title: Differential survival following trastuzumab treatment based on quantitative HER2 expression and HER2 homodimers in a clinic-based cohort of patients with metastatic breast cancer.
abstract: BACKGROUND
  We have recently described the correlation between quantitative measures of HER2 expression or HER2 homodimers by the HERmark assay and objective response (RR), time-to progression (TTP), and overall survival (OS) in an expanded access cohort of trastuzumab-treated HER2-positive patients with metastatic breast cancer (MBC) who were stringently selected by fluorescence in situ hybridization (FISH). Multivariate analyses suggested a continuum of HER2 expression that correlated with outcome following trastuzumab. Here we investigate the relationship between HER2 expression or HER2 homodimers and OS in a clinic-based population of patients with MBC selected primarily by IHC.
  
  
  METHODS
  HERmark, a proximity-based assay designed to detect and quantitate protein expression and dimerization in formalin-fixed paraffin-embedded (FFPE) tissues, was used to measure HER2 expression and HER2 homodimers in FFPE samples from patients with MBC. Assay results were correlated with OS using univariate Kaplan-Meier, hazard function plots, and multivariate Cox regression analyses.
  
  
  RESULTS
  Initial analyses revealed a parabolic relationship between continuous measures of HER2 expression and risk of death, suggesting that the assumption of linearity for the HER2 expression measurements may be inappropriate in subsequent multivariate analyses. Cox regression analyses using the categorized variable of HER2 expression level demonstrated that higher HER2 levels predicted better survival outcomes following trastuzumab treatment in the high HER2-expressing group.
  
  
  CONCLUSIONS
  These data suggest that the quantitative amount of HER2 expression measured by Hermark may be a new useful marker to identify a more relevant target population for trastuzumab treatment in patients with MBC.
authors.affiliation: Faculty of Medicine, Kyoto University, Kyoto, Japan. toi@kuhp.kyoto-u.ac.jp
authors.forename: Masakazu
authors.initials: M
authors.lastname: Toi
authors.forename: Jeff
authors.initials: J
authors.lastname: Sperinde
authors.forename: Weidong
authors.initials: W
authors.lastname: Huang
authors.forename: Shigehira
authors.initials: S
authors.lastname: Saji
authors.forename: John
authors.initials: J
authors.lastname: Winslow
authors.forename: Xueguang
authors.initials: X
authors.lastname: Jin
authors.forename: Yuping
authors.initials: Y
authors.lastname: Tan
authors.forename: Shinji
authors.initials: S
authors.lastname: Ohno
authors.forename: Seigo
authors.initials: S
authors.lastname: Nakamura
authors.forename: Hiroji
authors.initials: H
authors.lastname: Iwata
authors.forename: Norikazu
authors.initials: N
authors.lastname: Masuda
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Aogi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Morita
authors.forename: Christos
authors.initials: C
authors.lastname: Petropoulos
authors.forename: Michael
authors.initials: M
authors.lastname: Bates
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D015331:Cohort Studies; D019281:Dimerization; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D015999:Multivariate Analysis; D009362:Neoplasm Metastasis; D016016:Proportional Hazards Models; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000737:chemistry*; D000068878:Trastuzumab; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human