title: Trastuzumab in combination with metronomic cyclophosphamide and methotrexate in patients with HER-2 positive metastatic breast cancer.
abstract: BACKGROUND
  HER2/neu overexpression is linked to promotion of angiogenesis in breast cancer. We therefore tested the activity of the combination of Trastuzumab with metronomic, low dose chemotherapy with cyclophosphamide (CTX) and methotrexate (MTX) in metastatic breast cancer (MBC).
  
  
  METHODS
  Between April 2002 and June 2005, twenty-two patients with metastatic breast cancer with the presence of overexpression or amplification of HER2-/neu, all pre-treated with trastuzumab plus other cytotoxics, were treated with trastuzumab (6 mg/kg every three weeks) in combination with metronomic chemotherapy (MTX 2.5 mg, bid on Day 1 and Day 4 every week) and CTX (50 mg daily) (CM).
  
  
  RESULTS
  The 22 enrolled patients are evaluable: most had an ECOG performance status of 0 (17 pts), and all were pre-treated with chemotherapy for metastatic disease; 14 had progressive disease at study entry, and 11 had progressive disease during the last trastuzumab therapy. Metastatic sites included: lung (5 pts), liver (14 pts), bone (12 pts), lymph nodes (8 pts), central nervous system (CNS) (9 pts). We observed 4 partial remission (PR) (18%, 95% CI 5-40%), 10 stable disease (SD) (46%, 95% CI 24-68%), and 8 PD (36%, CI 17-59%). The clinical benefit (RP plus RC plus SD for > or = 24 weeks) in all pts and in pts with disease resistant to previous trastuzumab therapy were 46% (95% CI, 24-68%) and 27% (95% CI, 6-61%), respectively. Median time to progression was 6 months and median duration of treatment was 5 months (range, 0,7 to 18.4 months and range, 1 to 18 months, respectively). Overall clinical toxicity was generally mild. Grade > or =2 reversible liver toxicity and leukopenia were reported in 5 and 3 pts, respectively.
  
  
  CONCLUSIONS
  The combination of trastuzumab and metronomic chemotherapy is effective and minimally toxic in advanced breast cancer patients. The efficacy observed in patients with disease resistant to trastuzumab supports the need of larger trial to confirm a role of this combination to delay acquired trastuzumab resistance.
authors.affiliation: Unit of Research in Medical Senology, Department of Medicine, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy. laura.orlando@ieo.it
authors.forename: Laura
authors.initials: L
authors.lastname: Orlando
authors.forename: Anna
authors.initials: A
authors.lastname: Cardillo
authors.forename: Raffaella
authors.initials: R
authors.lastname: Ghisini
authors.forename: Andrea
authors.initials: A
authors.lastname: Rocca
authors.forename: Alessandra
authors.initials: A
authors.lastname: Balduzzi
authors.forename: Rosalba
authors.initials: R
authors.lastname: Torrisi
authors.forename: Giulia
authors.initials: G
authors.lastname: Peruzzotti
authors.forename: Aron
authors.initials: A
authors.lastname: Goldhirsch
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Pietri
authors.forename: Marco
authors.initials: M
authors.lastname: Colleoni
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000556:secondary / Q000628:therapy; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000556:secondary / Q000628:therapy; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D004334:Drug Administration Schedule; D005260:Female; D005784:Gene Amplification; D018734:Genes, erbB-2; D006801:Humans; D007116:Immunization, Passive; D007970:Leukopenia / Q000139:chemically induced; D008113:Liver Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000556:secondary / Q000628:therapy; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000556:secondary / Q000628:therapy; D008207:Lymphatic Metastasis; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D009503:Neutropenia / Q000139:chemically induced; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology; D012074:Remission Induction; D000068878:Trastuzumab; D016896:Treatment Outcome; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D003520:Cyclophosphamide; D008727:Methotrexate; D009363:Neoplasm Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab