title: In vitro activity of pertuzumab in combination with trastuzumab in uterine serous papillary adenocarcinoma.
abstract: BACKGROUND
  Uterine serous papillary adenocarcinoma (USPC) is a rare but highly aggressive variant of endometrial cancer. Pertuzumab is a new humanised monoclonal antibody (mAb) targeting the epidermal growth factor type II receptor (HER2/neu). We evaluated pertuzumab activity separately or in combination with trastuzumab against primary USPC cell lines expressing different levels of HER2/neu.
  
  
  METHODS
  Six USPC cell lines were assessed by immunohistochemistry (IHC), flow cytometry, and real-time PCR for HER2/neu expression. c-erbB2 gene amplification was evaluated using fluorescent in situ hybridisation (FISH). Sensitivity to pertuzumab and trastuzumab-induced antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) was evaluated in 5 h chromium release assays. Pertuzumab cytostatic activity was evaluated using proliferation-based assays.
  
  
  RESULTS
  Three USPC cell lines stained heavily for HER2/neu by IHC and showed amplification of the c-erbB2 gene by FISH. The remaining FISH-negative USPCs expressed HER2/neu at 0/1+ levels. In cytotoxicity experiments against USPC with a high HER2/neu expression, pertuzumab and trastuzumab were similarly effective in inducing strong ADCC. The addition of complement-containing plasma and interleukin-2 increased the cytotoxic effect induced by both mAbs. In low HER2/neu USPC expressors, trastuzumab was more potent than pertuzumab in inducing ADCC. Importantly, in this setting, the combination of pertuzumab with trastuzumab significantly increased the ADCC effect induced by trastuzumab alone (P=0.02). Finally, pertuzumab induced a significant inhibition in the proliferation of all USPC cell lines tested, regardless of their HER-2/neu expression.
  
  
  CONCLUSIONS
  Pertuzumab and trastuzumab induce equally strong ADCC and CDC in FISH-positive USPC cell lines. Pertuzumab significantly increases tratuzumab-induced ADCC against USPC with a low HER2/neu expression and may represent a new therapeutic agent in patients harbouring advanced/recurrent and/or refractory USPC.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520-8063, USA.
authors.forename: K
authors.initials: K
authors.lastname: El-Sahwi
authors.forename: S
authors.initials: S
authors.lastname: Bellone
authors.forename: E
authors.initials: E
authors.lastname: Cocco
authors.forename: M
authors.initials: M
authors.lastname: Cargnelutti
authors.forename: F
authors.initials: F
authors.lastname: Casagrande
authors.forename: M
authors.initials: M
authors.lastname: Bellone
authors.forename: M
authors.initials: M
authors.lastname: Abu-Khalaf
authors.forename: N
authors.initials: N
authors.lastname: Buza
authors.forename: F A
authors.initials: FA
authors.lastname: Tavassoli
authors.forename: P
authors.initials: P
authors.lastname: Hui
authors.forename: D-A
authors.initials: DA
authors.lastname: Silasi
authors.forename: M
authors.initials: M
authors.lastname: Azodi
authors.forename: P E
authors.initials: PE
authors.lastname: Schwartz
authors.forename: T J
authors.initials: TJ
authors.lastname: Rutherford
authors.forename: S
authors.initials: S
authors.lastname: Pecorelli
authors.forename: A D
authors.initials: AD
authors.lastname: Santin
mesh_terms: D000231:Adenocarcinoma, Papillary / Q000473:pathology*; D000368:Aged; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D003165:Complement System Proteins / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D019281:Dimerization; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects; D000068878:Trastuzumab; D014594:Uterine Neoplasms / Q000473:pathology*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D003165:Complement System Proteins; D007074:Immunoglobulin G; D007376:Interleukin-2; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human; C485206:pertuzumab