title: Trastuzumab-associated cardiac events in the Persephone trial.
abstract: BACKGROUND
  We report cardiac events in the Persephone trial which compares 6-12 months of adjuvant trastuzumab in women with confirmed HER2-positive, early-stage breast cancer.
  
  
  METHODS
  Clinical cardiac events were defined as any of the following: symptoms and/or signs of congestive heart failure (CHF) and new or altered CHF medication. In addition, left ventricular ejection fraction (LVEF) was measured at baseline and then 3 monthly for 12 months.
  
  
  RESULTS
  A total of 2500 patients, aged 22-82, were included: 1251 randomised to 12 months and 1249 to 6 months of trastuzumab treatment. A total of 93% (2335/2500) received anthracyclines, 49% of these (1136/2335) with taxanes. Cardiotoxicity delayed treatment in 6% of 12-month and 4% of 6-month patients (P=0.01), and stopped treatment early in 8% (96/1214) of 12-month and 4% (45/1216) of 6-month patients (P<0.0001). Between 7 and 12 months, more 12-month than 6-month patients had LVEFs<50% (8% vs 5%; P=0.004). LVEFs showed quadratic change over time, and 6-month patients had a more rapid recovery (P=0.02). In a landmark analysis twice as many 12-month patients, free of cardiac events at 6 months, had cardiac problems in months 7-12 (6% (66/1046) vs 3% (29/1035) of 6-month patients (P=0.0002)). Lower baseline LVEF predicted more cardiac dysfunction in both arms (reference ⩾65%: 55 to <65% OR 1.61 (95% CI 1.26-2.04); <55% OR 5.22 (3.42-7.95)) as did increasing age (reference <50: 50-59 OR 1.58 (1.17-2.12), 60-69 OR 1.91 (1.42-2.57)) 70+ OR 2.72 (1.82-4.08)) and prior use of cardiac medication (OR 8.46 (4.69-15.25)). >3 cycles of anthracycline was associated with higher risk of cardiac events only for 12-month patients (OR 1.41 (1.04-1.90)), and not for 6-month patients (OR 1.28 (0.91-1.79)).
  
  
  CONCLUSIONS
  We demonstrate significantly fewer cardiac events from 6 months of adjuvant trastuzumab compared with that from 12 months. This cardiac signal adds importance to the question of the optimum duration of adjuvant trastuzumab treatment. If 6 months is proven to have non-inferior outcomes to 12 months treatment, these data would support 6 months as the standard of care.
authors.affiliation: Department of Oncology, University of Cambridge, (Box 193-R4) Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.|NIHR Cambridge Biomedical Research Centre and Cambridge Experimental Cancer Medicine Centre, Box 277, Hills Road, Cambridge CB2 0QQ, UK.|Cambridge Breast Unit and Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Helena M
authors.initials: HM
authors.lastname: Earl
authors.affiliation: Cambridge Clinical Trials Unit - Cancer Theme, Cambridge University NHS Foundation Trust, Box 279 (S4), Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Vallier
authors.affiliation: Warwick Clinical Trials Unit, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK.
authors.forename: Janet
authors.initials: J
authors.lastname: Dunn
authors.affiliation: Warwick Clinical Trials Unit, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK.
authors.forename: Shrushma
authors.initials: S
authors.lastname: Loi
authors.affiliation: Warwick Clinical Trials Unit, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Ogburn
authors.affiliation: Cambridge Breast Unit and Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, UK.|Peterborough and Stamford Hospitals NHS Foundation Trust and Cambridge University Hospital NHS Foundation Trust, Peterborough City Hospital, Edith Cavell Campus, Bretton Gate, Peterborough PE3 9GZ, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: McAdam
authors.affiliation: Department of Oncology, University of Cambridge, (Box 193-R4) Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.|Cambridge Breast Unit and Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Luke
authors.initials: L
authors.lastname: Hughes-Davies
authors.affiliation: Norfolk & Norwich University Hospital, Colney Lane, Norwich NR4 7UY, UK.|James Paget University Hospital, Lowestoft Rd, Gorleston-on-Sea, Great Yarmouth, Norfolk NR31 6LA, UK.
authors.forename: Adrian
authors.initials: A
authors.lastname: Harnett
authors.affiliation: Department of Oncology, University of Cambridge, (Box 193-R4) Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.|NIHR Cambridge Biomedical Research Centre and Cambridge Experimental Cancer Medicine Centre, Box 277, Hills Road, Cambridge CB2 0QQ, UK.|Cambridge Breast Unit and Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Jean
authors.initials: J
authors.lastname: Abraham
authors.affiliation: The Christie NHS Foundation Trust, 550 Wilmslow Rd, Manchester M20 4BX, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wardley
authors.affiliation: University of Edinburgh Cancer Research Centre, IGMM, Western General Hospital, Crewe Road South, Edinburgh EH4 2XR, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Cameron
authors.affiliation: Mount Vernon Cancer Centre, Rickmansworth Rd, Northwood, London HA6 2RN, UK.
authors.forename: David
authors.initials: D
authors.lastname: Miles
authors.affiliation: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.|The Queen Elizabeth Hospital King's Lynn NHS Foundation Trust, Gayton Rd, King's Lynn, Norfolk PE30 4ET, UK.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Gounaris
authors.affiliation: Department of Cardiology, Freeman Hospital, Freeman Rd, Newcastle upon Tyne, Tyne and Wear NE7 7DN, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Plummer
authors.affiliation: Warwick Clinical Trials Unit, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Hiller
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects*; D006333:Heart Failure / Q000139:chemically induced*; D006801:Humans; D008875:Middle Aged; D000068878:Trastuzumab / Q000009:adverse effects*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D000068878:Trastuzumab