title: 11 years' follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial.
abstract: 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.
  
  
  
  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).
  
  
  
  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.
  
  
  
  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.
  
  
  
  F Hoffmann-La Roche (Roche).
authors.affiliation: University of Edinburgh Cancer Research Centre, Western General Hospital, Edinburgh, UK. Electronic address: d.cameron@ed.ac.uk.
authors.forename: David
authors.initials: D
authors.lastname: Cameron
authors.affiliation: Department of Medicine, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Piccart-Gebhart
authors.affiliation: 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.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Gelber
authors.affiliation: Frontier Science Scotland Ltd, Kincraig, Kingussie, UK.
authors.forename: Marion
authors.initials: M
authors.lastname: Procter
authors.affiliation: European Institute of Oncology, Milan, Italy.
authors.forename: Aron
authors.initials: A
authors.lastname: Goldhirsch
authors.affiliation: Medical Oncology Clinic, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Evandro
authors.initials: E
authors.lastname: de Azambuja
authors.affiliation: Clinical Oncology, Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Gilberto
authors.initials: G
authors.lastname: Castro
authors.affiliation: Helios Klinikum Berlin Buch, Multidisciplinary Breast Cancer Center, Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Untch
authors.affiliation: Breast Unit, Royal Marsden Hospital, and The Institute of Cancer Research, London, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Smith
authors.affiliation: Department of Medical Oncology, San Raffaele Hospital, Scientific Institute, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Gianni
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Jose
authors.initials: J
authors.lastname: Baselga
authors.affiliation: F Hoffmann-La Roche, Basel, Switzerland.
authors.forename: Nedal
authors.initials: N
authors.lastname: Al-Sakaff
authors.affiliation: F Hoffmann-La Roche, Basel, Switzerland.
authors.forename: Sabine
authors.initials: S
authors.lastname: Lauer
authors.affiliation: Frontier Science Scotland Ltd, Kincraig, Kingussie, UK.
authors.forename: Eleanor
authors.initials: E
authors.lastname: McFadden
authors.affiliation: Avera Cancer Institute Center for Precision Oncology, Sioux Falls, SD, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Leyland-Jones
authors.affiliation: Deakin University, Waurn Ponds, VIC, Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: Bell
authors.affiliation: Breast Unit, Royal Marsden Hospital, and The Institute of Cancer Research, London, UK.
authors.forename: Mitch
authors.initials: M
authors.lastname: Dowsett
authors.affiliation: Department of Gynecology and Obstetrics, Sana Klinikum Offenbach, Offenbach, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Jackisch
mesh_terms: D000328:Adult; D000368:Aged; D000074322:Antineoplastic Agents, Immunological / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D017024:Chemotherapy, Adjuvant / Q000379:methods; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006331:Heart Diseases / Q000139:chemically induced; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D000068878:Trastuzumab / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000074322:Antineoplastic Agents, Immunological; D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human