title: 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.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  F Hoffmann-La Roche, Michelangelo Foundation.
authors.affiliation: Department of Medical Oncology, San Raffaele Institute, Milan, Italy. gianni.luca@hsr.it
authors.forename: Luca
authors.initials: L
authors.lastname: Gianni
authors.forename: Urania
authors.initials: U
authors.lastname: Dafni
authors.forename: Richard D
authors.initials: RD
authors.lastname: Gelber
authors.forename: Evandro
authors.initials: E
authors.lastname: Azambuja
authors.forename: Susanne
authors.initials: S
authors.lastname: Muehlbauer
authors.forename: Aron
authors.initials: A
authors.lastname: Goldhirsch
authors.forename: Michael
authors.initials: M
authors.lastname: Untch
authors.forename: Ian
authors.initials: I
authors.lastname: Smith
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.forename: Christian
authors.initials: C
authors.lastname: Jackisch
authors.forename: David
authors.initials: D
authors.lastname: Cameron
authors.forename: Max
authors.initials: M
authors.lastname: Mano
authors.forename: José Luiz
authors.initials: JL
authors.lastname: Pedrini
authors.forename: Andrea
authors.initials: A
authors.lastname: Veronesi
authors.forename: Cesar
authors.initials: C
authors.lastname: Mendiola
authors.forename: Anna
authors.initials: A
authors.lastname: Pluzanska
authors.forename: Vladimir
authors.initials: V
authors.lastname: Semiglazov
authors.forename: Eduard
authors.initials: E
authors.lastname: Vrdoljak
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Eckart
authors.forename: Zhenzhou
authors.initials: Z
authors.lastname: Shen
authors.forename: George
authors.initials: G
authors.lastname: Skiadopoulos
authors.forename: Marion
authors.initials: M
authors.lastname: Procter
authors.forename: Kathleen I
authors.initials: KI
authors.lastname: Pritchard
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Piccart-Gebhart
authors.forename: Richard
authors.initials: R
authors.lastname: Bell
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008875:Middle Aged; D016032:Randomized Controlled Trials as Topic; D018719:Erb-b2 Receptor Tyrosine Kinases; D016019:Survival Analysis; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human