title: Correlation between quantitative HER-2 protein expression and risk for brain metastases in HER-2+ advanced breast cancer patients receiving trastuzumab-containing therapy.
abstract: BACKGROUND
  Patients with human epidermal growth factor receptor (HER)-2+ breast cancer are at particularly high risk for brain metastases; however, the biological basis is not fully understood. Using a novel HER-2 assay, we investigated the correlation between quantitative HER-2 expression in primary breast cancers and the time to brain metastasis (TTBM) in HER-2+ advanced breast cancer patients treated with trastuzumab.
  
  
  METHODS
  The study group included 142 consecutive patients who were administered trastuzumab-based therapy for HER-2+ metastatic breast cancer. HER-2/neu gene copy number was quantified as the HER-2/centromeric probe for chromosome 17 (CEP17) ratio by central laboratory fluorescence in situ hybridization (FISH). HER-2 protein was quantified as total HER-2 protein expression (H2T) by the HERmark® assay (Monogram Biosciences, Inc., South San Francisco, CA) in formalin-fixed, paraffin-embedded tumor samples. HER-2 variables were correlated with clinical features and TTBM was measured from the initiation of trastuzumab-containing therapy.
  
  
  RESULTS
  A higher H2T level (continuous variable) was correlated with shorter TTBM, whereas HER-2 amplification by FISH and a continuous HER-2/CEP17 ratio were not predictive (p = .013, .28, and .25, respectively). In the subset of patients that was centrally determined by FISH to be HER-2+, an above-the-median H2T level was significantly associated with a shorter TTBM (hazard ratio, [HR], 2.4; p = .005), whereas this was not true for the median HER-2/CEP17 ratio by FISH (p = .4). Correlation between a continuous H2T level and TTBM was confirmed on multivariate analysis (HR, 3.3; p = .024).
  
  
  CONCLUSIONS
  These data reveal a strong relationship between the quantitative HER-2 protein expression level and the risk for brain relapse in HER-2+ advanced breast cancer patients. Consequently, quantitative assessment of HER-2 protein expression may inform and facilitate refinements in therapeutic treatment strategies for selected subpopulations of patients in this group.
authors.affiliation: Department of Oncology and Radiotherapy, Medical University of Gdańsk, ul. Dbinki 7, 80-211 Gdańsk, Poland.  jjassem@gumed.edu.pl.
authors.forename: Renata
authors.initials: R
authors.lastname: Duchnowska
authors.forename: Wojciech
authors.initials: W
authors.lastname: Biernat
authors.forename: Barbara
authors.initials: B
authors.lastname: Szostakiewicz
authors.forename: Jeff
authors.initials: J
authors.lastname: Sperinde
authors.forename: Fanny
authors.initials: F
authors.lastname: Piette
authors.forename: Mojgan
authors.initials: M
authors.lastname: Haddad
authors.forename: Agnes
authors.initials: A
authors.lastname: Paquet
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Lie
authors.forename: Bogumiła
authors.initials: B
authors.lastname: Czartoryska-Arłukowicz
authors.forename: Piotr
authors.initials: P
authors.lastname: Wysocki
authors.forename: Tomasz
authors.initials: T
authors.lastname: Jankowski
authors.forename: Barbara
authors.initials: B
authors.lastname: Radecka
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Foszczynska-Kłoda
authors.forename: Maria
authors.initials: M
authors.lastname: Litwiniuk
authors.forename: Sylwia
authors.initials: S
authors.lastname: Debska
authors.forename: Jodi
authors.initials: J
authors.lastname: Weidler
authors.forename: Weidong
authors.initials: W
authors.lastname: Huang
authors.forename: Marc
authors.initials: M
authors.lastname: Buyse
authors.forename: Michael
authors.initials: M
authors.lastname: Bates
authors.forename: Jacek
authors.initials: J
authors.lastname: Jassem
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000139:chemically induced / Q000201:enzymology* / Q000556:secondary*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D009362:Neoplasm Metastasis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D012307:Risk Factors; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab