title: Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 adjuvant breast cancer trial.
abstract: OBJECTIVE
  To assess cardiac safety and potential cardiac risk factors associated with trastuzumab in the NCCTG N9831 Intergroup adjuvant breast cancer trial.
  
  
  METHODS
  Patients with HER2-positive operable breast cancer were randomly assigned to doxorubicin plus cyclophosphamide (AC) followed by either weekly paclitaxel (arm A); paclitaxel then trastuzumab (arm B); or paclitaxel plus trastuzumab then trastuzumab alone (arm C). Left ventricular ejection fraction (LVEF) was evaluated at registration and 3, 6, 9, and 18 to 21 months.
  
  
  RESULTS
  Of 2,992 patients completing AC, 5.0% had LVEF decreases disallowing trastuzumab (decrease below normal: 2.4%, decrease > 15%: 2.6%). There were 1,944 patients with satisfactory or no LVEF evaluation who proceeded to post-AC therapy. Cardiac events (congestive heart failure [CHF] or cardiac death [CD]): arm A, n = 3 (2 CHF, 1 CD); arm B, n = 19 (18 CHF, 1 CD); arm C, n = 19 (all CHF); 3-year cumulative incidence: 0.3%, 2.8%, and 3.3%, respectively. Cardiac function improved in most CHF cases following trastuzumab discontinuation and cardiac medication. Factors associated with increased risk of a cardiac event in arms B and C: older age (P < .003), prior/current antihypertensive agents (P = .005), and lower registration LVEF (P = .033). Incidence of asymptomatic LVEF decreases requiring holding trastuzumab was 8% to 10%; LVEF recovered and trastuzumab was restarted in approximately 50%.
  
  
  CONCLUSIONS
  The cumulative incidence of post-AC cardiac events at 3 years was higher in the trastuzumab-containing arms versus the control arm, but by less than 4%. Older age, lower registration LVEF, and antihypertensive medications are associated with increased risk of cardiac dysfunction in patients receiving trastuzumab following AC.
authors.affiliation: Division of Hematology/Oncology, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224, USA. perez.edith@mayo.edu
authors.forename: Edith A
authors.initials: EA
authors.lastname: Perez
authors.forename: Vera J
authors.initials: VJ
authors.lastname: Suman
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Davidson
authors.forename: George W
authors.initials: GW
authors.lastname: Sledge
authors.forename: Peter A
authors.initials: PA
authors.lastname: Kaufman
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Hudis
authors.forename: Silvana
authors.initials: S
authors.lastname: Martino
authors.forename: Julie R
authors.initials: JR
authors.lastname: Gralow
authors.forename: Shaker R
authors.initials: SR
authors.lastname: Dakhil
authors.forename: James N
authors.initials: JN
authors.lastname: Ingle
authors.forename: Eric P
authors.initials: EP
authors.lastname: Winer
authors.forename: Karen A
authors.initials: KA
authors.lastname: Gelmon
authors.forename: Bernard J
authors.initials: BJ
authors.lastname: Gersh
authors.forename: Allan S
authors.initials: AS
authors.lastname: Jaffe
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Rodeheffer
mesh_terms: D000293:Adolescent; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000150:complications / Q000188:drug therapy*; D003520:Cyclophosphamide / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006321:Heart / Q000187:drug effects*; D006333:Heart Failure / Q000139:chemically induced* / Q000188:drug therapy; D006801:Humans; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D012307:Risk Factors; D015996:Survival Rate; D013629:Tamoxifen / Q000008:administration & dosage; D000068878:Trastuzumab; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D003520:Cyclophosphamide; D004317:Doxorubicin; D005472:Fluorouracil; D018719:Erb-b2 Receptor Tyrosine Kinases; D013629:Tamoxifen; D000068878:Trastuzumab