title: Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31.
abstract: OBJECTIVE
  Trastuzumab is effective in treating human epidermal growth factor receptor 2 (HER2) -positive breast cancer, but it increases frequency of cardiac dysfunction (CD) when used with or after anthracyclines.
  
  
  METHODS
  National Surgical Adjuvant Breast and Bowel Project trial B-31 compared doxorubicin and cyclophosphamide (AC) followed by paclitaxel with AC followed by paclitaxel plus 52 weeks of trastuzumab beginning concurrently with paclitaxel in patients with node-positive, HER2-positive breast cancer. Initiation of trastuzumab required normal post-AC left ventricular ejection fraction (LVEF) on multiple-gated acquisition scan. If symptoms suggestive of congestive heart failure (CHF) developed, source documents were blindly reviewed by an independent panel of cardiologists to determine whether criteria were met for a cardiac event (CE), which was defined as New York Heart Association class III or IV CHF or possible/probable cardiac death. Frequencies of CEs were compared between arms.
  
  
  RESULTS
  Among patients with normal post-AC LVEF who began post-AC treatment, five of 814 control patients subsequently had confirmed CEs (four CHFs and one cardiac death) compared with 31 of 850 trastuzumab-treated patients (31 CHFs and no cardiac deaths). The difference in cumulative incidence at 3 years was 3.3% (4.1% for trastuzumab-treated patients minus 0.8% for control patients; 95% CI, 1.7% to 4.9%). Twenty-seven of the 31 patients in the trastuzumab arm have been followed for > or = 6 months after diagnosis of a CE; 26 were asymptomatic at last assessment, and 18 remained on cardiac medication. CHFs were more frequent in older patients and patients with marginal post-AC LVEF. Fourteen percent of patients discontinued trastuzumab because of asymptomatic decreases in LVEF; 4% discontinued trastuzumab because of symptomatic cardiotoxicity.
  
  
  CONCLUSIONS
  Administering trastuzumab with paclitaxel after AC increases incidence of CHF and lesser CD. Potential cardiotoxicity should be carefully considered when discussing benefits and risks of this therapy.
authors.affiliation: National Surgical Adjuvant Breast and Bowel Project (NSABP), University of Pittsburgh, PA, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Tan-Chiu
authors.forename: Greg
authors.initials: G
authors.lastname: Yothers
authors.forename: Edward
authors.initials: E
authors.lastname: Romond
authors.forename: Charles E
authors.initials: CE
authors.lastname: Geyer
authors.forename: Michael
authors.initials: M
authors.lastname: Ewer
authors.forename: Deborah
authors.initials: D
authors.lastname: Keefe
authors.forename: Richard P
authors.initials: RP
authors.lastname: Shannon
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Swain
authors.forename: Ann
authors.initials: A
authors.lastname: Brown
authors.forename: Louis
authors.initials: L
authors.lastname: Fehrenbacher
authors.forename: Victor G
authors.initials: VG
authors.lastname: Vogel
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Seay
authors.forename: Priya
authors.initials: P
authors.lastname: Rastogi
authors.forename: Eleftherios P
authors.initials: EP
authors.lastname: Mamounas
authors.forename: Norman
authors.initials: N
authors.lastname: Wolmark
authors.forename: John
authors.initials: J
authors.lastname: Bryant
mesh_terms: D000911:Antibodies, Monoclonal / Q000009:adverse effects*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D006321:Heart / Q000187:drug effects*; D006333:Heart Failure / Q000139:chemically induced* / Q000188:drug therapy; D006801:Humans; D015994:Incidence; D008198:Lymph Nodes; D008207:Lymphatic Metastasis; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D017239:Paclitaxel / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D000068878:Trastuzumab; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced* / Q000188:drug therapy
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D003520:Cyclophosphamide; D004317:Doxorubicin; D017239:Paclitaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab