title: Increased MET and HGF gene copy numbers are associated with trastuzumab failure in HER2-positive metastatic breast cancer.
abstract: BACKGROUND
  To investigate whether copy number gain of MET or hepatocyte growth factor (HGF) affect trastuzumab sensitivity in HER2-positive metastatic breast cancer (MBC).
  
  
  METHODS
  We analysed 130 HER2-positive MBC treated with trastuzumab-based therapy. MET and HGF gene copy numbers (GCN) were assessed by fluorescence in situ hybridisation (FISH) in primary breast cancer samples. Receiver operating characteristic analysis was applied to find the best cutoff point for both MET and HGF GCN.
  
  
  RESULTS
  MET FISH-positive cases (N=36, mean 3.72) had a significantly higher trastuzumab failure rate (44.4% vs 16.0%; P=0.001) and a significantly shorter time to progression (5.7 vs 9.9 months; HR 1.74; P=0.006) than MET FISH-negative cases (N=94, mean <3.72). Hepatocyte growth factor GCN was evaluated in 84 cases (64.6%). Receiver operating characteristic analysis identified 33 HGF FISH-positive patients (mean HGF GCN 3.01). HGF FISH-positive status was significantly associated with higher risk of failure (30.3% vs 7.8%; P=0.007) as compared with HGF FISH-negative cases (N=51, mean <3.01). MET and HGF FISH-positive status was highly correlated (P<0.001) and combination of both biomarkers did not increase predictive value of either considered separately.
  
  
  CONCLUSIONS
  High GCNs of MET and HGF associate with an increased risk of trastuzumab-based therapy failure in HER2-positive MBC.
authors: Department of Medical Oncology, Civil Hospital of Livorno, Istituto Toscano Tumori, Viale Alfieri 36, Livorno 57100, Italy.
authors: G
authors: G
authors: Minuti
authors: F
authors: F
authors: Cappuzzo
authors: R
authors: R
authors: Duchnowska
authors: J
authors: J
authors: Jassem
authors: A
authors: A
authors: Fabi
authors: T
authors: T
authors: O'Brien
authors: A D
authors: AD
authors: Mendoza
authors: L
authors: L
authors: Landi
authors: W
authors: W
authors: Biernat
authors: B
authors: B
authors: Czartoryska-Arłukowicz
authors: T
authors: T
authors: Jankowski
authors: D
authors: D
authors: Zuziak
authors: J
authors: J
authors: Zok
authors: B
authors: B
authors: Szostakiewicz
authors: M
authors: M
authors: Foszczyńska-Kłoda
authors: A
authors: A
authors: Tempińska-Szałach
authors: E
authors: E
authors: Rossi
authors: M
authors: M
authors: Varella-Garcia
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D005260:Female; D018628:Gene Dosage; D017228:Hepatocyte Growth Factor / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D011379:Prognosis; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000378:metabolism; D012189:Retrospective Studies; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C066855:HGF protein, human; C491743:MET protein, human