title: Trastuzumab mediates antibody-dependent cell-mediated cytotoxicity and phagocytosis to the same extent in both adjuvant and metastatic HER2/neu breast cancer patients.
abstract: BACKGROUND
  Monoclonal antibodies (mAb), such as trastuzumab are a valuable addition to breast cancer therapy. Data obtained from neoadjuvant settings revealed that antibody-dependent cell-mediated cytotoxicity (ADCC) is a major mechanism of action for the mAb trastuzumab. Conflicting results still call into question whether disease progression, prolonged treatment or concomitant chemotherapy influences ADCC and related immunological phenomena.
  
  
  METHODS
  We analyzed the activity of ADCC and antibody-dependent cell-mediated phagocytosis (ADCP) of peripheral blood mononuclear cells (PBMCs) from human epidermal growth factor receptor 2 (HER2/neu) positive breast cancer patients receiving trastuzumab therapy either in an adjuvant (n = 13) or metastatic (n = 15) setting as well as from trastuzumab treatment-naive (t-naive) HER2/neu negative patients (n = 15). PBMCs from healthy volunteers (n = 24) were used as controls. ADCC and ADCP activity was correlated with the expression of antibody binding Fc-gamma receptor (FcγR)I (CD64), FcγRII (CD32) and FcγRIII (CD16) on CD14+ (monocytes) and CD56+ (NK) cells, as well as the expression of CD107a+ (LAMP-1) on CD56+ cells and the total amount of CD4+CD25+FOXP3+ (Treg) cells. In metastatic patients, markers were correlated with progression-free survival (PFS).
  
  
  RESULTS
  ADCC activity was significantly down regulated in metastatic, adjuvant and t-naive patient cohorts as compared to healthy controls. Reduced ADCC activity was inversely correlated with the expression of CD107a on CD56+ cells in adjuvant patients. ADCC and ADCP activity of the patient cohorts were similar, regardless of treatment duration or additional chemotherapy. PFS in metastatic patients inversely correlated with the number of peripheral Treg cells.
  
  
  CONCLUSIONS
  The reduction of ADCC in patients as compared to healthy controls calls for adjuvant strategies, such as immune-enhancing agents, to improve the activity of trastuzumab. However, efficacy of trastuzumab-specific ADCC and ADCP appears not to be affected by treatment duration, disease progression or concomitant chemotherapy. This finding supports the application of trastuzumab at any stage of the disease.
authors: Branka
authors: B
authors: Petricevic
authors: Johannes
authors: J
authors: Laengle
authors: Josef
authors: J
authors: Singer
authors: Monika
authors: M
authors: Sachet
authors: Judit
authors: J
authors: Fazekas
authors: Guenther
authors: G
authors: Steger
authors: Rupert
authors: R
authors: Bartsch
authors: Erika
authors: E
authors: Jensen-Jarolim
authors: Department of Surgery, Medical University of Vienna, Vienna General Hospital, Waehringer Guertel 18-20, Vienna A-1090, Austria. michael.bergmann@meduniwien.ac.at.
authors: Michael
authors: M
authors: Bergmann
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects*; D015703:Antigens, CD / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D005260:Female; D005434:Flow Cytometry; D018734:Genes, erbB-2; D006801:Humans; D016130:Immunophenotyping; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010587:Phagocytosis / Q000187:drug effects*; D000068878:Trastuzumab; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D000970:Antineoplastic Agents; D000068878:Trastuzumab