title: Response to cyclophosphamide, methotrexate, and fluorouracil in lymph node-positive breast cancer according to HER2 overexpression and other tumor biologic variables.
abstract: OBJECTIVE
  There is considerable interest in biologic markers able to predict the response of cancer patients to therapy. HER2 overexpression is a potential indicator of responsiveness to doxorubicin and paclitaxel and of unresponsiveness to tamoxifen in breast carcinoma patients. However, the significance of HER2 overexpression in responsiveness to cyclophosphamide, methotrexate, and fluorouracil (CMF) has remained unclear. In this study, we investigated this issue in the 386 breast cancer patients in the first CMF controlled clinical trial with a 20-year follow-up.
  
  
  METHODS
  Node-positive breast carcinoma patients were randomly assigned to receive either no further treatment after radical mastectomy (179 women) or 12 monthly cycles of adjuvant CMF chemotherapy (207 women). Overexpression of HER2 and the status of other tumor variables was assessed by immunohistochemistry in at least 324 (84%) of the 386 patients. Statistical analyses were performed to assess the efficacy of CMF treatment for the subgroups defined by HER2 and the status of other variables using a Bayesian approach. The end points considered were relapse-free survival (RFS) and cause-specific survival (CSS).
  
  
  RESULTS
  Bayesian analysis of the treatment effect for HER2 and other variables indicated a clinical benefit from CMF treatment in all subgroups defined according to variables status. In particular regarding HER2 status, Bayesian estimates of RFS hazard ratios were equal to 0.484 and 0.641 and estimates of CSS hazard ratios were equal to 0.495 and 0.730 for HER2-positive and -negative tumors, respectively.
  
  
  CONCLUSIONS
  CMF treatment showed a clinical benefit in the considered subgroups, defined according to HER2 and other tumor variables status. Patients with HER2-positive or HER2-negative tumors benefit from CMF treatment, and the poor prognosis associated with the HER2 overexpression in the untreated group could be completely overcome by the chemotherapy treatment.
authors.affiliation: Molecular Targeting Unit, Department of Experimental Oncology, Scientific Direction, Istituto Nazionale Tumori, Milan, Italy. menard@istitutotumori.mi.it
authors.forename: S
authors.initials: S
authors.lastname: Ménard
authors.forename: P
authors.initials: P
authors.lastname: Valagussa
authors.forename: S
authors.initials: S
authors.lastname: Pilotti
authors.forename: L
authors.initials: L
authors.lastname: Gianni
authors.forename: E
authors.initials: E
authors.lastname: Biganzoli
authors.forename: P
authors.initials: P
authors.lastname: Boracchi
authors.forename: G
authors.initials: G
authors.lastname: Tomasic
authors.forename: P
authors.initials: P
authors.lastname: Casalini
authors.forename: E
authors.initials: E
authors.lastname: Marubini
authors.forename: M I
authors.initials: MI
authors.lastname: Colnaghi
authors.forename: N
authors.initials: N
authors.lastname: Cascinelli
authors.forename: G
authors.initials: G
authors.lastname: Bonadonna
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D001499:Bayes Theorem; D015415:Biomarkers; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D015409:Mastectomy, Radical; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D016016:Proportional Hazards Models; D011446:Prospective Studies; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D016019:Survival Analysis
chemical_list: D015415:Biomarkers; D003520:Cyclophosphamide; D005472:Fluorouracil; D008727:Methotrexate; D018719:Erb-b2 Receptor Tyrosine Kinases