title: Classical cyclophosphamide, methotrexate, and fluorouracil chemotherapy is more effective in triple-negative, node-negative breast cancer: results from two randomized trials of adjuvant chemoendocrine therapy for node-negative breast cancer.
abstract: OBJECTIVE
  Retrospective studies suggest that primary breast cancers lacking estrogen receptor (ER) and progesterone receptor (PR) and not overexpressing human epidermal growth factor receptor 2 (HER2; triple-negative tumors) are particularly sensitive to DNA-damaging chemotherapy with alkylating agents.
  
  
  METHODS
  Patients enrolled in International Breast Cancer Study Group Trials VIII and IX with node-negative, operable breast cancer and centrally assessed ER, PR, and HER2 were included (n = 2,257). The trials compared three or six courses of adjuvant classical cyclophosphamide, methotrexate, and fluorouracil (CMF) with or without endocrine therapy versus endocrine therapy alone. We explored patterns of recurrence by treatment according to three immunohistochemically defined tumor subtypes: triple negative, HER2 positive and endocrine receptor absent, and endocrine receptor present.
  
  
  RESULTS
  Patients with triple-negative tumors (303 patients; 13%) were significantly more likely to have tumors > 2 cm and grade 3 compared with those in the HER2-positive, endocrine receptor-absent, and endocrine receptor-present subtypes. No clear chemotherapy benefit was observed in endocrine receptor-present disease (hazard ratio [HR], 0.90; 95% CI, 0.74 to 1.11). A statistically significantly greater benefit for chemotherapy versus no chemotherapy was observed in triple-negative breast cancer (HR, 0.46; 95% CI, 0.29 to 0.73; interaction P = .009 v endocrine receptor-present disease). The magnitude of the chemotherapy effect was lower in HER2-positive endocrine receptor-absent disease (HR, 0.58; 95% CI, 0.29 to 1.17; interaction P = .24 v endocrine receptor-present disease).
  
  
  CONCLUSIONS
  The magnitude of benefit of CMF chemotherapy is largest in patients with triple-negative, node-negative breast cancer.
authors.affiliation: Research Unit in Medical Senology, Department of Medicine, European Institute of Oncology, Università degli Studi di Milano, Milan, Italy. marco.colleoni@ieo.it
authors.forename: Marco
authors.initials: M
authors.lastname: Colleoni
authors.forename: Bernard F
authors.initials: BF
authors.lastname: Cole
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Viale
authors.forename: Meredith M
authors.initials: MM
authors.lastname: Regan
authors.forename: Karen N
authors.initials: KN
authors.lastname: Price
authors.forename: Eugenio
authors.initials: E
authors.lastname: Maiorano
authors.forename: Mauro G
authors.initials: MG
authors.lastname: Mastropasqua
authors.forename: Diana
authors.initials: D
authors.lastname: Crivellari
authors.forename: Richard D
authors.initials: RD
authors.lastname: Gelber
authors.forename: Aron
authors.initials: A
authors.lastname: Goldhirsch
authors.forename: Alan S
authors.initials: AS
authors.lastname: Coates
authors.forename: Barry A
authors.initials: BA
authors.lastname: Gusterson
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007124:Immunoenzyme Techniques; D008198:Lymph Nodes / Q000378:metabolism*; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D009367:Neoplasm Staging; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism*; D012189:Retrospective Studies; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D003520:Cyclophosphamide; D005472:Fluorouracil; D008727:Methotrexate; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone
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