title: 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial.
abstract: BACKGROUND
  Since 2005, 12 months of adjuvant trastuzumab has been the standard treatment for patients with HER2-positive early-stage breast cancer. However, the optimum duration of treatment has been debated. We did a non-inferiority trial of a shorter exposure of 6 months versus the standard 12 months of trastuzumab for patients with early breast cancer.
  
  
  METHODS
  We did an open-label, randomised, phase 3 trial in 156 centres in France. Patients with HER2-positive early breast cancer who had received at least four cycles of chemotherapy, had breast-axillary surgery, and had received up to 6 months of trastuzumab (administered by intravenous infusions over 30-90 min every 3 weeks; initial loading dose 8 mg/kg; 6 mg/kg thereafter) before randomisation were eligible. Patients were randomly assigned via central randomisation procedure with web-based software to continue trastuzumab for another 6 months (12 months total duration; control group) or to discontinue trastuzumab at 6 months (6 months total duration; experimental group). Randomisation was stratified by concomitant or sequential administration of trastuzumab with chemotherapy, oestrogen-receptor status, and centre using a minimisation algorithm. The primary endpoint was disease-free survival, with a prespecified non-inferiority margin of 1·15. Analyses were done in the intention-to-treat population. This study is registered at ClinicalTrials.gov, number NCT00381901.
  
  
  RESULTS
  1691 patients were randomly assigned to receive 12 months of trastuzumab and 1693 to receive 6 months of trastuzumab; 1690 patients in each group were included in the intention-to-treat analyses. After a median follow-up of 42·5 months (IQR 30·1-51·6), 175 disease-free survival events were noted in the 12-month group and 219 in the 6-month group. 2-year disease-free survival was 93·8% (95% CI 92·6-94·9) in the 12-month group and 91·1% (89·7-92·4) in the 6-month group (hazard ratio 1·28, 95% CI 1·05-1·56; p=0·29). 119 (93%) of the 128 cardiac events (clinical or based on assessment of left ventricular ejection fraction) occurred while patients were receiving trastuzumab. Significantly more patients in the 12-month group experienced a cardiac event than did those in the 6-month group (96 [5·7%] of 1690 patients vs 32 [1·9%] of 1690 patients, p<0·0001).
  
  
  CONCLUSIONS
  After 3·5 years follow-up, we failed to show that 6 months of treatment with trastuzumab was non-inferior to 12 months of trastuzumab. Despite the higher rates of cardiac events, 12 months of adjuvant trastuzmab should remain the standard of care.
  
  
  BACKGROUND
  French National Cancer Institute.
authors.affiliation: University Hospital J Minjoz, Besançon, France. xavier.pivot@univ-fcomte.fr
authors.forename: Xavier
authors.initials: X
authors.lastname: Pivot
authors.forename: Gilles
authors.initials: G
authors.lastname: Romieu
authors.forename: Marc
authors.initials: M
authors.lastname: Debled
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Pierga
authors.forename: Pierre
authors.initials: P
authors.lastname: Kerbrat
authors.forename: Thomas
authors.initials: T
authors.lastname: Bachelot
authors.forename: Alain
authors.initials: A
authors.lastname: Lortholary
authors.forename: Marc
authors.initials: M
authors.lastname: Espié
authors.forename: Pierre
authors.initials: P
authors.lastname: Fumoleau
authors.forename: Daniel
authors.initials: D
authors.lastname: Serin
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Jacquin
authors.forename: Christelle
authors.initials: C
authors.lastname: Jouannaud
authors.forename: Maria
authors.initials: M
authors.lastname: Rios
authors.forename: Sophie
authors.initials: S
authors.lastname: Abadie-Lacourtoisie
authors.forename: Nicole
authors.initials: N
authors.lastname: Tubiana-Mathieu
authors.forename: Laurent
authors.initials: L
authors.lastname: Cany
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Catala
authors.forename: David
authors.initials: D
authors.lastname: Khayat
authors.forename: Iris
authors.initials: I
authors.lastname: Pauporté
authors.forename: Andrew
authors.initials: A
authors.lastname: Kramar
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000556:secondary / Q000601:surgery*; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D055088:Early Detection of Cancer; D005260:Female; D005602:France; D006331:Heart Diseases / Q000139:chemically induced; D006801:Humans; D007262:Infusions, Intravenous; D053208:Kaplan-Meier Estimate; D008408:Mastectomy; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D016609:Neoplasms, Second Primary; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D018714:Radiotherapy, Adjuvant; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis* / Q000235:genetics; D013997:Time Factors; D000068878:Trastuzumab; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human