Long-Term Cardiac Safety Analysis of NCCTG N9831 (Alliance) Adjuvant Trastuzumab Trial

J Clin Oncol. 2016 Feb 20;34(6):581-7. doi: 10.1200/JCO.2015.61.8413. Epub 2015 Sep 21.


Purpose: 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.

Conclusion: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age Factors
  • Aged
  • Antihypertensive Agents / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Arrhythmias, Cardiac / mortality
  • Breast Neoplasms / chemistry
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / surgery
  • Cardiovascular Diseases / epidemiology*
  • Cardiovascular Diseases / mortality
  • Chemotherapy, Adjuvant
  • Cyclophosphamide / administration & dosage
  • Doxorubicin / administration & dosage
  • Female
  • Follow-Up Studies
  • Heart Failure / epidemiology
  • Humans
  • Incidence
  • Middle Aged
  • Myocardial Infarction / mortality
  • Paclitaxel / administration & dosage
  • Receptor, ErbB-2 / analysis
  • Risk Factors
  • Stroke Volume
  • Trastuzumab / administration & dosage*
  • Ventricular Function, Left
  • Young Adult


  • Antihypertensive Agents
  • Doxorubicin
  • Cyclophosphamide
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Trastuzumab
  • Paclitaxel