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

J Clin Oncol. 2005 Nov 1;23(31):7811-9. doi: 10.1200/JCO.2005.02.4091.

Abstract

Purpose: 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.

Patients and 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.

Conclusion: 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.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antibodies, Monoclonal / adverse effects*
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / secondary
  • Chemotherapy, Adjuvant
  • Cyclophosphamide / administration & dosage
  • Doxorubicin / administration & dosage
  • Female
  • Heart / drug effects*
  • Heart Failure / chemically induced*
  • Heart Failure / drug therapy
  • Humans
  • Incidence
  • Lymph Nodes
  • Lymphatic Metastasis
  • Middle Aged
  • Neoadjuvant Therapy
  • Paclitaxel / administration & dosage
  • Receptor, ErbB-2 / metabolism*
  • Trastuzumab
  • Ventricular Dysfunction, Left / chemically induced*
  • Ventricular Dysfunction, Left / drug therapy

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Doxorubicin
  • Cyclophosphamide
  • Receptor, ErbB-2
  • Trastuzumab
  • Paclitaxel