title: First-line trastuzumab plus epirubicin and cyclophosphamide therapy in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: cardiac safety and efficacy data from the Herceptin, Cyclophosphamide, and Epirubicin (HERCULES) trial.
abstract: OBJECTIVE
  A high incidence of congestive heart failure (CHF) has been observed in patients with metastatic breast cancer (MBC) receiving doxorubicin-based chemotherapy and trastuzumab. The Herceptin, Cyclophosphamide, and Epirubicin (HERCULES) trial evaluated trastuzumab plus cyclophosphamide and the less cardiotoxic anthracycline epirubicin.
  
  
  METHODS
  This prospective trial combined a phase I dose-finding stage with a phase II randomized stage. In total, 120 patients with human epidermal growth factor receptor 2 (HER2) -positive MBC and adequate cardiac function received first-line trastuzumab (4 mg/kg intravenous loading dose, then 2 mg/kg every week) plus cyclophosphamide (600 mg/m(2)) and either epirubicin 60 mg/m(2) (HEC-60) or 90 mg/m(2) (HEC-90) for six cycles, followed by trastuzumab monotherapy until progression. Sixty patients with HER2-negative disease received epirubicin (90 mg/m(2)) and cyclophosphamide (EC-90) alone. The primary end point was dose-limiting cardiotoxicity (DLC).
  
  
  RESULTS
  Incidence of DLC was 5.0%, 1.7%, and 0% in the HEC-90, HEC-60, and EC-90 arms, respectively. All DLC events were manageable. There were no cardiac-related deaths. Other adverse-event profiles were comparable across the three arms, except febrile neutropenia, which was reported in 10% of the HEC-90 arm compared with 3% of the other arms. Tumor response rates were 57%, 60%, and 25% in the HEC-60, HEC-90, and EC-90 arms, respectively; median time to progression was 12.5, 10.1, and 7.6 months, respectively.
  
  
  CONCLUSIONS
  The HEC regimen is a promising treatment option for patients with HER2-positive MBC. The lower incidence of DLC with HEC, compared with the historic incidence associated with trastuzumab plus doxorubicin, supports further evaluation of the regimen, especially in adjuvant or neoadjuvant settings.
authors.affiliation: HELIOS Klinikum Berlin-Buch, Frauenheilkunde mit Geburtshilfe, Berlin, Germany. michael.untch@helios-kliniken.de
authors.forename: Michael
authors.initials: M
authors.lastname: Untch
authors.forename: Michael
authors.initials: M
authors.lastname: Muscholl
authors.forename: Sergei
authors.initials: S
authors.lastname: Tjulandin
authors.forename: Walter
authors.initials: W
authors.lastname: Jonat
authors.forename: Hans-Gerd
authors.initials: HG
authors.lastname: Meerpohl
authors.forename: Mikhail
authors.initials: M
authors.lastname: Lichinitser
authors.forename: Alexey G
authors.initials: AG
authors.lastname: Manikhas
authors.forename: Alexandra
authors.initials: A
authors.lastname: Coumbos
authors.forename: Rolf
authors.initials: R
authors.lastname: Kreienberg
authors.forename: Andreas
authors.initials: A
authors.lastname: du Bois
authors.forename: Nadia
authors.initials: N
authors.lastname: Harbeck
authors.forename: Christian
authors.initials: C
authors.lastname: Jackisch
authors.forename: Volkmar
authors.initials: V
authors.lastname: Müller
authors.forename: Matthias
authors.initials: M
authors.lastname: Pauschinger
authors.forename: Christoph
authors.initials: C
authors.lastname: Thomssen
authors.forename: Michaela
authors.initials: M
authors.lastname: Lehle
authors.forename: Olivier
authors.initials: O
authors.lastname: Catalani
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Lück
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D015331:Cohort Studies; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D015251:Epirubicin / Q000008:administration & dosage / Q000009:adverse effects; D005240:Feasibility Studies; D005260:Female; D006331:Heart Diseases / Q000139:chemically induced; D006801:Humans; D008875:Middle Aged; D011446:Prospective Studies; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis; D000068878:Trastuzumab; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D003520:Cyclophosphamide; D015251:Epirubicin; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human