title: Efficacy of high-dose alkylating chemotherapy in HER2/neu-negative breast cancer.
abstract: BACKGROUND
  High-dose chemotherapy in the adjuvant treatment of breast cancer has been abandoned by many.
  
  
  METHODS
  885 patients with stage III primary breast cancer and four or more axillary lymph node metastases were randomised to receive either five courses of FEC (fluorouracil, epirubicin and cyclophosphamide) followed by radiation therapy and tamoxifen, or the same treatment but with high-dose alkylating chemotherapy (cyclophosphamide, thiotepa and carboplatin) replacing the fifth course of FEC. Of these patients, 621 had HER2/neu-negative disease, as determined by immunohistochemistry and chromogenic in situ hybridisation.
  
  
  RESULTS
  At a median follow-up of 84 months, a trend for a better relapse-free survival was observed in the high-dose arm: (hazard ratio (HR) 0.84, P = 0.076, two-sided). The 621 patients with HER2/neu-negative disease benefited from high-dose therapy, while patients with HER2/neu-positive disease did not (test for interaction, P = 0.006). There was a marked relapse-free survival benefit for patients with HER2/neu-negative disease (71.5% versus 59.1%, 5 years after randomisation; HR 0.68, P = 0.002) and also a survival benefit (78.2% versus 71.0% at 5 years; HR 0.72, P = 0.02).
  
  
  CONCLUSIONS
  The findings from this subgroup analysis provide additional evidence that HER2/neu-positive breast cancer is relatively resistant to alkylating agents. For HER2/neu-negative tumours, however, high-dose chemotherapy should remain the subject of clinical studies.
authors.affiliation: Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam. sroden@nki.nl
authors.forename: S
authors.initials: S
authors.lastname: Rodenhuis
authors.forename: M
authors.initials: M
authors.lastname: Bontenbal
authors.forename: Q G C M
authors.initials: QG
authors.lastname: van Hoesel
authors.forename: W M
authors.initials: WM
authors.lastname: Smit
authors.forename: M A
authors.initials: MA
authors.lastname: Nooij
authors.forename: E E
authors.initials: EE
authors.lastname: Voest
authors.forename: E
authors.initials: E
authors.lastname: van der Wall
authors.forename: P
authors.initials: P
authors.lastname: Hupperets
authors.forename: H
authors.initials: H
authors.lastname: van Tinteren
authors.forename: J L
authors.initials: JL
authors.lastname: Peterse
authors.forename: M J
authors.initials: MJ
authors.lastname: van de Vijver
authors.forename: E G E
authors.initials: EG
authors.lastname: de Vries
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D018734:Genes, erbB-2; D006801:Humans; D007150:Immunohistochemistry; D016609:Neoplasms, Second Primary / Q000139:chemically induced; D011446:Prospective Studies; D016019:Survival Analysis
chemical_list: D018906:Antineoplastic Agents, Alkylating