Increased MET and HGF gene copy numbers are associated with trastuzumab failure in HER2-positive metastatic breast cancer

Br J Cancer. 2012 Aug 21;107(5):793-9. doi: 10.1038/bjc.2012.335. Epub 2012 Jul 31.


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.

Conclusion: High GCNs of MET and HGF associate with an increased risk of trastuzumab-based therapy failure in HER2-positive MBC.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal, Humanized / administration & dosage
  • Antineoplastic Agents / administration & dosage
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Drug Resistance, Neoplasm
  • Female
  • Gene Dosage*
  • Hepatocyte Growth Factor / genetics*
  • Hepatocyte Growth Factor / metabolism
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization, Fluorescence
  • Middle Aged
  • Prognosis
  • Proto-Oncogene Proteins c-met / genetics*
  • Proto-Oncogene Proteins c-met / metabolism
  • Receptor, ErbB-2 / biosynthesis
  • Receptor, ErbB-2 / metabolism
  • Retrospective Studies
  • Trastuzumab


  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • HGF protein, human
  • Hepatocyte Growth Factor
  • MET protein, human
  • Proto-Oncogene Proteins c-met
  • Receptor, ErbB-2
  • Trastuzumab