title: Long-Term Cardiac Safety Analysis of NCCTG N9831 (Alliance) Adjuvant Trastuzumab Trial.
abstract: OBJECTIVE
  Significant improvement in survival outcomes has been established with the addition of trastuzumab to adjuvant chemotherapy for human epidermal growth factor receptor 2 (HER2) -positive early breast cancer treatment. However, trastuzumab may increase the risk of cardiac toxicity, and long-term evaluation of its incidence and risk factors are warranted.
  
  
  METHODS
  NCCTG (Alliance) N9831 trial compared adjuvant doxorubicin and cyclophosphamide (AC) followed by either weekly paclitaxel (arm A); paclitaxel then trastuzumab (arm B); or paclitaxel plus trastuzumab followed by trastuzumab alone (arm C) in patients with HER2-positive breast cancer. Cumulative incidence of cardiac events (CE) and left ventricular ejection fraction (LVEF) were evaluated in 1,944 women who proceeded to post-AC therapy. Risk factors for trastuzumab-induced cardiac toxicity were identified by Cox regression models.
  
  
  RESULTS
  The 6-year cumulative incidence of CE was 0.6% in arm A, 2.8% in arm B, and 3.4% in arm C. At a median follow-up of 9.2 years, only two additional CHF diagnoses (of 1,046 patients) occurred beyond our previously reported follow-up time of 3.75 years. LVEF recovered in the majority of the patients who developed CHF. There were two cardiac deaths in arm A and one each in arms B and C. Age of 60 years or older, registration LVEF less than 65%, and use of antihypertensive medications were associated with an increased risk of CE in arms B and C.
  
  
  CONCLUSIONS
  The cumulative incidence of CE at 6 years was slightly higher with the addition of trastuzumab; however, the late development of CE is infrequent. Trastuzumab (in the context of anthracycline- and taxane-based therapy) continues to have a favorable benefit-risk ratio.
authors.affiliation: Pooja P. Advani, Gerardo Colon-Otero, and Edith A. Perez, Mayo Clinic, Jacksonville, FL; and Karla V. Ballman and Travis J. Dockter, Mayo Clinic, Rochester, MN.
authors.forename: Pooja P
authors.initials: PP
authors.lastname: Advani
authors.affiliation: Pooja P. Advani, Gerardo Colon-Otero, and Edith A. Perez, Mayo Clinic, Jacksonville, FL; and Karla V. Ballman and Travis J. Dockter, Mayo Clinic, Rochester, MN.
authors.forename: Karla V
authors.initials: KV
authors.lastname: Ballman
authors.affiliation: Pooja P. Advani, Gerardo Colon-Otero, and Edith A. Perez, Mayo Clinic, Jacksonville, FL; and Karla V. Ballman and Travis J. Dockter, Mayo Clinic, Rochester, MN.
authors.forename: Travis J
authors.initials: TJ
authors.lastname: Dockter
authors.affiliation: Pooja P. Advani, Gerardo Colon-Otero, and Edith A. Perez, Mayo Clinic, Jacksonville, FL; and Karla V. Ballman and Travis J. Dockter, Mayo Clinic, Rochester, MN.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Colon-Otero
authors.affiliation: Pooja P. Advani, Gerardo Colon-Otero, and Edith A. Perez, Mayo Clinic, Jacksonville, FL; and Karla V. Ballman and Travis J. Dockter, Mayo Clinic, Rochester, MN. perez.edith@mayo.edu.
authors.forename: Edith A
authors.initials: EA
authors.lastname: Perez
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000959:Antihypertensive Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001145:Arrhythmias, Cardiac / Q000401:mortality; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000601:surgery; D002318:Cardiovascular Diseases / Q000453:epidemiology* / Q000401:mortality; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D006333:Heart Failure / Q000453:epidemiology; D006801:Humans; D015994:Incidence; D008875:Middle Aged; D009203:Myocardial Infarction / Q000401:mortality; D017239:Paclitaxel / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D012307:Risk Factors; D013318:Stroke Volume; D000068878:Trastuzumab / Q000008:administration & dosage*; D016277:Ventricular Function, Left; D055815:Young Adult
chemical_list: D000959:Antihypertensive Agents; D003520:Cyclophosphamide; D004317:Doxorubicin; D017239:Paclitaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human