title: Pilot study of the mechanism of action of preoperative trastuzumab in patients with primary operable breast tumors overexpressing HER2.
abstract: OBJECTIVE
  To elucidate the mechanism by which trastuzumab, a humanized monoclonal antibody against HER2 with proven survival benefit in women with HER2-positive metastatic breast cancer, mediates its antitumor activity.
  
  
  METHODS
  A pilot study including 11 patients with HER2-positive tumors treated in a neo-adjuvant setting with trastuzumab was performed. Trastuzumab was administered i.v. at a dose of 4 mg/kg followed by three weekly i.v. doses of 2 mg/kg. The primary tumor was surgically removed 7 days after the last treatment. Surgical samples, tumor biopsies, and lymphocytes from these patients were collected for biological studies.
  
  
  RESULTS
  Clinical data indicated one complete pathological remission and four partial remissions using RECIST (Response Evaluation Criteria in Solid Tumors). Trastuzumab was well tolerated and neither serious adverse events nor changes in cardiac function were observed during this short-term treatment and after surgery. The biological data showed that, independent of response, (a) all patients showed high levels of circulating trastuzumab; (b) saturating level of trastuzumab was present in all of the tumors; (c) no down-modulation of HER2 was observed in any tumors; (d) no changes in vessel diameter was observed in any tumors; (e) no changes in proliferation was observed in any tumors; and (f) a strong infiltration by lymphoid cells was observed in all cases. Patients with complete remission or partial remission were found to have a higher in situ infiltration of leukocytes and a higher capability to mediate in vitro antibody-dependent cellular cytotoxicity activity.
  
  
  CONCLUSIONS
  The results of this pilot study argue against trastuzumab activity in patients through down-modulation of HER2 but in favor of antibody-dependent cellular cytotoxicity guiding efforts to optimize the use of trastuzumab in breast cancer patients.
authors.affiliation: Department of Surgery, European Institute of Oncology, Milano, 1taly.
authors.forename: Roberto
authors.initials: R
authors.lastname: Gennari
authors.forename: Sylvie
authors.initials: S
authors.lastname: Menard
authors.forename: Francesco
authors.initials: F
authors.lastname: Fagnoni
authors.forename: Luisa
authors.initials: L
authors.lastname: Ponchio
authors.forename: Mario
authors.initials: M
authors.lastname: Scelsi
authors.forename: Elda
authors.initials: E
authors.lastname: Tagliabue
authors.forename: Fabio
authors.initials: F
authors.lastname: Castiglioni
authors.forename: Laura
authors.initials: L
authors.lastname: Villani
authors.forename: Cesare
authors.initials: C
authors.lastname: Magalotti
authors.forename: Nadia
authors.initials: N
authors.lastname: Gibelli
authors.forename: Barbara
authors.initials: B
authors.lastname: Oliviero
authors.forename: Bettina
authors.initials: B
authors.lastname: Ballardini
authors.forename: Gianantonio
authors.initials: G
authors.lastname: Da Prada
authors.forename: Alberto
authors.initials: A
authors.lastname: Zambelli
authors.forename: Alberto
authors.initials: A
authors.lastname: Costa
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000473:pathology / Q000601:surgery / Q000628:therapy*; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020360:Neoadjuvant Therapy; D010865:Pilot Projects; D011300:Preoperative Care; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D012074:Remission Induction; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab