pirkko-Liisa Kellokumpu-Lehtinen; Henrik Lindman Journal: JAMA Oncol Date: 2018-09-01 Impact factor: 31.777
Authors: Ali Agha; Abdulrazzak Zarifa; Peter Kim; Cezar Iliescu; Greg Gladish; Saamir Hassan; Nicolas Palaskas; Jean B Durand; Yang Lu; Juan Lopez-Mattei Journal: Methodist Debakey Cardiovasc J Date: 2019 Oct-Dec